Mechanisms of Irritant and Allergic Contact Dermatitis

Rustemeyer, Thomas; van Hoogstraten, Ingrid M. W.; von Blomberg, B. Mary E.; Gibbs, Sue; Scheper, Rik J.

doi:10.1007/978-3-642-03827-3_3

Thomas Rustemeyer⁴,
Ingrid M. W. van Hoogstraten⁵,
B. Mary E. von Blomberg⁵,
Sue Gibbs⁴ &
…
Rik J. Scheper⁵

3348 Accesses
26 Citations

Abstract

Contact dermatitis describes the skin reaction resulting from exposure to irritants (irritant contact dermatitis) or allergens (allergic contact dermatitis). In most patients, irritant and allergic contact dermatitis (ACD) are clinically indistinguishable. Also histopathologically, no distinguishing markers have been identified. This is in line with the fact that in irritant and ACD, principal inflammatory pathways are essentially similar. The pivotal different factor in ACD is the involvement of “allergen-specific” T cells as initiators of the inflammatory skin reaction. In irritant contact dermatitis (ICD), the inflammatory reaction mainly depends on either or both chemical and physical irritation. The most frequent chemical irritative factors are long-lasting and repetitive contacts to water, detergents, solvents, or a combination of these factors, often aggravated by too high or too low humidity. Inflammatory reactions to irritants are not triggered by one specific substance or cause, and do not show rapid amplification of severity by repeated insults and are thus called “unspecific.”

Access provided by Autonomous University of Puebla. Download chapter PDF

Contact Dermatitis Due to Irritation

Contact Dermatitis due to Irritation

Pathophysiology of Allergic and Irritant Contact Dermatitis

1 Introduction

Contact dermatitis describes the skin reaction resulting from exposure to irritants (irritant contact dermatitis) or allergens (allergic contact dermatitis). In most patients, irritant and allergic contact dermatitis (ACD) are clinically indistinguishable. Also histopathologically, no distinguishing markers have been identified. This is in line with the fact that in irritant and ACD, principal inflammatory pathways are essentially similar. The pivotal different factor in ACD is the involvement of “allergen-specific” T cells as initiators of the inflammatory skin reaction. In irritant contact dermatitis (ICD), the inflammatory reaction mainly depends on either or both chemical and physical irritation. The most frequent chemical irritative factors are long-lasting and repetitive contacts to water, detergents, solvents, or a combination of these factors, often aggravated by too high or too low humidity. Inflammatory reactions to irritants are not triggered by one specific substance or cause, and do not show rapid amplification of severity by repeated insults and are thus called “unspecific.”

In the following chapter the immunopathological mechanisms of ICD and ACD reactions will be discussed further in detail.

2 Irritant Contact Dermatitis

2.1 Skin Barrier Perturbation Can Lead to Irritant Contact Dermatitis

The skin functions as a barrier protecting an individual from dehydration, mechanical trauma, irradiation, microbial insults, and direct exposure to harmful sensitizing or irritant chemicals [1, 2]. Perturbation of the skin barrier can result in ICD. The barrier function is provided by the uppermost layer of the epidermis, the stratum corneum. The epidermis consists of more than 90% keratinocytes. Proliferating basal keratinocytes undergo a commitment to terminally differentiate and, in doing so, form a compact multilayered cellular compartment consisting of, depending on the skin region, approximately eight living cell layers (approximately 50–100 μm thick). As the keratinocytes become more differentiated, they approach the outermost layers and ultimately form the stratum corneum (10–20 μm thick). The stratum corneum consists of dead, terminally differentiated keratinocytes (corneocytes) embedded in extracellular lipid. The corneocytes and the lipid component of the stratum corneum can be considered as bricks and mortar and form the barrier to the environment and potentially harmful substances [3–5]. In order for a potential irritant to cause an irritant reaction, it must first penetrate or damage the stratum corneum to exert its effect on the viable epidermal and dermal layers below.

A chemical can penetrate the skin via three routes: the intercellular lipid route, the transcellular route across cornified cells and lipid bilayers, and via diffusion along hair follicles and sweat glands [4, 6–9]. Chemicals can also penetrate at sites of skin trauma (wounds) and where the barrier function is impaired by other diseases. Hydrophobic substances have the potential to penetrate via the lipid layers, whereas hydrophilic substances preferentially penetrate via the hair follicles and sweat lands. The lipid bilayer is the primary target for common skin damaging factors such as solvents and soaps since these substances degrade the lipid bilayer directly and expose the underlying viable epidermal layers to the irritant. Once an irritant has penetrated the stratum corneum, it may exert cytotoxic effects on the keratinocytes and trigger keratinocytes to release alarm signals in the form of cytokines and chemokines. In this way, the innate immune system is triggered and the ICD reaction is initiated.

2.2 Pathogenesis of Acute Irritant Contact Dermatitis

Thus, ICD reflects an innate inflammatory response of the skin to direct injury. Frequency and intensity of skin contacts with harmful agents determine the outcome. For acute ICD, the reaction is often caused by a single exposure to the irritant and the skin manifestations usually disappear within days to weeks. The source of the irritant is most often a chemical or abrasion to the skin. One of the major initial events before skin damage is observed is the release of proinflammatory cytokines. This in turn amplifies the inflammatory reaction by releasing chemokines, resulting in vasodilation and infiltration of cells (e.g., lymphocytes, eosinophils, macrophages, neutrophils, T cells) into the epidermis and dermis. The resulting physiological signs of irritation are damage to the epidermis as observed by spongiosis and microvesicle formation, erythema, induration, and edema leading to localized painful areas of skin [10–13] (Fig. 3.1).

However, the clinical appearance is often very variable and, moreover, difficult to distinguish from ACD [14, 15]. ACD shows all the features of ICD, but in an accelerated and/or augmented fashion due to the involvement of allergen-reactive T cells. Proinflammatory cytokines locally released by the latter, such as IFN-γ, IL-4, and IL-17, as will be discussed below, serve to amplify the overall inflammatory reactivity and protect the body against potentially harmful agents. Indeed, clinical observations show a clear role for irritancy in ACD: virtually all allergens have irritant properties, whereas irritated skin is easier to sensitize than nonirritated skin. During both an ACD and an ICD reaction, alarm signals provided by skin barrier disruption, epidermal cellular changes and cytokine/chemokine release, stimulate the initial trafficking of immune cells to the site under attack.

Core Message

In acute ICD, similar immunological mechanisms are involved as in acute ACD. However, the crucial difference is the involvement of specific T cells in ACD. Major events in acute contact dermatitis include damage of the epidermal skin barrier by contact irritants and subsequent activation of unspecific innate immune responses.

2.3 Development of Chronic Irritant Contact Dermatitis

Chronic ICD is one of the most frequent forms of ICD and is caused by repeated contact of the skin to weak irritants [16, 17]. Multiple subthreshold skin damaging exposures, each starting before complete recovery from the previous insult, result in this eczematous skin condition (Fig. 3.2). Chronic ICD is characterized by dryness, fissuring, and hyperkeratosis (more pronounced than in acute ICD) and is diagnosed when the ICD persists for longer than 6 weeks. It is often located on the hands, and despite removal of the irritant, the clinical reaction may remain for several years. Factors such as water, detergents, organic solvents, oils, alkalis, acids, oxidizing agents, heat, cold friction all contribute to the elicitation of chronic ICD [16, 17]. Such factors are frequently associated with a wet working environment, and therefore, chronic ICD is a frequent work-related dermatitis [18, 19]. A wet work environment is defined as regular work with the hands in a wet environment for longer than 2 h per day, regular use of occlusive gloves over the same period of time, and / or frequent and intensive hand washing (approximately 20 times per day) [18, 20].

Chronic ICD is a multifactorial disorder in that both exogenous and endogenous factors are involved in its development. The exogenous factors have already been mentioned above and involve direct exposure of the skin to irritants. Endogenous factors are based on the individual’s susceptibility to develop chronic ICD. These factors include variations in the skin barrier structure and composition, innate immune reactivity variations, and a skin atopic background. In the past, differences in transepidermal water loss (TEWL), erythema, irritation thresholds, and gender-related differences have been investigated [21–27]. However, no significant differences were found that could explain why one individual develops chronic ICD at the work environment, whereas another individual in the same work environment does not. Recently, much attention has been paid to atopic dermatitis (AD) as a potentially important predisposing factor since a history of AD more than quadruples the risk of hand eczema in cases of skin exposure in a wet work environment [28]. It was shown that penetration of the irritant SLS and subsequent increase in TEWL and erythema was higher in subjects with AD than in healthy individuals indicating that more permeable skin is more susceptible to irritants [29]. Also, genetic risk factors have been linked with the development of AD, which in turn may influence the development of chronic ICD [30–34].

Core Message

In chronic ICD, repetitive skin contacts to different contact irritants cause substantial and prolonged skin barrier damage. A skin atopic background is a strong risk factor for developing chronic ICD.

2.4 Genetic Risk Factors in Irritant Contact Dermatitis and Atopic Dermatitis

AD is a hereditary disease and, as already mentioned, is an important predisposing factor for chronic ICD. It is associated with hyperreactivity of the skin to irritants, aero-allergens, microbes, and scratching. Next to overexpression of the epithelial cell and fibroblast-produced cytokine TSLP [35], recently two loss-of-function polymorphisms in the gene encoding for filaggrin have been described as strong predisposing factors for AD [33]. Depending on the disease phenotype, 16–56% of patients with AD carry one or more filaggrin null mutations compared to only 5–10% of the general European population [33, 34, 36–39]. Filaggrin is involved in the formation of corneocytes, and therefore, in the formation of the stratum corneum [37]. Once cornification is complete, filaggrin is degraded into free amino acids. These free amino acids contribute to the natural moisturizing factor component of the stratum corneum by retaining water. Therefore, it is possible that filaggrin null alleles may be responsible in part for the dry skin characteristic of AD. De Jong et al. showed that FLG null alleles are associated with increased susceptibility to chronic ICD; however, whether or not the filaggrin null allele is an independent risk factor needs further study [32].

Until now, no genetic factors have been identified that contribute to hand eczema in the absence of AD. However, it is possible that unidentified polymorphisms in cytokines and chemokines may be involved in chronic ICD. Indeed, such polymorphisms have already been reported in several other inflammatory diseases e.g., rheumatoid arthritis and multiple sclerosis [40]. A case–control study in 197 patients with chronic ICD vs. 217 healthy individuals showed that polymorphisms in several cytokine genes (IL-1α, IL-1β, IL-8, IL-10 and TNF-α) and the two loss-of-function polymorphisms in the filaggrin gene did not provide a substantial risk factor for development of chronic ICD [30]. However, the study did show that (1) both the variant TNFA-308A allele and the filaggrin null alleles predispose to flexural eczema, (2) the variant TNFA-308A allele can increase susceptibility to chronic ICD, and (3) the IL1A-889T allele might protect against hand dermatitis. Here, the ratio of IL-1 receptor antagonist (IL-RA)/IL-1α increased 2–3-fold, corresponding to a reduced level of agonistic IL-1a in the stratum corneum in subjects expressing the variant genotype as compared to the wild type genotype. In conclusion, genetic polymorphisms of TNFA-308 and IL1A-889 may influence the susceptibility of chronic ICD.

2.5 Cellular Immunological Changes in Irritant Contact Dermatitis

Next to its barrier function, the skin is recognized as an immunologically active organ. Barrier perturbation results in the generation of the first alarm signal. Skin epidermal cells, notably keratinocytes, melanocytes and Langerhans cells (LC), respond to nonspecific irritant stimuli by producing cytokines, adhesion molecules, and chemotactic factors [41–43]. Keratinocyes are the major source of skin derived cytokines. Epidermal cytokines diffuse into the dermis and trigger dermal cells (e.g., fibroblasts and endothelial cells) to also secrete chemokines [44, 45]. In this way the proinflammatory response is amplified and a chemotactic gradient is introduced directing infiltrating cells into the site of tissue damage. The initial proinflammatory response can result in Langerhans’ cell migration out of the epidermis, potentially contributing to allergenicity, and infiltration of monocytes, neutrophils, macrophages, and lymphocytes into the skin. This skin innate immune response is rapid, provides the initial line of defense against damage caused by irritants, is antigen-nonspecific, and lacks immunological memory [13, 46, 47].

As stated, ACD and ICD reactions share alarm signal(s) [14, 48, 49]. This is supported by several in vivo and in vitro studies in which both allergen and irritant exposures result in increased cytokine levels in keratinocytes and fibroblasts [41, 45]. So, which is the initiating cytokine, and is it prestored or does de novo synthesis occur? Of all the cytokines produced by keratinocytes, only IL-1α, IL-1β, and TNF-α activate a sufficient number of effector mechanisms to independently trigger cutaneous inflammation [47]. Furthermore, large stores of preformed and biologically active IL-1α have also been detected as a depot in the stratum corneum and within the epidermis [50, 51]. In contrast, other cytokines such as TNF-α and IL-8 are detectable only at low amounts deep within the stratum corneum [50, 52]. These results strongly suggest that the release of prestored IL-1α upon barrier perturbation is the initiating cytokine signal, which triggers the induction of other inflammatory mediators. Upon release, IL-1α stimulates further release of IL-1α and the production and release of other cytokines. While resting keratinocytes produce some cytokines constitutively, exposure to irritants induces production of (pro-) inflammatory cytokines (IL-1α, TNF-α), chemotactic cytokines (IL-6, IL-8, CCL20, CCL27), growth-promoting cytokines (GM-CSF, TGF-β), and cytokines regulating specific immune responses (IL-10, IL-12, IL-18) [11, 43]. Thus, via cytokine cascades, an inflammatory response can be rapidly generated. In this way, keratinocytes act as proinflammatory signal transducers, responding to nonspecific external stimuli with the production of inflammatory cytokines, adhesion molecules, and chemotactic factors, stimulating the dermal stroma to amplify the response.

In this context, it should be mentioned that in the skin, TNF-α is stored in dermal mast cells, and following stimulation, it is produced by keratinocytes and LC. Antibodies to TNF-α abolish many inflammatory skin reactions, including allergic and ICD [53]. An in vitro study using a full thickness human skin equivalent model showed that antibodies directed against either TNF-α or IL-1α were able to completely inhibit inflammatory chemokine secretion by dermal fibroblasts [45]. Therefore, taken together, these findings suggest that both TNF-α and IL-1α are pivotal cytokines in mediating irritant induced skin inflammation. In conclusion, several cell types and downstream mechanisms act in concert in inducing different types of skin irritant responses. Determining the cell source, kinetics of production, and the regulation of inflammatory mediators in the skin will be the key to predicting and treating irritant responses arising from different environmental agents (Table 3.1).

Table 3.1 Cytokines, chemokines, and growth factors expressed by epidermal cells and dermal fibroblasts

Full size table

Core Message

Unspecific innate immune reactions cause the development of ICD reactions. Some genetic risk factors including polymorphisms in TNF-α genes have been detected. Further research is needed to unravel the inflammatory innate immune cascades involved in ICD.

3 Introduction Allergic Contact Dermatitis

During the past few decades, our understanding of why, where, and when ACD might develop has rapidly increased. Critical discoveries include the identification of T cells as mediators of cell-mediated immunity, their thymic origin and recirculation patterns, and the molecular basis of their specificity to just one or few allergens out of the thousands of allergens known. Progress has also resulted from the identification of genes that determine T-cell function and the development of monoclonal antibodies that recognize their products. Moreover, the production of large amounts of recombinant products, e.g., cytokines and chemokines, and the breeding of mice with disruptions in distinct genes (knock-out mice) or provided with additional genes of interest (transgenic mice) have allowed in-depth analysis of skin-inflammatory processes, such as those taking place in ACD.

Although humoral antibody-mediated reactions can be a factor, ACD depends primarily on the activation of allergen-specific T cells [54], and is regarded as a prototype of delayed hypersensitivity, as classified by Turk [55] and Gell and Coombs (type IV hypersensitivity) [56]. Evolutionarily, cell-mediated immunity has developed in vertebrates to facilitate eradication of microorganisms and toxins. Elicitation of ACD by usually nontoxic doses of small molecular-weight allergens indicates that the T-cell repertoire is often slightly broader than one might wish. Thus, ACD can be considered to reflect an untoward side effect of a well-functioning immune system.

Subtle differences can be noted in macroscopic appearance, time course, and histopathology of allergic contact reactions in various vertebrates, including rodents and man [57]. Nevertheless, essentially all basic features are shared. Since both mouse and guinea pig models, next to clinical studies, have greatly contributed to our present knowledge of ACD, both data sets provide the basis for this chapter.

In ACD, a distinction should be made between induction (also known as sensitization or primary) and effector (also known as elicitation or secondary) phases [58] (Fig. 3.3). The induction phase includes the events following a first contact with the allergen and is complete when the individual is sensitized and capable of giving a positive ACD reaction. The effector phase begins upon elicitation (challenge) and results in clinical manifestation of ACD. The entire process of the induction phase requires at least 4 days to several weeks, whereas the effector phase reaction is fully developed within 1–4 days. Main episodes in the induction phase (steps 1–5) and effector phase (step 6) are:

1.
Binding of allergen to skin components. The allergen penetrating the skin readily associates with all kinds of skin components, including major histocompatibility complex (MHC) proteins. These molecules, in humans encoded for by histocompatibility antigen (HLA) genes, are abundantly present on epidermal antigen presenting cells, called LC.
2.
Hapten-induced activation of allergen-presenting cells. Allergen-carrying LC become activated, mature, and travel via the afferent lymphatics to the regional lymph nodes, where they settle as so-called interdigitating cells (IDC) in the paracortical T-cell areas.
3.
Recognition of allergen-modified LC by specific T cells. In nonsensitized individuals the frequency of T cells with certain specificities is usually far below one per million. Within the paracortical areas, conditions are optimal for allergen-carrying IDC to encounter naïve T cells that specifically recognize the allergen–MHC molecule complexes. The dendritic morphology of these allergen-presenting cells strongly facilitates multiple cell contacts, leading to binding and activation of allergen-specific T cells.
4.
Proliferation of specific T cells in draining lymph nodes. Supported by interleukin (IL)-1, released by the allergen-presenting cells, activated T cells start producing several growth factors, including IL-2. A partly autocrine cascade follows since at the same time receptors for IL-2 are upregulated in these cells, resulting in vigorous blast formation and proliferation within a few days.
5.
Systemic propagation of the specific T-cell progeny. The expanded progeny is subsequently released via the efferent lymphatics into the blood flow and begins to recirculate. Thus, the frequency of specific effector memory T cells in the blood may rise to as high as one in a thousand, whereas most of these cells display receptor molecules facilitating their migration into peripheral tissues. In the absence of further allergen contacts, their frequency gradually decreases in subsequent weeks or months, but does not return to the low levels found in naive individuals.
6.
Effector phase. By renewed allergen contact, the effector phase is initiated, which depends not only on the increased frequency of specific T cells, and their altered migratory capacities, but also on their low activation threshold. Thus, within the skin, allergen-presenting cells and specific T cells can meet, and lead to plentiful local cytokine and chemokine release. The release of these mediators, many of which have a proinflammatory action, causes the arrival of more inflammatory cells, thus further amplifying local mediator release. This leads to a gradually developing eczematous reaction that reaches its maximum after 18–72 h and then declines.

In the following sections, we will discuss these six main episodes of the ACD reaction in more detail. Furthermore, we will discuss local hyperreactivity, such as flare-up and retest reactivity, and hyporeactivity, i.e., upon desensitization or tolerance induction.

3.1 Binding of Contact Allergens to Skin Components

3.1.1 Chemical Nature of Contact Allergens

Most contact allergens are small, chemically reactive molecules with a molecular weight less than 500 Da [59] (Fig. 3.4). Since these molecules are too small to be antigenic themselves, contact sensitizers are generally referred to as haptens.

Upon penetration through the epidermal horny layer, haptens readily conjugate to endogenous epidermal and dermal molecules. Sensitizing organic compounds may covalently bind to protein nucleophilic groups, such as thiol, amino, and hydroxyl groups, as is the case with poison oak/ivy allergens (reviewed in [60, 61]). Examples of contact allergens containing electrophilic components include aldehydes, ketones, amides, or polarized bonds. Metal ions, e.g., nickel cations, instead form stable metal–protein chelate complexes by coordination bonds [62]. The most reactive nucleophilic side chains are those found in the amino acids lysine, cysteine and histidine [63]. Of note, their degree of ionization and hence nucleophilicity is dependent on the pH of the microenvironment, which is influenced by surrounding amino acids as well as protein location within the epithelium [64]. Predicting the chemicals that can function as haptens in ACD as well as identifying cutaneous proteins involved in hapten–protein complexes is the subject of current intense investigations [65, 66] and discussed in more detail elsewhere in this textbook.

3.1.2 Hapten Presentation by Langerhans Cells (LC)

Sensitization is critically dependent on direct association of haptens with epidermal LC-bound MHC molecules, or peptides present in the groove of these molecules. Both MHC class I and class II molecules may be altered this way, and thus give rise to allergen-specific CD8⁺ and CD4⁺ T cells, respectively. Distinct differences between allergens can, however, arise from differences in chemical reactivity and lipophilicity (Fig. 3.4), since association with MHC molecules may also result from internalization of the haptens, followed by their intracellular processing as free hapten molecules or hapten–carrier complexes. Lipophilic haptens can directly penetrate into LC, conjugate with cytoplasmic proteins, and be processed along the “endogenous” processing route, thereby favoring association with MHC class I molecules [67]. In contrast, hydrophilic allergens such as nickel ions may, after conjugation with skin proteins, be processed along the “exogenous” route of antigen processing and thus favor the generation of altered MHC class II molecules. Thus, the chemical nature of the haptens can determine to what extent allergen-specific CD8⁺ and/ or CD4⁺ T cells will be activated [68–70].

3.1.3 Pre and Prohaptens

Whereas most contact allergens can form hapten–carrier complexes spontaneously, some need activation first. Contact allergens requiring activation outside the body, e.g., by UV-light or oxygen, are called prehaptens [71, 72]. The typical photoallergen tetrachlorosalicylanilide is a prototype of this. Tetrachlorosalicylanilide, which undergoes photochemical dechlorination with UV irradiation, ultimately provides photoadducts with skin proteins [73]. Contact allergens dependent on activation inside the body, e.g., by enzyme-induced metabolic conversion, are referred to as prohaptens. A classical prohapten is p-phenylenediamine, which needs to be oxidized by N-acetyltransferases to a reactive metabolite that can form a trimer, known as Bandrowski’s base [74, 75]. Reduced enzyme activity in certain individuals, related to genetic enzyme polymorphisms, explains the reduced risk of sensitization to prohaptens that need enzymatic activation [76, 77]. Subsequent chapters of this book will present in extensive detail the numerous groups of molecules that have earned disrepute for causing ACD.

Core Message

Allergenicity depends on several factors determined by the very physicochemical nature of the molecules themselves, i.e., their capacity to penetrate the horny layer, lipophilicity, and chemical reactivity. The sensitizing property of the majority of contact allergens could be predicted from these characteristics [63, 78]. Two other factors, however, further contribute to the allergenicity of chemicals, viz their proinflammatory activity and capacity to induce maturation of LC. These issues will be dealt with in more detail in the following sections.

3.2 Hapten-Induced Activation of Allergen-Presenting Cells

3.2.1 Physiology of Langerhans Cells

Although originally thought to be neurons based on their staining properties and cellular morphology [79], LC were subsequently surmised to function as “professional” antigen-presenting-cells [80]. They form a contiguous network within the epidermis and represent 2–5% of the total epidermal cell population [81]. Their principal functions are internalization, processing, transport, and presentation of skin-encountered antigens [82, 83]. As such, LC play a pivotal role in the induction of cutaneous immune responses to infectious agents as well as to contact sensitizers [84–86]. Recent studies of LC indicate that this cell type has direct epidermal innervations and can respond to a number of neurotransmitters (among them are calcitonin gene-related peptide, α-melanocyte stimulating hormone, and substance P). Most of the experimental evidence to date indicates a suppressive effect of the neurohormones and neuropeptides on Langerhans cell function and cutaneous inflammation, but it has become evident lately that the timing of exposure to a stimulus is critical to the outcome of the immune response. Thus, administration of a stress hormone or exposure to a stressor before the LC encounters an allergen may diminish the immune response toward that substance, while a stressor may enhance immune function when acting on a maturing LC or before reexposure to the allergen [87]. LC originate from CD34⁺ bone marrow progenitors, entering the epidermis via the blood stream [88]. Their continuous presence in the epidermis is also assured by local proliferation [89, 90]. They reside as relatively immature DC, characterized by a high capacity to gather antigens by macropinocytosis, whereas their capacity to stimulate naïve T cells is still underdeveloped at this stage [91]. Their prominent dendritic morphology and the presence of distinctive Birbeck granules were observed long ago [79, 92, 93]. In the last decade, their pivotal function in the induction of skin immune responses was explained by high expression of molecules mediating antigen-presentation (e.g., MHC class I and II, CD1), as well as of cellular adhesion and costimulatory molecules (e.g., CD54, CD80, CD86, and cutaneous lymphocyte antigen [CLA]) [94–96].

3.2.2 Hapten-Induced LC Activation

Upon topical exposure to contact sensitizers, or other appropriate stimuli (e.g., trauma, irradiation), up to 40% of the local LC become activated [97, 98], leave the epidermis, and migrate, via afferent lymphatic vessels, to the draining lymph nodes [99] (Fig. 3.5). This process of LC migration results from several factors, including contact allergen-induced production of cytokines favoring LC survival [100–102] and loosening from surrounding keratinocytes [103–105]. Thus, within 15 min after exposure to a contact sensitizer, production of IL-1β mRNA is induced [106, 107]. Along with this, caspase-1, formerly known as interleukin-1-converting enzyme, is activated and cleaves the active IL1β cytokine from the translated precursor-IL1β protein. Caspase-1 activates also IL-18 from its precursor form. These inflammatory processes are now viewed at as making up the “inflammasome” [108]. IL-1β in concert with IL-18 stimulates release of tumor necrosis factor (TNF)-α and granulocyte–macrophage colony-stimulating factor (GM-CSF) from keratinocytes [108]. Together these three cytokines facilitate migration of LC from the epidermis toward the lymph nodes [109]. IL-1β and TNF-α downregulate membrane-bound E-cadherin expression and thus cause disentanglement of LC from surrounding keratinocytes (Fig. 3.5) [104, 105, 110]. Simultaneously, adhesion molecules are upregulated promoting LC migration by mediating interactions with the extracellular matrix and dermal cells, such as CD54, α₆ integrin, and CD44 variants [111–115]. Also, production of the epidermal basement membrane degrading enzyme metalloproteinase-9 is upregulated in activated LC [116].

Next, LC migration is directed by hapten-induced alterations in chemokine receptor levels [117]. Upon maturation, LC downregulate expression of receptors for inflammatory chemokines (e.g., CCR1, 2, 5, and 6), whereas others (including CCR4, 7, and CXCR4) are upregulated (Fig. 2.3) (reviewed by [118] and [119–121]). Notably, CCR7 may guide maturing LC into the draining lymphatics and the lymph node paracortical areas, since two of its ligands (CCL19 and 21) are produced by both lymphatic and high endothelial cells [122, 123]. Importantly, the same receptor-ligand interactions cause naive T cells, which also express CCR7, to accumulate within the paracortical areas [124]. Migratory responsiveness of both cell types to CCR7 ligands is promoted by leukotriene C4, released from these cells via the transmembrane transporter molecule Abcc1 (previously called MRP1) [117, 125–127]. Interestingly, Abcc1 belongs to the same superfamily as the transporter associated with antigen-processing TAP, known to mediate intracellular peptide transport in the “endogenous route” which favors peptide association with MHC Class I molecules. Final positioning of the LC within the paracortical T-cell areas may be due to another CCR7 ligand, EBI1-ligand chemokine (ELC, CCL19), produced by resident mature DC [128].

Core Message

Along with their migration and settling within the draining lymph nodes, haptenized LC further mature, as characterized by their increased expression of costimulatory and antigen-presentation molecules [129, 130]. In addition, they adopt a strongly veiled, interdigitating appearance, thereby maximizing the chances of productive encounters with naive T lymphocytes and recognition of altered self [131–133].

3.3 Recognition of Allergen-Modified Langerhans’ Cells by Specific T Cells

3.3.1 Homing of Naive T Cells Into Lymph Nodes

More than 90% of naive lymphocytes present within the paracortical T-cell areas have entered the lymph nodes by high endothelial venules (HEV) [134]. These cells are characterized not only by CCR7 but also by the presence of a high molecular-weight isoform of CD45 (CD45RA) [134, 135]. Entering the lymph nodes via HEV is established by the lymphocyte adhesion molecule L-selectin (CD62L), which allows rolling interaction along the vessel walls by binding to peripheral node addressins (PNAd), such as GlyCAM-1 or CD34 [136–138]. Next, firm adhesion is mediated by the interaction of CD11a/CD18 with endothelial CD54, resulting in subsequent endothelial transmigration. Extravasation and migration of naïve T cells to the paracortical T-cell areas are supported by chemokines such as CCL18, 19, and 21 produced locally by HEV and by hapten-loaded and resident DC [125, 139–141]. In nonsensitized individuals, frequencies of contact allergen-specific T cells are very low, and estimates vary from 1 per 109 to maximally 1 per 106 [134, 142]. Nevertheless, the preferential homing of naive T cells into the lymph node paracortical areas and the large surface area of IDC make allergen-specific T-cell activation likely with only few dendritic cells exposing adequate densities of haptenized-MHC molecules [143, 144].

3.3.2 Activation of Hapten-Specific T Cells

As outlined in “Binding of Contact Allergens to Skin Components,” the chemical nature of the hapten determines its eventual cytoplasmic routing in antigen-presenting cells (APC), and thus whether presentation will be predominantly in context of MHC class I or II molecules (Fig. 3.4). T cells, expressing CD8 or CD4 molecules, can recognize hapten-MHC class I or II complexes showing stabilized MHC membrane expression [145, 146]. Chances of productive interactions with T cells are high since each MHC-allergen complex can trigger a high number of T-cell receptor (TCR) molecules (“serial triggering”) [147]. Moreover, after contacting specific CD4⁺ T cells, hapten-presenting DC may reach a stable superactivated state, allowing for efficient activation of subsequently encountered specific CD8⁺ T cells [148]. The actual T-cell activation is executed by TCRξ-chain mediated signal transduction, followed by an intracellular cascade of biochemical events, including protein phosphorylation, inositol phospholipid hydrolysis, increase in cytosolic Ca²⁺ [149, 150], and activation of transcription factors, ultimately leading to gene activation (Fig. 3.6) [151].

For activation and proliferation, TCR triggering (“signal 1”) is insufficient, but hapten-presenting APC also provide the required costimulation (“signal 2”; Fig. 3.7) [152, 153]. The costimulatory signals may involve secreted molecules, such as cytokines (IL-1), or sets of cellular adhesion molecules (CAMs) and their counter-structures present on the outer cellular membranes of APC and T cells. Expression levels of most of these CAMs vary with their activational status, and thus can provide positive stimulatory feedback-loops. For example, as mentioned above, after specific TCR binding and ligation of CD40L (CD154) on T cells with CD40 molecules, APC reach a superactivated state, characterized by overexpression of several CAMs, including CD80 and CD86 (Fig. 3.6) [154, 155]. In turn, these molecules bind to and increase expression of CD28 on T cells. This interaction stabilizes CD154 expression, causing amplified CD154–CD40 signaling [155, 156].

The activational cascade is, as illustrated above, characterized by mutual activation of both hapten-presenting APC and hapten-reactive T cells. While this activation protects the APC from apoptotic death and prolongs their life to increase the chance of activating their cognate T cells, only the latter capitalize on these interactions by giving rise to progeny. As discussed below, to promote T-cell growth, cellular adhesion stimuli need to be complimented by a broth of cytokines, many of which are released by the same APC. Together, elevated expression levels of (co-)stimulatory molecules on APC and local abundance of cytokines overcome the relatively high activation threshold of naive T cells [157].

Core Message

The intricate structure of lymph node paracortical areas, the differential expression of chemokines and their receptors, the characteristic membrane ruffling of IDC, and the predominant circulation of naïve T lymphocytes through these lymph node areas provide optimal conditions for T-cell receptor binding, i.e., the first signal for induction of T-cell activation [158]. Intimate DC–T cell contacts are further strengthened by secondary signals, provided by sets of CAMs, and growth-promoting cytokines (reviewed in [159, 160]).

3.4 Proliferation and Differentiation of Specific T Cells

3.4.1 T-Cell Proliferation

Upon their activation, naive allergen-specific T cells start producing several cytokines, including IL-2, the classical T-cell growth factor [161, 162]. In particular, ligation of T cell-bound CD28 receptors unleashes full-scale IL-2 production in T cells by increasing IL-2 transcription and mRNA stabilization [163]. T-cell IL-2 production peaks within 24 h, and declines subsequently (Villarino 2007). Concomitant upregulation of the IL-2 receptor α-chain facilitates the assembly of high affinity IL-2 receptor complexes that augment autocrine T-cell responsiveness, thus providing a positive feedback loop leading to T-cell clonal expansions up to 1,000-fold [164]. The process of proliferation can be visible as an impressive, sometimes painful lymph node swelling.

3.4.2 T-Cell Differentiation

Whereas allergen-specificity remains strictly conserved along with their proliferation, within few days T cells show distinct expression of transcription factors associated with varying cytokine production profiles and [165–168]. Thus, the recent offspring of allergen-specific CD4⁺ T cells can show at least five distinct cytokine profiles, generally associated with helper/effector or regulatory/suppressive functions (Fig. 3.7). Type 1 Th cells are characterized by a predominant release of IFN-γ, IL-2, and TNF-β, all known as prototypical proinflammatory and cytotoxic cytokines. Type 2 Th cells secrete IL-4, IL-5, and IL-13, which have distinct proinflammatory activities, but are most prominent in promoting humoral antibody production, e.g., along mucosal surfaces where IgA contributes to exclusion of microbial entry [169, 170]. Next, the Th3 subset is distinguished by its release of transforming growth factor (TGF)-β, which displays anti-inflammatory activities [170]. Recently, Th-17 cells have been recognized as a separate lineage of proinflammatory T cells, characterized by the production of IL-17A and IL-17E, as well as IL-22, all of which play pivotal roles in autoimmune diseases, e.g., by recruiting neutrophils and macrophages [171, 172]. Finally, still another subset of CD4⁺ T cells is recognized for its strong regulatory role in controlling inflammatory reactivities, i.e., the Tr1 cells or “inducible Tregs,” characterized by the secretion of IL-10 [166, 167]. This CD4⁺ T cell population is phenotypically remarkably heterogeneous, with part of the cells expressing high amounts of the high affinity IL-2 receptor (“CD25^high”), either or not accompanied by expression of the transcription factor FoxP3 [173–175] (Fig. 3.7). Tr1 cells have essential roles in the maintenance of immune homeostasis, regulating effector T-cell responses and preventing their potentially pathogenic effects by various indirect ways, e.g., by suppressing macrophage functions [176, 177]. Each of these five cytokine profiles is under control of distinct sets of transcription factors that are shown in Fig. 3.7, but are discussed further elsewhere (e.g., [165, 166, 178–180].

To some extent, the same distinct cytokine profiles may develop in CD8+ T cells, where at least type 1 and 2 cytokine releasing CD8⁺ cells are known to contribute to ACD [68, 181].

Several factors are thought to contribute to the above described polarized cytokine production profiles in allergen-specific T cells, including (1) the site and cytokine environment of first allergenic contact, (2) the molecular nature and concentrations of the allergen, and (3) the neuroendocrine factors.

3.4.3 Cytokine Environment

In the skin-draining lymph nodes, allergen-activated LC and dermal dendritic cells rapidly produce large amounts of IL-12, switching off IL-4 cytokine production, thereby promoting the differentiation of Th1 cells [182–184]. Of note, since Th1 cells retain, next to IL12R, high IL-4R expression, they remain sensitive to IL-4 as a growth factor [185]. Thus, they also retain the capacity to shift cytokine production toward the type 2 profile. In contrast, type-2 T cells, e.g., developing in mucosa-draining lymph nodes, rapidly lose the genes encoding the IL-12-R β2 chain and thus type-2 differentiation is irreversible [186, 187].

Early differentiation of type-1 T cells is promoted by microbial danger-signal-induced IL-12 and IL-18, leading to IFN-γ release by nonspecific “bystander” cells, e.g., DC and NK cells, within the lymph nodes [188, 189]. IFN-γ interferes with skewing toward other cytokine profiles. Since Th1 cells rapidly lose functional IFN-γR expression, these cells, in contrast to Th2, Th3, and Th17 cells, become refractory to the growth-inhibitory effects of IFN-γ [190–192]. Interestingly, T-cell skewing may also be facilitated by primary contact-mediated signals, e.g., Th1 skewing by CD154 ligation through APC-bound CD40 [193] or Th2 skewing by ligation of CD134 (OX40) through APC-bound CD252 [194, 195].

In the process of T-cell skewing toward the other major cytokine profiles, TGF-β plays a central role. TGF-β can be produced by various cell types, including Th3 cells themselves, but is most prominently produced by mucosal epithelial cells [166, 192, 196]. Apparently, in conjunction with IL-10 production, e.g., produced by mucosal B cells, allergen-stimulated T cells rapidly initiate endogenous TGF-β production thus revealing the Th3 phenotype [197]. These cells may stimulate IgA production along the mucosae, but elsewhere immunosuppressive activities prevail. Interestingly, in conjunction with abundant local IL-2 production, such as induced by strong antigenic stimulation involving most effective CD28 triggering, TGF-β favors skewing toward IL-10 production, thereby providing an effective immunoregulatory feedback loop [198, 199]. Still, in the presence of strong and persistant microbial molecule-induced danger/growth signals, e.g., IL-6, IL-21, and IL-23, TGF-β induces the development of Th17 and/or Th22 cells, which both have been postulated to contribute to various allergic and autoimmune disorders [168, 172, 192, 200, 201] (Fig. 3.7).

Thus, ACD may be caused by any combination of at least three distinct types of effector T cells, releasing type-1, -2, and –17/22 cytokines, respectively. Considering that contact allergens will mainly enter via the skin, type-1 proinflammatory T cells are thought to represent the primary effector cells in ACD [202, 203]. Nevertheless, in sensitized individuals, type-2 T cells also play a role, as shown by both IL-4 production and allergen-specific type-2 T cells in the blood and at ACD reaction sites (see Sect. 3.3.6) [204–206]. Their role may increase along with the longevity of sensitization, since several factors contribute to shifting type-1 to type-2 responses, including reversibility of the former and not of the latter T cells, as mentioned above [207, 208]. Still, other sets of cytokines, including IL-17 and/or IL-22, are important in immune defense mechanisms, and thus Th17 and or Th22 cells have also been found to mediate allergic and autoimmune disorders [209]. Given rapid local release of both IL-4 and TGF-β within mucosal tissues, mucosal allergen contacts, if accompanied by strong danger signals, may lead in particular to Th2 and Th17 effector cells. Without these signals, rather immunoregulatory subsets (Th3, Tr1) would develop, as is observed in the induction of “oral tolerance” (see below) [210].

3.4.4 Nature of the Allergen

A second factor in determining T-cell cytokine production profiles, although still poorly understood, is the molecular character of the contact allergen itself, and the resulting extent of TCR triggering [211, 212]. For both protein and peptide antigens, high doses of antigen might favor type-2 responses, whereas intermediate/low doses would induce type-1 T-cell responses [211, 213]. Strong antigenic stimulation was also shown to upregulate CD40L expression on T cells and, in combination with microbial-induced IL-6, to promote Th17 differentiation. To what extent this translates to contact allergens is still unclear. Certainly, endogenous capacities of contact allergens to provide danger signals and activate the “inflammasome,” in combination with their capacity to induce differentiation-skewing cytokines (in particular IL-4, IL-6, IL-12, and IL-23), will affect the outcome [214, 215]. In this respect, some contact allergens are notorious for inducing type-2 responses, even if their primary contact is by the skin route, e.g., trimellitic acid, which is also known as a respiratory sensitizer [216].

3.4.5 Neuroendocrine Factors

Diverse neuroendocrine factors codetermine T-cell differentiation [217–219]. An important link has been established between nutritional deprivation and decreased T cell-mediated allergic contact reactions [220]. Apparently, adipocyte-derived leptin, a hormone released by adequately nourished and functioning fat cells, is required for type-1 T-cell differentiation. Administration of leptin to mice restored ACD reactivity in mice during starvation [220]. Also, androgen hormones and adrenal cortex-derived steroid hormones, e.g., dehydroepiandrosterone (DHEA), promote type-1 T-cell and ACD reactivity. DHEA, like testosterone, may favor differentiation of type-1 T cells by promoting IFN-γ and suppressing IL-4 release [221, 222]. In contrast, the female sex hormone progesterone furthers the development of type-2 CD4⁺ T cells and even induces, at least transient, IL-4 production and CD30 expression in established type-1 T cells [223, 224]. Type-2 T-cell polarization is also facilitated by adrenocorticotrophic hormone (ACTH) and glucocorticosteroids [225], and by prostaglandin (PG)E₂ [226]. PGE₂, released from mononuclear phagocytes, augments intracellular cAMP levels, resulting in inhibition of proinflammatory cytokine, like IFN-γ and TNF-α, production [227–230] and thus can influence the development of effector T cells in ACD.

Core Message

In healthy individuals, primary skin contacts with contact allergens lead to differentiation and expansion of allergen-specific effector T cells displaying Th1, Th2, and/or Th17 cytokine profiles. The same allergens, if encountered along mucosal surfaces, favor the development of allergen-specific Th2 and Th17 effector cells, and/or Th3 and Tr1 allergen-specific regulatory T cells. While the first two subsets may assist or replace Th1 cells in proinflammatory effector functions, the latter two subsets are mainly known for downregulating immune responsiveness. For most, if not all allergens, along with prolonged allergenic contacts, the role of Th2 cells as effector cells gradually increases given reduced longevity of Th1 responses.
The respective contributions of similar subsets of allergen-specific CD8+ T cells are still unknown, but distinct effector roles of allergen-specific Tc1 and Tc2 have been postulated.

3.5 Systemic Propagation of the Specific T-Cell Progeny

3.5.1 T-Cell Recirculation

Upon sensitization via the skin, the progeny of primed T cells is released via the efferent lymphatic vessels of the skin-draining lymph nodes and the thoracic duct into the blood (Fig. 3.8). If the first encounter with allergen occurs via the intestinal route, (e.g., along with induction of oral tolerance), priming will take place in the Peyer’s patches and mesenteric lymph nodes, and primed T cells will be released from there to the circulation. The subsequent recirculation and homing pattern of primed T cells is guided by adhesion molecules and chemokine receptors, which they express on the cell membrane (Table 3.2). As outlined below, expression of these molecules is determined by the site of priming, as well as by the activational state of the T cells. In addition, there is a distinct relationship between the sets of chemokine and homing receptors expressed by T cells and their type of differentiation.

Table 3.2 Molecules involved in the migration of hapten-specific T lymphocytes

Full size table

First, primed T cells have different homing receptors depending on the site of priming, a process called “imprinting” [231, 232]. During priming of allergen-specific T cells in the skin-draining lymph nodes, both CD4⁺ and CD8⁺ T cells are stimulated to express CLA [233] and the chemokine receptors CCR4 and CCR10, a phenotype that predisposes for eventual migration to the skin. In the mesenteric lymph nodes, on the other hand, T cells are stimulated to express the integrin α4:β7 and the chemokine receptor CCR9, a phenotype which predisposes for gut homing. An instructive role of the peripheral tissues in this imprinting process was demonstrated in a mouse model on T cell priming by dendritic cells, where either dermal or intestinal cells were added to the cultures, resulting in T cells expressing mouse “CLA” or α4:β7 integrin, respectively [231]. For the imprint of gut homing, retinoic acid was identified as a crucial factor, while for the imprint of skin homing, the active metabolite of vitamin D3 was shown to be essential, because it induces CCR10 expression in T cells [234]. Still, for induction of CLA and thus for establishing the full skin-homing profile, cell–cell contact and/or other mediators, like IL-12, seem to be required [231].

After priming and imprinting, circulating gut homing memory T lymphocytes, bearing the α4:β7 integrin, can attach to intestinal endothelial cells by binding to the mucosal vascular addressin MAdCAM-1. Further infiltration in the mucosa is guided by chemokines, such as CCL25, produced by small intestinal epithelial cells [235]. Thus, along the gut, T lymphocyte progeny is attracted that has been generated in other mucosal tissues. Likewise, in the skin, CLA-positive cells that have been generated in skin-draining lymph nodes are attracted. CLA binds to E-selectin (CD62E) on dermal endothelial cells, while CCR4 and CCR10 expression allow the lymphocytes to migrate in the skin toward CCL17 and CCL27 produced by keratinocytes in the epidermis.

At least as important for the recirculation and homing characteristics of T cells is the activational state of the cells. In this respect, primed T cells can be divided into two main subsets: the central memory T cells (T_CM) and the effector memory T cells (T_EM). Like their naive precursors, T_CM can still enter the peripheral lymphoid tissues due to the fact that they continue to express CD62L and CCR7, allowing for binding to HEV in the lymph nodes and migration into the paracortical areas. T_EM, on the other hand, have lost these molecules and migrate, due to simultaneous upregulation of several other adhesion molecules, preferentially to peripheral inflamed tissues. T_EM are characterized by rapid effector function upon antigenic stimulation, but, in the absence of antigenic stimuli, T_EM eventually convert to T_CM by reacquiring CCR7 and CD62L. In turn, T_CM may convert to T_EM upon antigenic restimulation [167, 232, 236, 237].

Peripheral endothelial binding and extravasation of T cells to inflamed tissues require the expression of both selectins and integrins on the T cell membrane, such as LFA-1, VLA-4, and PSGL-1. The vascular expression of their respective ligands (Table 3.2) is strongly increased by cytokines released at inflammatory sites. The density of adhesion molecules on the T cell membrane is generally upregulated upon activation, in particular in T_EM. Since their expression is highest only for short periods after activation, only recently activated T cells show a unique propensity to enter skin sites and exert effector functions.

Third, the differentiation of T cells (Th1, Th2 etc.) is clearly associated with distinct homing characteristics. T cells biased toward a proinflammatory phenotype show a higher propensity to enter skin sites, as compared to mucosal tissues [233, 238]. [201, 239] In mice, the early influx of type-1 T cells into delayed-type hypersensitivity (DTH) reactions was found to be more efficient than that of type-2 T cells, although both cell types expressed CLA. Here, CD162, highly expressed by type-1 T cells, was found to be important for this preferential homing [240]. Also, the pattern of chemokine receptors differs between the Th subsets (Table 3.2). Some receptors, such as CXCR3, are preferentially expressed on Th1 cells, whereas others, such as CCR4 and CCR8, are in particular expressed by Th2 cells [167, 175, 241, 242]. The latter chemokine receptors are not only overexpressed on type-2 cytokine-producing T cells, but also on basophils and eosinophils. Together these cells strongly contribute to local immediate allergic hyperresponsiveness. The more recently described Th17 and Th22 lymphocyte subsets expressing CCR4, CCR6, and CCR10 [239, 241] are attracted to the skin by epidermal CCL17, CCL20, and CCL27, respectively (Table 3.2). Overall, results obtained thus far favor the view that the proinflammatory subsets (Th1 and Th17/22) will be the first to enter skin sites upon local inflammatory stimuli, their primary function being an early control of antigenic pressure, e.g., through amplification of macrophage effector functions. The ACD reaction is, however, a dynamic process, in which the first influx of cells influences the local chemokine environment and determines the type of subsequent infiltrating cells. Thus, upon repeated exposure to contact allergens, gradually Th2 cells and regulatory cells may dominate [243]. Interestingly, also at the T cell level modulation of the cytokine and chemokine receptor profiles may occur, thereby maintaining plasticity of the immune response [167, 180]. The actual composition of the T cell infiltrate in ACD skin lesions does not only depend on the influx of lymphocytes, but should rather be regarded as the resultant of infiltration, apoptosis and retention of lymphocytes, next to their emigration to the lymphatics.

Finally, the antigen specificity of T cells contributes to their migration pattern. Allergens penetrated via the epidermis and displayed at the dermal endothelial surface may be recognized by allergen-specific T cells, thereby resulting in activation, immobilization, and transendothelial migration of these cells at sites of allergen exposure [241].

Core Message

Priming via the skin results in CLA-positive T cells, which upon inflammatory stimuli preferentially enter the skin; on the other hand, gut homing T cells have been primed and generated along mucosal surfaces. Upon priming, T cells loose much of their capacity to recirculate via the lymph nodes, but gain the capacity to enter the tissues. In particular, recently activated T cells will enter skin-inflammatory sites. ACD reactions are primarily infiltrated by CD4 and/or CD8 proinflammatory cells, later reactions may be dominated by Th2 cells and regulatory T cells. Skin infiltration by T cells is fine tuned by sets of adhesion molecules and chemokine receptors, whose expression is not rigid, but can be modulated by microenvironmental factors.

3.5.2 Allergen-Specific T-Cell Recirculation: Options for In Vitro Testing

The dissemination and recirculation of primed, allergen-specific T cells in the body suggests that peropheral blood offers a most useful and accessible source for T-cell based in vitro assays for ACD. A major advantage of in vitro testing would be the noninterference with the patient’s immune system, thereby eliminating any potential risk of primary sensitization and boosting by in vivo skin testing. Although such tests have found several applications in fundamental research, e.g., on recognition of restriction elements, cross-reactivities, and cytokine profile analyses, their use for routine diagnostic purposes is still limited. Even in highly sensitized individuals, frequencies of contact allergen-specific memory/effector cells may still be below 1 per 10⁴ [244–246]. Given the relatively small samples of blood obtainable by venepuncture (at only one or a few time points), numbers of specific T cells in any culture well used for subsequent in vitro testing would typically be below 100 cells/well. For comparison, in vivo skin test reactions recruit at least 1,000 times more specific T cells from circulating lymphocytes passing by for the period of testing, i.e., at least 24 h [247].

Therefore, the sensitivity of in vitro assays, e.g., allergen-induced proliferation or cytokine production, may not always be sufficient to pick up weak sensitization. Intermediate or strong sensitization is, however, readily detected in vitro by both proliferation and cytokine production assays [245, 248–250]. With respect to the latter, both the “Elispot” assay, where allergen-induced cytokine production is evaluated at the single cell level, and the cytokine evaluation in allergen-stimulated culture supernatants provide adequate information [249, 251, 252]. Notably with respect to cytokine production, type-2 cytokines appear to provide most specific parameters for contact sensitization in these assays, [251, 253] although generally both Th1 and Th2 cytokines are being produced in vitro by allergic individuals, upon allergen exposure [250, 254].

Importantly, most of the above mentioned successful in vitro studies evaluated hydrophilic allergens, such as nickel, chromium, and palladium salts. Reports on successful in vitro assays with other hydrophobic and more toxic allergens are scarce [250, 255, 256]. Appropriate allergen presentation is a major hurdle in in vitro studies because of the broad range of requirements for different allergens with unique solubilities, toxicities, and reactivity profiles. Moreover, in the absence of LC, monocytes are the major source of APC, and their numbers in peripheral blood vary substantially within and between donors. Of note, optimal APC function is particularly critical for in vitro activation of resting memory T cells, since in the absence of repeated allergenic contacts, activated effector memory T cells (T_EM) may finally revert to a more naïve phenotype, with a higher threshold for triggering [236, 257]. Supplementing in vitro test cultures with appropriate mixtures of cytokines may, however, compensate for suboptimal APC function [250, 251, 258].

Core Message

After antigenic activation the progeny of primed T cells is released via the efferent lymphatics into the bloodstream. Circulating allergen-specific cells can be challenged in vitro to provide diagnostic parameters for contact hypersensitivity. At least for water-soluble allergens, such as metal salts, the degree of allergen-specific proliferation and cytokine production, in particular type-2 cytokines, correlates with clinical allergy. For routine application of a broad spectrum of allergens, culture conditions still need to be improved. For mechanistic in vitro studies in ACD, however, with selected sets of relatively nontoxic allergens, peripheral blood provides an excellent source of lymphocytes and APC.

3.6 The Effector Phase of Allergic Contact Dermatitis

3.6.1 Elicitation of ACD

Once sensitized, individuals can develop ACD upon reexposure to the contact allergen. Positive patch test reactions mimic this process of allergen-specific skin hyperreactivity. Thus, skin contacts induce an inflammatory reaction that, in general, is maximal within 2–3 days and, without further allergen supply, declines thereafter (Fig. 2.8). Looked at superficially, the mechanism of this type of skin hyperreactivity is straightforward: allergen elicitation or challenge leads to the (epi)dermal accumulation of contact allergen-specific memory/effector T lymphocytes, which, upon encountering allergen-presenting cells, are reactivated to release proinflammatory cytokines. These, in turn, spark the inflammatory process, resulting in macroscopically detectable erythema and induration. As compared to immediate allergic reactions, developing within a few minutes after mast-cell degranulation, ACD reactions show a delayed time course, since both the migration of allergen-specific T cells from the dermal vessels and local cytokine production need several hours to become fully effective. Still, the picture of the rise and fall of ACD reactions is far from clear. Some persistent issues are discussed below, notably: (1) irritant properties of allergens, (2) role of early phase reactivity, (3) T-cell patrol and specificity, (4) effector T-cell phenotypes, and (5) downregulatory processes.

3.6.2 Irritant Properties of Allergens

Within a few hours after allergenic skin contact, immunohistopathological changes can be observed, including vasodilatation, upregulation of endothelial adhesion molecules [259, 260], mast-cell degranulation [261, 262], keratinocyte cytokine and chemokine production, [45, 263] influx of leucocytes [264, 265], and LC migration toward the dermis [112, 266–268]. These proinflammatory phenomena, which are also observed in nonsensitized individuals [269] and in T cell-deficient nude mice [270], strongly contribute to allergenicity [58]. Clearly most, if not all, of these effects can also be caused by irritants and, therefore, do not unambiguously discriminate between irritants and contact allergens [45, 271–273]. Apparently, true differences between these types of compounds depend on whether or not allergen-specific T cells become involved. Thus, only after specific T-cell triggering, distinctive features might be observed, e.g., local release of certain chemokines such as the Th1 associated chemokines CXCL9, CXCL10 (IP-10), and CXCL11 (I-TAC/IP-9) [263, 274] or the Th2 related chemokines CCL11, CCL17, and CCL22 [263, 274]. Certainly, proinflammatory effects of contact allergens increase, in many ways, the chance of allergen-specific T cells meeting their targets. The first cells affected by skin contact, i.e., keratinocytes and LC, are thought to represent major sources of pivotal mediators such as IL-1β and TNF-α [106, 275]. First, as described in “Hapten-Induced Activation of Allergen-Presenting Cells,” these cytokines cause hapten-bearing LC to mature and migrate toward the dermis [94, 131, 268]. But these cytokines also cause (over)expression of adhesion molecules on dermal postcapillary endothelial cells, and loosen intercellular junctions. In that way, extravasation of leucocytes, including allergen-specific T cells, is strongly promoted [241, 275–278]. Moreover, haptens can stimulate nitric oxide (NO) production of the inducible NO-synthase (iNOS) of LC and keratinocytes, which contributes to local edema, vasodilatation, and cell extravasation [279, 280].

Histopathological analyses support the view that the major causative events take place in the papillary dermis, close to the site of entry of allergen-specific T cells, for instance at hair follicles, where haptens easily penetrate and blood capillaries are nearby [281]. Here, perivascular mononuclear cell infiltrates develop, giving the highest chance of encounters between allergen-presenting cells and specific T cells. Once triggered, extravasated T cells will readily enter the lower epidermal layers, in which haptenized keratinocytes produce lymphocyte-attracting chemokines, such as CXCL9/10, CCL17, CCL20, and CCL27 ([201, 232, 263, 274]; Table 3.2). Subsequently, since effector memory T cells can also be triggered by “nonprofessional” APC, including KC, fibroblasts, and infiltrating mononuclear cells, ACD reactivity is amplified in the epidermis [157, 159, 269]. Together, these events result in the characteristic epidermal damage seen in ACD, such as spongiosis and hyperplasia. Notably, in ongoing ACD reactions, the production of chemokines attracting lymphocytes and monocytes/macrophages, in addition to the production of cytokines, adds to the nonspecific recruitment and activation of leucocytes [119, 282, 283]. Thus, like the very early events in the effector phase reaction, the final response to a contact allergen is antigen-nonspecific. It is, therefore, not surprising that allergic and irritant reactions are histologically alike.

3.6.3 Early Phase Reactivity

In the elicitation phase allergen-specific T cells are triggered by MHC-bound allergen, just like in the afferent phase. The role of LC in allergen presentation upon elicitation is, however, less prominent, and also other cells such as mast cells, macrophages, and keratinocytes may now contribute, since effector T cells are easily triggered and do not require professional antigen presentation. The role of keratinocytes in the onset of the ACD reaction is important because of the cytokines and chemokines they produce upon hapten application [237, 263], thereby facilitating the influx of effector T cells. In addition, a variety of other cells and mediators may contribute to the initiation of the ACD reaction, as summarized below.

The role of neutrophils in the onset of ACD reactions has not been well-established, though recent studies in mice demonstrate that skin reactivity to haptens largely depends on CXCL1, released from endothelial cells when the first hapten-specific CD8 T cells encounter the allergen and produce IL-17. CXCL1 may then attract neutrophils to the elicitation site, thus facilitating further influx of allergen-specific T cells [284]. In the human system, neutrophil infiltration was also observed in skin biopsies from nickel patch tests, presumably as a result of IL-17/IL-22 mediated inflammation [201]. Moreover, it has been shown that IL-8/CXCL8, a potent neutrophil chemoattractant, is readily produced by human antigen-presenting cells upon hapten exposure [285]; this could also contribute to an early influx of neutrophils in ACD reactions.

The role of an antibody-mediated early-phase reaction in the development of ACD is still unclear in man, although Askenase and his colleagues have generated robust data to support this view in murine models [286]: Hapten-specific IgM, produced upon sensitization by distant hapten-activated B-1 cells, can bind antigen early after challenge and activate complement. The resulting C5a causes the release of serotonin and TNF-α from local mast cells and platelets, leading to vascular dilatation and permeabilization, detectable as an early ear swelling peaking at 2 h [287]. Furthermore, C5a and TNF-α induce the upregulation of adhesion molecules on local endothelial cells [288, 289], thereby contributing to the recruitment of T cells in hapten challenge sites [289, 290]. In addition, human T cells were found to express the C5a receptor and are chemoattracted to endothelium-bound C5a [291]. However, against most contact allergens, including nickel, no antibodies have been detected in man, arguing against humoral mechanisms playing more than a minor role in clinical ACD [292, 293]. Interestingly in mice, immunoglobulin light chains, which have long been considered as the meaningless remnants of a spillover in the regular immunoglobulin production of B cells, were discovered to mediate very early hypersensitivity reactions by mast cell activation [294].

In addition to an auxiliary role of B cells and antibodies, natural killer (NK) cells have been reported to play a role in the onset of ACD reactions. Mice lacking both T and B cells (RAG2−/−) could still be sensitized to contact allergens, and Thy1+ NK cells were identified here as effector cells with a prominent role for the activating NK receptor NKG2D [295]. Interestingly, another NK-like cell, the invariant NKT cell, that recognizes CD1d bound glycolipids resulting in rapid IL-4 and IFN-γ release, was also found to play a role in the elicitation of contact sensitivity in mice: blocking of CD1d prevented both sensitization and elicitation by contact allergens [296]. Notably, in human ACD reactions relatively high frequencies of invariant NKT cells have been observed, ranging from 1.7 to 33% of total infiltrating T cells, which is 10–100-fold higher than the frequency found in the circulation [297]. Also, other T cells with relatively restricted TCR repertoire, such as Tγδ cells, have been reported to contribute in a nonantigen-specific, probably non-MHC-restricted manner, to (early) elicitation responses [298].

To conclude, using various mouse models, different types of early allergen-specific reactivity have been claimed to play initiating roles in ACD, but clinical evidence for such mechanisms is still lacking.

3.6.4 T-Cell Patrol and Specificity of T-Cell Infiltrates

Whereas early nonspecific skin reactivity to contact allergens is pivotal for both sensitization and elicitation, full-scale development of ACD, of course, depends on allergen-specific T cells within the (epi)dermal infiltrates. In healthy skin there is a constant flow of memory T cells ending up in the draining lymph nodes: about 200 T cells/h/cm² skin [115]. Since one single antigen-specific T cell can already trigger visible skin inflammation [299, 300], randomly skin-patrolling memory/effector T cells might account for the initiation of the allergen-specific effector phase. However, since frequencies of hapten-specific T cells in sensitized individuals may still remain below 1 in 10,000, this does not seem to be a realistic scenario. Thus, augmented random and/or specific T-cell infiltration accompanies the development of ACD. Apparently, local chemokine release upon allergen contact is pivotal in this respect (see T-Cell recirculation; 482). Chemokine gene expression evaluated 48 h after NiSO4 application was increased for both Th1 related cytokines (CXCL9, CXCL10, and CXCL11) and Th2 related cytokines (CCL11, CCL17, and CCL22). On the other hand, CCL27 that attracts preferentially CCR10 bearing Th17/22 cells is constitutively produced in resting skin, but is rapidly released upon allergen contact to accumulate in the draining lymph nodes.

The question concerning the specificity of ACD T-cell infiltrates has so far received little attention. In a guinea pig model, preferential entry of dinitrochlorobenzene (DNCB)-specific T cells was observed within 18 h after elicitation of skin tests with DNCB, as compared to nonrelated compounds [301]. Probably, extravasation of hapten-specific T cells benefits from T-cell receptor-mediated interactions with endothelial MHC molecules, presenting hapten penetrated from the skin [241]. Within minutes after epicutaneous application, hapten can indeed be found in dermal tissues and on endothelial cells [259, 302, 303]. Indeed, the frequency of allergen-specific cells in positive patch tests to urushiol was found to be 10–100-fold higher than in the blood [246]. Interestingly, whereas preferential entry may already contribute to relatively high frequencies of allergen-specific T cells (within 48 h up to 10%) [205, 299], at later stages, when the ACD reaction fades away, the local frequency of allergen-specific T cells may increase even further, due to allergen-induced proliferation and rescue from apoptosis. Thus, at former skin reaction sites, these cells can generate “local skin memory” (see Sect. 3.3.7).

3.6.5 Effector T-Cell Phenotypes

The debate on phenotypes of effector T cells in ACD is still ongoing and the number of T cell subsets potentially involved is growing every year (Fig. 3.7). Consensus exists, however, on the phenotype of the skin-homing T cell, i.e., CLA positive. This molecule enables binding to cutaneous endothelial cells via E-selectin (CD62E) and thus migration into the dermis.

Since cutaneous infiltrates show a clear preponderance of CD4⁺ T cells, it is not surprising that these cells have most often been held responsible for mediating ACD. In nickel allergic individuals, indeed, allergen responding cells were found to be CD4⁺CLA⁺ memory T cells [304]. Other studies, however, revealed CD8⁺CLA⁺ nickel reactive T cells as most discriminating for allergic individuals, since CD4⁺ nickel reactive T cells were also found in healthy controls [244]. While the effector mechanism of CD4⁺T cells is mainly based on cytokine production, CD8+ T cells may mediate skin inflammation also through killing of hapten-bearing target cells. In mice, generally CD8⁺ T cells are found to cause contact sensitivity reactions, certainly to strong allergens, like DNFB [284, 297]. In mice CD4⁺ T cells are rather found to be regulatory, as shown by the fact that contact sensitization to weak allergens succeeded only after depletion of the CD4⁺ T cells [305]. Of note, most model allergens studied in mice are hydrophobic molecules such as DNFB and oxazolone, whereas in human studies, very often, water-soluble metal salts, such as NiSO4, are used as model allergen. This could, at least partly, explain the different T cell subsets involved (Fig MHCI/II presentation). So, taken together, it has become clear that both CD4⁺ and CD8⁺ T cells can act as effector cells in DTH and ACD reactions. Likewise, neither of these subsets can be regarded simply as regulatory or suppressor cells, although both of these subsets may, depending on the allergen models and read-out assays, play such roles [68, 306].

An essentially similar conclusion holds true for T-cell subsets (whether CD4⁺ or CD8⁺), releasing type-1, type-2, or type-17 cytokines or combinations thereof. While type-1 cytokines, in particular IFN-γ, display well-established proinflammatory effects by fi increasing MHC and ICAM-1 expression [284, 307], thereby contributing to improved allergen presentation and infiltration, IL-4, a hallmark type-2 cytokine, can cause erythema and induration, when released in the skin [308, 309]. Indeed, blockage of IL-4 can interfere with ACD [309]. IL-17 plays a role in recruitment and activation of neutrophils. It was shown to be produced both by CD8⁺ T cells (in mouse models with DNFB; 483) and by CD4⁺ T cells (in human nickel patch tests; 456). The latter study shows, interestingly, that within a few hours after challenge, CCL20 expression is upregulated in the skin, attracting CCR6 positive cells. Since all Th17 cells do express this receptor, an early preferential influx of Th17 and, as a consequence, IL-17 and IL-22 production could be an essential early event in the development of the ACD reaction.

Thus, a picture emerges in which ACD reactions can be caused both by allergen-specific type-1, type-2, and type-17 T cells [168, 201, 244, 251, 297, 304]. In retrospect, the downregulatory effects of IL-4 on ACD reactions observed earlier in some mouse models [310] might be ascribed to accelerated allergen-clearance, rather than to blunt suppression. Still, both with time and repeated allergen-pressure, type-2 responsiveness may rapidly take over [243, 311]. Allergen-specific T cells isolated from skin test sites of sensitized individuals, as compared to blood, showed a strong bias toward type-2 cytokine profiles [204]. Additional local IFN-γ release seems, however, indispensable, since for a broad panel of contact allergens, clinical ACD reactions were characterized by increased expression of mRNA encoding IFN-γ-inducible chemokines [274]. In addition, transgenic mice expressing IFN-γ in the epidermis showed strongly increased ACD reactivity [312].

3.6.6 Downregulatory Processes

Resolution of ACD reactions and risk factors for the development of chronicity are not yet fully understood. Of course, if the allergen source is limited, as with skin testing, local concentrations of allergen usually rapidly decrease, thus taking away the critical trigger of the ACD reaction cascade. Since even ACD reactions due to chronic exposure to allergen seldomly result in permanent tissue destruction and scarification, immunoregulatory factors most likely contribute to prevention of excessive cytotoxicity and fatal destruction of the basal membrane. Both IL-1 and heparinase, secreted from activated keratinocytes and T cells, protect keratinocytes from TNF-α-induced apoptosis [313, 314]. Moreover, activated effector T cells can undergo activation-induced cell death (AICD) during the resolution phase [315]. Notably, proinflammatory type-1 T cells, expressing high levels of Fas-ligand (CD95L) and low amounts of apoptosis-protecting FAP-1 protein, are more susceptible to AICD than type-2 cells [316]. This may partly explain the shift toward type-2 reactivity that is observed upon prolonged allergen exposure [311]. Moreover, during the late phase of ACD, keratinocytes, infiltrated macrophages, and T cells start producing IL-10 [317–319], which has many anti-inflammatory activities, including suppression of antigen-presenting cell and macrophage functions [320, 321]. In addition, the release of factors, such as PGE₂ and TGF-β, derived from activated keratinocytes and infiltrated leucocytes, e.g., type-3 T cells, contribute to dampening of the immune response [322, 323]. Release of PGE₂, on the one hand, inhibits production of proinflammatory cytokines [230, 324] and, on the other hand, activates basophils [325]. These may constitute up to 5–15% of infiltrating cells in late phase ACD reactions [326] and are also believed to contribute to downregulation of the inflammatory response [327, 328]. TGF-β silences activated T cells and inhibits further infiltration by downregulating the expression of adhesion molecules on both endothelial and skin cells [236]. Regulatory cells producing these suppressive mediators might even predominate in skin sites, frequently exposed to the same allergen, and known to show local (allergen-specific) hyporesponsiveness [329]. It is of interest in this context that CD4⁺ memory T cells expanded from late DTH reactions could be educated to become CD4⁺CD25⁺⁺ regulatory T cells expressing Foxp3.

Core Message

ACD reactions can be mediated by classical effector cells, i.e., allergen-specific CD4⁺ type-1 T cells, which, upon triggering by allergen-presenting cells, produce IFN-γ to activate nonspecific inflammatory cells such as macrophages. However, CD8⁺ T cells and other cytokines, including IL-4, IL-17, and IL-22, can also play major roles in ACD. The conspicuous difference with DTH reactions induced by intradermal administration of protein antigens, i.e., the epidermal infiltrate, can largely be attributed to hapten-induced chemokine release by keratinocytes.

3.7 Flare-Up and Retest Reactivity

3.7.1 Local Allergen Retention

Flare-up reactivity of former ACD and patch test reaction sites is sometimes observed [330–332]. From the basic mechanisms of ACD, it can be inferred that allergen-specific flare-up reactions depend either on local allergen or T-cell retention at these skin sites. Upon short-lasting, low-dose contacts, e.g., by skin testing, local allergen retention usually does not exceed a 2-week period, which is actually long enough to exceed the time required for active sensitization. In experimental guinea pig studies, we observed that skin tests with DNCB, chromium, or penicillin could become positive even if primary sensitization was postponed to 1 week after skin testing. Apparently effector T cells released into the circulation at that late time still detected sufficient residual allergen at the former skin test sites to cause flare-up reactivity (Scheper et al., unpublished results). Maximum allergen-persistence for around 14 days was also reported by Saint-Mezard et al., [58] using the hapten fluorescein-isothiocyanate in a mouse model for flare-up reactivity. Also in humans flare-up reactions due to locally persisting allergen can be observed, when from about 4–6 days after primary sensitization, peripheral effector T cell frequency increases [333]. Clinically, this phenomenon can explain anomalous results from patch testing with multiple contact allergens. When a patient suspected for penicillin allergy was patch tested with cross-reactive penicillin derivatives, a regular 24–72 h reaction was only observed to one of the penicillins, but all others also became positive from about 8–9 days after skin testing. The first penicillin derivative turned out to release formaldehyde to which the patient was found to be allergic. Positive reactivity to formaldehyde apparently had potentiated primary sensitization to penicillin, causing the other previously negative reaction sites to flare-up (Neering, personal communication). Thus, skin test sites may occasionally flare-up if the testing dose itself led to the release or activation of sufficiently high numbers of effector T cells in the circulation.

3.7.2 Local T-Cell Retention

In contrast, allergen-specific T cells may persist for at least several months in the skin causing “local skin memory” (Figs. 3.9 and 3.10) [334, 335]. Thus, locally increased allergen-specific hyperreactivity, detectable through either accelerated “retest” reactivity (after repeated allergenic contact at the same skin site) or flare-up reactivity (after allergen entry from the circulation, e.g., derived from food ingestion), may be observed for long periods of time at former skin reaction sites [336–338]. Typically, the erythematous reactions peak between 2 and 6 h after contact with the allergen. Histological examination of such previously positive skin reaction sites shows that the majority of remaining T cells is CD4⁺ CCR10⁺ [335]. The remarkable flare-up reactivity at such sites can be understood by considering that just one specific effector T cell can be sufficient to generate macroscopic reactivity [300]. Moreover, a very high frequency of the residual T cells may be specific for the allergen, as discussed above in Sect. 3.3.6. Apparently, local specific T cell retention is highly advantageous in combating microbial infections, since memory T cells localized in peripheral tissues contribute to robust protection, e.g., to viral infections [232]. Only in highly sensitized individuals unrelated skin test sites may also show flare-up reactions [334] and even generalized erythematous macular eruptions can be observed with higher allergen doses [339]. The latter reactivities probably relate to the fact that recently activated T cells show strong expression of adhesion and homing molecules, e.g., CLA and chemokine receptors such as CCR5, facilitating random migration into peripheral tissues and thus allergen-specific T cell patrol in the skin [232, 340]. Upon subsequent allergen entry from the circulation, these allergen-specific T cells could mediate generalized erythematous reactions [331].

Interestingly, local allergen-specific T cell retention/ “local skin memory” can be clinically exploited to discriminate between simultaneous sensitization to different sensitizers (“concomitant sensitization”) and cross-reactivity between different sensitizers [341–343]. Using several different combinations of contact allergens in a guinea pig model, we retested guinea pigs previously sensitized to DNCB and methyl methacrylate (MMA), with the same allergens and some other methacrylate congeners. Accelerated retest reactivities were observed with the latter congeners on the former MMA, but not DNCB, patch test sites [341]. Thus, with preferential local retention of MMA-specific T cells at the MMA skin test site, no accelerated retest reactivity could be elicited with DNCB, but to varying degrees with all four MMA-related compounds. In clinical practice using this approach, Matura [342] confirmed positive cross-retest reactions for cloprednol and tixocortol pivalate, both belonging to group A, and budesonide, amcinonide, and triamcinolone, all belonging to group B corticosteroids (see also [344]).

3.8 Hyporeactivity: Tolerance and Desensitization

Of course, uncontrolled development and expression of T cell-mediated immune function would be detrimental to the host. During evolution, several mechanisms developed to curtail lymph node hyperplasia or prevent excessive skin damage upon persisting antigen exposure.

3.8.1 Regulation of Immune Responses

First, allergen contacts, e.g., by oral or intravenous administration, may lead to large-scale presentation of allergen by cells other than skin DC (Fig. 3.11). In the absence of appropriate costimulatory signals (as described above in Sect. 3.3.3), allergen presented by, e.g., immature Langerhans’ cells may anergize naive T cells, i.e., cause receptor-downregulation associated with an unresponsive state, eventually leading to their death by apoptosis (Fig. 3.12) [345–347]. With increasing densities of MHC-antigen complexes on the surface of professional APC, at least three different levels of T-cell tolerance may be induced, characterized by active suppression, anergy, or deletion [348, 349]. Unresponsiveness of T cells, induced by allergenic contacts at skin sites where LC/DC functions have been damaged, e.g., by UV irradiation, or are naturally absent, e.g., in the tail skin of mice, may be ascribed to T-cell anergy, frequently associated with TCR/CD4 or CD8 downregulation, and apoptosis/deletion [350, 351]. Whereas anergy and deletion reflect “passive” unresponsiveness, tolerance by active suppression may also be induced under similar circumstances [352]. Actually, with increasing dose and exposure times, even regular epicutaneous allergenic contacts induce not only T effector cells but also lymphocytes controlling T-cell proliferation (afferently acting regulatory cells) and/or causing decreased skin reactivity (regulatory cells of effector phase). Thus, allergic contact hypersensitivity is the resultant of a delicate balance between effector and regulatory mechanisms [329, 353].

3.8.2 Cellular Basis of Active Tolerance

Upon preferential stimulation of regulatory cells, e.g., by feeding nonprimed, naïve individuals with contact allergens, strong, and stable allergen-specific, active tolerance may develop [354–356]. The concept of active regulatory (“suppressor”) cells controlling ACD is based on the fact that in experimental animal models, such allergen-specific tolerance can be transferred by lymphoid cells from tolerant to naive animals [298, 357]. Active suppression, as revealed by these adoptive cell transfers, is a critical event in regulating T-cell responses to contact sensitizers and to all possible peptide/ protein antigens, including bacterial, autoimmune, and graft rejection antigens [358–360].

Like effector T cells in ACD, regulatory cells are not a single subpopulation of cells. As outlined above, depending on, e.g., the nature of the allergen and route of exposure, ACD can be mediated by both CD4⁺ and CD8⁺ T cells, either or both releasing Th1, Th2, Th3, Th17/22 cytokines. With distinct effector phenotypes for particular allergens, each of the other phenotypes can act as regulatory cells ([361, 362]: CD8+ Treg). Notwithstanding, type-2 cytokine-producing cells are prominent in regulating ACD, with allergic contact hypersensitivity enhanced and tolerance reversed by interfering with type-2 T cell functions [363–366]. Also, interferons and IL-12, both impairing Th2 and Th17/22 cells, were shown to inhibit regulatory cells and stimulate effector cell functions in mouse models [367–369]. In particular, after mucosal allergen contact stimulation, T cells producing IL-10 and/or TGF-β (type-3 cytokine profile), many of which coexpressing CD4, CD25, and the transcription factor Foxp3 (Treg), may act as regulatory cells [174, 370, 371]. These T cells promote anti-inflammatory immunity, e.g., by switching antibody production to IgA, which mediates secretory immunity and thus contributes to antigen exclusion in the lumen, e.g., of the gastro-intestinal tract [372]. Of note, TGF-β strongly suppresses development of both type-1 and -2 effector T cells, and can silence T cells in a seminaïve state [236].

3.8.3 Regulatory Mechanisms of the Effector Phase

A critical feature of the regulatory principles involving mutual regulation of T-cell subpopulations by Th1, Th2, Th3, and Th17/22 cytokines is that regulatory functions are most effective during initiation of immune responses (Fig. 3.7). Thus, once established, effector T cell and cytokine profiles show remarkable stability and refractoriness to regulatory forces. Downregulation of allergic skin reactions may, therefore, take considerable time. Of course, the preliminary factor facilitating decreased allergic skin reactivity is the removal of hapten by exudate and innate immune cells of the inflammatory infiltrate. But, at chronically exposed sites, specific regulatory mechanisms can also be involved, such as CD8⁺ T cells, acting either as regulator/ suppressor (CD28⁻CD11b⁺) or cytotoxic (CD28⁺CD11b^–) T cells [373, 374], which may downregulate skin reactivity by targeting allergen-presenting DC [374]. Multiplicity and redundancy of regulatory mechanisms have thus far hampered development of robust clinical treatments exploiting regulatory T cell functions to provide for allergen-specific downregulation of the effector phase of ACD. The development of potential therapeutic applications of regulatory cells in various disorders, such as ACD and autoimmune diseases, therefore, needs much more time than envisioned earlier [375].

3.8.4 Redundancy of Tolerance Mechanisms

Besides regulatory T cells, producing different cytokines or exerting distinct cytotoxicities, other mechanisms may also contribute to immune regulation and tolerance. Clearly, the risk of excessive immune reactivity should be very low. These mechanisms involve allergen-specific T cells shedding truncated TCRs, acting as antagonists and blocking allergen presentation [376], and high-dose allergen-induced anergic T cells [349]. Possibly, the latter cells, by actively suppressing DC functions, can function as “active” suppressor cells [377, 378]. Interestingly, DC, becoming suppressive by this mechanism [378] or by suppressive cytokines like IL-10 and PGE₂ [230, 379, 380], can, in turn, act themselves as suppressor cells by conferring antigen-specific anergy to subsequently encountered T cells [377, 378, 381]. Although, at present, consensus has been reached about a critical role of regulatory/ suppressor cells in the development and expression of ACD, the relative contributions of each of the various mechanisms are still far from clear.

3.8.5 Induction of Lasting Tolerance Only in Naive Individuals

Both clinical and experimental findings indicate that full and persistent tolerance can only be induced prior to any sensitizing allergen contacts [356, 382, 383]. Upon primary allergenic contacts, naive T cells differentiate to produce polarized cytokine profiles (Figs. 3.7 and 3.11). Once polarized, however, T-cell profiles are irreversible, due to loss of cytokine (receptor) genes, or at least very stable, due to the mutually suppressive activities of T-cell cytokines. An important corollary of the latter concept of active suppression is the bystander effect, in which the response to any antigen can be downregulated by immunosuppressive cytokines acting in a local tolerogenic microenvironment [384]. The latter was observed for both protein antigens [385] and methacrylate contact allergens [357]. Stable polarization/ skewing may also explain why even low, nonsensitizing doses of nickel applied to the skin prevented subsequent tolerance induction by feeding the metal allergen [386]. Apparently, the progeny of naïve allergen-specific cells, once “on the stage,” has been triggered to a “subclinical” degree toward effector cell differentiation and becomes refractory to regulatory cell action. This may also have contributed to incomplete tolerance induction in earlier clinical studies when feeding with poison ivy-/oak-derived allergens [387]. Indeed, to our knowledge, permanent reversal of existing ACD in healthy individuals has, as yet, never been achieved. Nevertheless, as described above, effector cells still seem susceptible, though transiently, to the downregulation of allergen reactivity, as was observed in desensitization procedures [386, 388].

3.8.6 Transient Desensitization in Primed Individuals

For dermatologists, methods by which patients might be desensitized for existing ACD would be a welcome addition to the currently prevailing symptomatic therapies, and investigators have made a wide variety of attempts to achieve this goal. Unfortunately, as mentioned above, therapeutic protocols involving ingestion of poison ivy allergen, penicillin, or nickel sulfate were of only transient benefit to the patients [387–391]. Similarly, in animal models, only a limited and transient degree of hyposensitization was obtained by Chase [392] when feeding DNCB-contact-sensitized guinea pigs with the allergen, whereas for achieving persistent chromium-unresponsiveness in presensitized animals, Polak and Turk [393] needed a rigorous protocol involving up to lethal doses of the allergen. As outlined above, mechanisms underlying specific desensitization in ACD probably depend on direct interference of allergen with effector T-cell function by blocking or downregulating TCRs, leading to anergy and apoptosis [394]. As the onset of desensitization is immediate, no suppressor mechanisms may initially be involved. Apparently in the absence of LC, MHC class II-positive keratinocytes can serve as APC and are very effective in rendering allergen-specific effector cells anergic [395]. Moreover, at later stages active suppression may come into play resulting from secondary inactivation of DC function by anergized T cells [350]. Nevertheless, major problems with in vivo desensitization procedures relate to the refractoriness of effector T cells to regulatory cell functions, and the rapid replacement of anergized effector cells by naïve T cells from relatively protected peripheral lymphoid tissues provides a source of new effector cells upon sensitizing allergen contacts. The same conclusions can be drawn from attempts to achieve local desensitization. It was found that local desensitization by repeatedly applying allergen at the same skin site did not result from local skin hardening or LC inactivation, as local reactivity to an unrelated allergen at the site was unimpaired [329]. Persistence of cellular infiltrates, in the absence of erythematous reactivity, at a desensitized skin site could reflect local anergy, but also locally active regulatory cells. Upon discontinuation of allergen exposure, however, local unresponsiveness was rapidly (within 1 week) lost. Collectively, this data illustrate the problems encountered in attempting to eradicate established effector T-cell function, not only in ACD but also in autoimmune diseases [356, 360].

4 Summary and Conclusions

Extensive research has led to a better understanding of the mechanisms of ICD and ACD. The primary role of innate immune cells in coping with exogenous potential harmful threats is rapidly being uncovered. Also, the basic immunology of ACD is now well-defined, including T-cell migratory patterns, recognition of distinct allergens, interactions with other inflammatory cells to generate inflammation, and cytokine profiles. But new complexities have emerged. For instance, in contrast to earlier belief, many of the currently known T-cell subpopulations can act either or both as effector and regulatory cells, depending on the nature of the allergen, the route of entry, frequency of exposure, and many other still ill-defined factors. In particular, the poor understanding of regulatory mechanisms in ACD still hampers further therapeutic progress. So far, no methods of permanent desensitization have been devised.

Nevertheless, next to the established anti-inflammatory drugs, recently defined cellular interaction molecules and mediators provide promising targets for new generations of anti-inflammatory drugs, some of which have already entered clinical trials. Clearly, drugs found to be effective in preventing severe T-cell-mediated conditions, e.g., rejection of a vital organ graft, should be very safe before their use in ACD would seem appropriate. To date, prudence favors alternative measures to prevent ICD and ACD, be it through legal action to outlaw the use of certain materials or through avoiding personal contact with these materials. In the meantime, for difficult-to-avoid allergens, further studies on the potential value of tolerogenic treatments prior to possible sensitization seem warranted.

References

Elias PM (2005) Stratum corneum defensive functions: an integrated view. J Invest Dermatol 125:183–200
PubMed CAS Google Scholar
Elias PM (2007) The skin barrier as an innate immune element. Semin Immunopathol 29:3–14
Article PubMed Google Scholar
Bouwstra JA, Ponec M (2006) The skin barrier in healthy and diseased state. Biochim Biophys Acta 1758:2080–2095
Article PubMed CAS Google Scholar
Elias PM (1983) Epidermal lipids, barrier function, and desquamation. J Invest Dermatol (80 suppl):44s–49s
Article CAS Google Scholar
Elias PM (2004) The epidermal permeability barrier: from the early days at Harvard to emerging concepts. J Invest Dermatol 122(2):xxxvi–xxxix
Article PubMed CAS Google Scholar
Hadgraft J, Lane ME (2005) Skin permeation: the years of enlightenment. Int J Pharm 305:2–12
Article PubMed CAS Google Scholar
Herkenne C, Alberti I, Naik A, Kalia YN, Mathy FX, Preat V, Guy RH (2008) In vivo methods for the assessment of topical drug bioavailability. Pharm Res 25:87–103
Article PubMed CAS Google Scholar
Moser K, Kriwet K, Naik A, Kalia YN, Guy RH (2001) Passive skin penetration enhancement and its quantification in vitro. Eur J Pharm Biopharm 52:103–112
Article PubMed CAS Google Scholar
Schaefer H, Lademann J (2001) The role of follicular penetration. A differential view. Skin Pharmacol Appl Skin Physiol (14 suppl 1):23–27
PubMed Google Scholar
Basketter DA, Gerbrick F, Kimber I, Willis C (1999) Contact irritation mechanism. In: Toxicology of contact dermatitis. Wiley, Chichester
Google Scholar
Enk AH, Katz SI (1992) Early events in the induction phase of contact sensitivity. J Invest Dermatol 99:39S–41S
Article PubMed CAS Google Scholar
Le TK, Schalkwijk J, van de Kerkhof PC, van HU, van der V (1998) A histological and immunohistochemical study on chronic irritant contact dermatitis. Am J Contact Dermatitis 9:23–28
Article PubMed CAS Google Scholar
Welss T, Basketter DA, Schroder KR (2004) In vitro skin irritation: facts and future. State of the art review of mechanisms and models. Toxicol In Vitro 18:231–243
Article PubMed CAS Google Scholar
Levin CY, Maibach HI (2002) Irritant contact dermatitis: is there an immunologic component? Int Immunopharmacol 2:183–189
Article PubMed CAS Google Scholar
Smith HR, Basketter DA, McFadden JP (2002) Irritant dermatitis, irritancy and its role in allergic contact dermatitis. Clin Exp Dermatol 27:138–146
Article PubMed Google Scholar
Chew AL, Maibach HI (2003) Occupational issues of irritant contact dermatitis. Int Arch Occup Environ Health 76:339–346
Article PubMed CAS Google Scholar
English JS (2004) Current concepts of irritant contact dermatitis. Occup Environ Med 61(8):722–726, 674
Article PubMed CAS Google Scholar
Dickel H, Kuss O, Schmidt A, Kretz J, Diepgen TL (2002) Importance of irritant contact dermatitis in occupational skin disease. Am J Clin Dermatol 3:283–289
Article PubMed Google Scholar
McDonald JC, Beck MH, Chen Y, Cherry NM (2006) Incidence by occupation and industry of work-related skin diseases in the United Kingdom, 1996-2001. Occup Med (Lond) 56:398–405
Article CAS Google Scholar
Diepgen TL, Coenraads PJ (1999) The epidemiology of occupational contact dermatitis. Int Arch Occup Environ Health 72:496–506
Article PubMed CAS Google Scholar
Bauer A, Bartsch R, Stadeler M, Schneider W, Grieshaber R, Wollina U, Gebhardt M (1998) Development of occupational skin diseases during vocational training in baker and confectioner apprentices: a follow-up study. Contact Dermatitis 39:307–311
Article PubMed CAS Google Scholar
Berndt U, Hinnen U, Iliev D, Elsner P (1999) Is occupational irritant contact dermatitis predictable by cutaneous bioengineering methods? Results of the Swiss Metalworker‘ Eczema Study (PROMETES). Dermatology 198:351–354
Article PubMed CAS Google Scholar
John SM, Uter W, Schwanitz HJ (2000) Relevance of multiparametric skin bioengineering in a prospectively-followed cohort of junior hairdressers. Contact Dermatitis 43:161–168
Article PubMed CAS Google Scholar
Koopman DG, Kezic S, Verberk MM (2004) Skin reaction and recovery: a repeated sodium lauryl sulphate patch test vs. a 24-h patch test and tape stripping. Br J Dermatol 150:493–499
Article PubMed CAS Google Scholar
Schmid K, Broding HC, Uter W, Drexler H (2005) Transepidermal water loss and incidence of hand dermatitis in a prospectively followed cohort of apprentice nurses. Contact Dermatitis 52:247–253
Article PubMed Google Scholar
Smith HR, Armstrong DK, Holloway D, Whittam L, Basketter DA, McFadden JP (2002) Skin irritation thresholds in hairdressers: implications for the development of hand dermatitis. Br J Dermatol 146:849–852
Article PubMed CAS Google Scholar
Smith HR, Rowson M, Basketter DA, McFadden JP (2004) Intra-individual variation of irritant threshold and relationship to transepidermal water loss measurement of skin irritation. Contact Dermatitis 51:26–29
Article PubMed CAS Google Scholar
Coenraads PJ, Diepgen TL (1998) Risk for hand eczema in employees with past or present atopic dermatitis. Int Arch Occup Environ Health 71:7–13
Article PubMed CAS Google Scholar
Jakasa I, De Jongh CM, Verberk MM, Bos JD, Kezic S (2006) Percutaneous penetration of sodium lauryl sulphate is increased in uninvolved skin of patients with atopic dermatitis compared with control subjects. Br J Dermatol 155:104–109
Article PubMed CAS Google Scholar
De Jongh CM, John SM, Bruynzeel DP, Calkoen F, van Dijk FJ, Khrenova L, Rustemeyer T, Verberk MM, Kezic S (2008) Cytokine gene polymorphisms and susceptibility to chronic irritant contact dermatitis. Contact Dermatitis 58:269–277
Article PubMed Google Scholar
De Jongh CM, Khrenova L, Kezic S, Rustemeyer T, Verberk MM, John SM (2008) Polymorphisms in the interleukin-1 gene influence the stratum corneum interleukin-1 alpha concentration in uninvolved skin of patients with chronic irritant contact dermatitis. Contact Dermatitis 58:263–268
Article PubMed Google Scholar
De Jongh CM, Khrenova L, Verberk MM, Calkoen F, van Dijk FJ, Voss H, John SM, Kezic S (2008) Loss-of-function polymorphisms in the filaggrin gene are associated with an increased susceptibility to chronic irritant contact dermatitis: a case-control study. Br J Dermatol 159:621–627
Article PubMed CAS Google Scholar
Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El HB, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38:441–446
Article PubMed CAS Google Scholar
Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M, Gruber R, Janecke AR, Elias PM, van Steensel MA, Nagtzaam I, van GM, Steijlen PM, Munro CS, Bradley DG, Palmer CN, Smith FJ, McLean WH, Irvine AD (2007) Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 39:650–654
Article PubMed CAS Google Scholar
Demehri S, Morimoto M, Holtzman MJ, Kopan R (2009) Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol 7(5)
Google Scholar
Marenholz I, Nickel R, Ruschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, Gruber C, Lau S, Worm M, Keil T, Kurek M, Zaluga E, Wahn U, Lee YA (2006) Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol 118:866–871
Article PubMed CAS Google Scholar
Sandilands A, Sutherland C, Irvine AD, McLean WH (2009) Filaggrin in the frontline: role in skin barrier function and disease. J Cell Sci 122:1285–1294
Article PubMed CAS Google Scholar
Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O’Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38:337–342
Article PubMed CAS Google Scholar
Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S (2007) Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J Invest Dermatol 127:722–724
Article PubMed CAS Google Scholar
Hollegaard MV, Bidwell JL (2006) Cytokine gene polymorphism in human disease: on-line databases, Supplement 3. Genes Immun 7:269–276
Article PubMed CAS Google Scholar
Corsini E, Galli CL (2000) Epidermal cytokines in experimental contact dermatitis. Toxicology 142:203–211
Article PubMed CAS Google Scholar
Jacobs JJ, Lehe CL, Hasegawa H, Elliott GR, Das PK (2006) Skin irritants and contact sensitizers induce Langerhans cell migration and maturation at irritant concentration. Exp Dermatol 15:432–440
Article PubMed CAS Google Scholar
Williams IR, Kupper TS (1996) Immunity at the surface: homeostatic mechanisms of the skin immune system. Life Sci 58:1485–1507
Article PubMed CAS Google Scholar
Ouwehand K, Santegoets SJ, Bruynzeel DP, Scheper RJ, de Gruijl TD, Gibbs S (2008) CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis. Eur J Immunol 38:3050–3059
Article PubMed CAS Google Scholar
Spiekstra SW, Toebak MJ, Sampat-Sardjoepersad S, van Beek PJ, Boorsma DM, Stoof TJ, von Blomberg BM, Scheper RJ, Bruynzeel DP, Rustemeyer T, Gibbs S (2005) Induction of cytokine (interleukin-1alpha and tumor necrosis factor-alpha) and chemokine (CCL20, CCL27, and CXCL8) alarm signals after allergen and irritant exposure. Exp Dermatol 14:109–116
Article PubMed CAS Google Scholar
Effendy I, Loffler H, Maibach HI (2000) Epidermal cytokines in murine cutaneous irritant responses. J Appl Toxicol 20:335–341
Article PubMed CAS Google Scholar
Kupper TS (1990) Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations. J Clin Invest 86:1783–1789
Article PubMed CAS Google Scholar
McFadden JP, Basketter DA (2000) Contact allergy, irritancy and ‘danger’. Contact Dermatitis 42:123–127
Article PubMed CAS Google Scholar
Slodownik D, Lee A, Nixon R (2008) Irritant contact dermatitis: a review. Australas J Dermatol 49:1–9
Article PubMed Google Scholar
De Jongh CM, Verberk MM, Spiekstra SW, Gibbs S, Kezic S (2007) Cytokines at different stratum corneum levels in normal and sodium lauryl sulphate-irritated skin. Skin Res Technol 13:390–398
Article PubMed Google Scholar
Wood LC, Elias PM, Calhoun C, Tsai JC, Grunfeld C, Feingold KR (1996) Barrier disruption stimulates interleukin-1 alpha expression and release from a pre-formed pool in murine epidermis. J Invest Dermatol 106:397–403
Article PubMed CAS Google Scholar
De Jongh CM, Verberk MM, Withagen CE, Jacobs JJ, Rustemeyer T, Kezic S (2006) Stratum corneum cytokines and skin irritation response to sodium lauryl sulfate. Contact Dermatitis 54:325–333
Article PubMed Google Scholar
Piguet PF, Grau GE, Hauser C, Vassalli P (1991) Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions. J Exp Med 173:673–679
Article PubMed CAS Google Scholar
Bergstresser PR (1989) Sensitization and elicitation of inflammation in contact dermatitis. In: Norris DA (ed) Immune mechanisms in cutaneous disease. Dekker, New York, pp 219–246
Google Scholar
Turk JL (1975) Delayed hypersensitivity, 2nd edn. North-Holland, Amsterdam
Google Scholar
Gell PDH, Coombs RRA, Lachman R (1975) Clinical aspects of immunology, 3rd edn. Blackwell, London
Google Scholar
Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738
PubMed CAS Google Scholar
Saint-Mezard P, Krasteva M, Chavagnac C, Bosset S, Akiba H, Kehren J, Kanitakis J, Kaiserlian D, Nicolas JF, Berard F (2003) Afferent and efferent phases of allergic contact dermatitis (ACD) can be induced after a single skin contact with haptens: evidence using a mouse model of primary ACD. J Invest Dermatol 120:641–647
Article PubMed CAS Google Scholar
Bos JD, Meinardi MMHM (2000) The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 9:165–169
Article PubMed CAS Google Scholar
Roberts DW, Lepoittevin J-P (1998) Allergic Contact Dermatitis. In: Lepoittevin J-P, Basketter DA, Goossens A, Karlberg A-T (eds). Springer, Berlin Heidelberg New York, pp 81–1118
Chapter Google Scholar
Eliasson E, Kenna JG (1996) Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. Mol Pharmacol 50:573–582
PubMed CAS Google Scholar
Budinger L, Hertl M (2000) Immunologic mechanisms in hypersensitivity reactions to metal ions: an overview. Allergy 55:108–115
Article PubMed CAS Google Scholar
Gerberick F, Aleksic M, Basketter D, Casati S, Karlberg AT, Kern P, Kimber I, Lepoittevin JP, Natsch A, Ovigne JM, Rovida C, Sakaguchi H, Schultz T (2008) Chemical reactivity measurement and the predicitve identification of skin sensitisers. The report and recommendations of ECVAM Workshop 64. Altern Lab Anim 36(2):215–242
PubMed CAS Google Scholar
Divkovic M, Pease CK, Gerberick GF, Basketter DA (2005) Hapten-protein binding: from theory to practical application in the in vitro prediction of skin sensitization. Contact Dermatitis 53(4):189–200
Article PubMed CAS Google Scholar
Mutschler J, Giménez-Arnau E, Foertsch L, Gerberick GF, Lepoittevin JP (2009) Mechanistic assessment of peptide reactivity assay to predict skin allergens with Kathon CG isothiazolinones. Toxicol In Vitro 23(3):439–446
Article PubMed CAS Google Scholar
Gerberick F, Aleksic M, Basketter D, Casati S, Karlberg AT, Kern P, Kimber I, Lepoittevin JP, Natsch A, Ovigne JM, Rovida C, Sakaguchi H, Schultz T (2008) Chemical reactivity measurement and the predicitve identification of skin sensitisers. The report and recommendations of ECVAM Workshop 64. Altern Lab Anim 36(2):215–242
PubMed CAS Google Scholar
Blauvelt A, Hwang ST, Udey MC (2003) Allergic and immunologic diseases of the skin. J Allergy Clin Immunol 111:S560–S570
Article PubMed CAS Google Scholar
Kimber I, Dearman RJ (2002) Allergic contact dermatitis: the cellular effectors. Contact Dermatitis 46:1–5
Article PubMed Google Scholar
Liberato DJ, Byers VS, Ennick RG, Castagnoli N (1981) Region specific attack of nitrogen and sulfur nucleophiles on quinones from poison oak/ivy catechols (urushiols) and analogues as models for urushiol-protein conjugate formation. J Med Chem 24:28–33
Article PubMed CAS Google Scholar
Kalish RS, Wood JA, LaPorte A (1994) Processing of urushiol (poison ivy) hapten by both endogenous and exogenous pathways for presentation to T cells in vitro. J Clin Invest 93:2039–2047
Article PubMed CAS Google Scholar
Naisbitt DJ (2004) Drug hypersensitivity reactions in skin: understanding mechanisms and the development of diagnostic and predictive tests. Toxicology 194:179–196
Article PubMed CAS Google Scholar
Lepoittevin JP (2006) Metabolism versus chemical transformation or pro- versus prehaptens? Contact Dermatitis 54(2):73–74
Article PubMed Google Scholar
Epling GA, Wells JL, Yoon UC (1988) Photochemical transformations in salicylanilide photoallergy. Photochem Photobiol 47:167–171
Article PubMed CAS Google Scholar
Krasteva M, Nicolas JF, Chabeau G, Garrigue JL, Bour H, Thivolet J, Schmitt D (1993) Dissociation of allergenic and immunogenic functions in contact sensitivity to para-phenylenediamine. Int Arch Allergy Immunol 102:200–204
Article PubMed CAS Google Scholar
Merk HF, Abel J, Baron JM, Krutmann J (2004) Molecular pathways in dermatotoxicology. Toxicol Appl Pharmacol 195:267–277
Article PubMed CAS Google Scholar
Schnuch A, Westphal GA, Muller MM, Schulz TG, Geier J, Brasch J, Merk HF, Kawakubo Y, Richter G, Koch P, Fuchs T, Gutgesell T, Reich K, Gebhardt M, Becker D, Grabbe J, Szliska C, Aberer W, Hallier E (1998) Genotype and phenotype of N-acetyltransferase 2 (NAT2) polymorphism in patients with contact allergy. Contact Dermatitis 38:209–211
Article PubMed CAS Google Scholar
Karlberg AT, Bergström MA, Börje A, Luthman K, Nilsson JL (2008) Allergic contact dermatitis–formation, structural requirements, and reactivity of skin sensitizers. Chem Res Toxicol 21(1):53–69
Article PubMed Google Scholar
Patlewicz GY, Basketter DA, Pease CK, Wilson K, Wright ZM, Roberts DW, Bernard G, Arnau EG, Lepoittevin JP (2004) Further evaluation of quantitative structure–activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens. Contact Dermatitis 50:91–97
Article PubMed CAS Google Scholar
Langerhans P (1868) Über die Nerven der menschlichen Haut. Virchows Arch Pathol Anat 44:325–337
Article Google Scholar
Wilson NS, Villadangos JA (2004) Lymphoid organ dendritic cells: beyond the Langerhans cells paradigm. Immunol Cell Biol 82:91–98
Article PubMed Google Scholar
Hoath SB, Leahy DG (2003) The organization of human epidermis: functional epidermal units and phi proportionality. J Invest Dermatol 121:1440–1446
Article PubMed CAS Google Scholar
Breathnach SM (1988) The Langerhans cell. Centenary review. Br J Dermatol 119:463–469
Article PubMed CAS Google Scholar
Romani N, Holzmann S, Tripp CH, Koch F, Stoitzner P (2003) Langerhans cells – dendritic cells of the epidermis. APMIS 111:725–740
Article PubMed CAS Google Scholar
Kimber I, Dearman RJ (2003) What makes a chemical an allergen? Ann Allergy Asthma Immunol 90:28–31
Article PubMed CAS Google Scholar
Inaba K, Schuler G, Witmer MD, Valinsky J, Atassi B, Steinman RM (1986) Immunologic properties of purified epidermal Langerhans cells. Distinct requirements for stimulation of unprimed and sensitized T lymphocytes. J Exp Med 164:605–613
Article PubMed CAS Google Scholar
Kimber I, Cumberbatch M (1992) Dendritic cells and cutaneous immune responses to chemical allergens. Toxicol Appl Pharmacol 117:137–146
Article PubMed CAS Google Scholar
Seiffert K, Granstein RD (2006) Neuroendocrine regulation of skin dendritic cells. Ann N Y Acad Sci 1088(1):195–206
Article PubMed CAS Google Scholar
Dieu M-C, Vanbervliet B, Vicari A, Bridon J-M, Oldham E, Ait-Yahia S, Brière F, Zlotnik A, Lebecque S, Caux C (1998) Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med 188:373–386
Article PubMed CAS Google Scholar
Stingl G, Katz SI, Clement L, Green I, Shevach EM (1978) Immunological functions of Ia-bearing epidermal Langerhans cells. J Immunol 121:2005–2013
PubMed CAS Google Scholar
Czernielewski SM, Demarchez M (1987) Further evidence for the self-reproducing capacity of Langerhans cells in human skin. J Invest Dermatol 88:17–20
Article PubMed CAS Google Scholar
Streilein JW, Grammer SF (1989) In vitro evidence that Langerhans cells can adopt two functionally distinct forms capable of antigen presentation to T lymphocytes. J Immunol 143:3925–3933
PubMed CAS Google Scholar
Birbeck M (1961) An electron microscope study of basal melanocytes and high level clear cells (Langerhans cells) in vitiligo. J Invest Dermatol 37:51–56
Google Scholar
Braathen LR (1980) Studies on human epidermal Langerhans cells. III. Induction of T lymphocyte response to nickel sulphate in sensitized individuals. Br J Dermatol 103:517–526
Article PubMed CAS Google Scholar
Kimber I, Dearman RJ, Cumberbatch M, Huby RJ (1998) Langerhans cells and chemical allergy. Curr Opinion Immunol 10:614–619
Article CAS Google Scholar
Kimber I, Basketter DA, Gerberick GF, Dearman RJ (2002) Allergic contact dermatitis. Int Immunopharmacol 2:201–211
Article PubMed CAS Google Scholar
Park SH, Chiu YH, Jayawardena J, Roark J, Kavita U, Bendelac A (1998) Innate and adaptive functions of the CD1 pathway of antigen presentation. Semin Immunol 10:391–398
Article PubMed CAS Google Scholar
Weinlich G, Heine M, Stössel H, Zanella M, Stoitzner P, Ortner U, Smolle J, Koch F, Sepp NT, Schuler G, Romani N (1998) Entry into afferent lymphatics and maturation in situ of migrating murine cutaneous dendritic cells. J Invest Dermatol 110:441–448
Article PubMed CAS Google Scholar
Richters CD, Hoekstra MJ, van Baare J, Du Pont JS, Hoefsmit EC, Kamperdijk EW (1994) Isolation and characterization of migratory human skin dendritic cells. Clin Exp Immunol 98:330–336
Article PubMed CAS Google Scholar
Jakob T, Ring J, Udey MC (2001) Multistep navigation of Langerhans/dendritic cells in and out of the skin. J Allergy Clin Immunol 108:688–696
Article PubMed CAS Google Scholar
Ozawa H, Nakagawa S, Tagami H, Aiba S (1996) Interleukin-1b and granulocyte-macrophage colony stimulating factor mediate Langerhans cell maturation differently. J Invest Dermatol 106:441–445
Article PubMed CAS Google Scholar
Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, Choi YW (1997) TRANCE (Tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med 186:2075–2080
Article PubMed CAS Google Scholar
Aiba S, Tagami H (1999) Dendritic cell activation induced by various stimuli, eg exposure to microorganisms, their products, cytokines, and simple chemicals as well as adhesion to extracellular matrix. J Dermatol Sci 20:1–13
Article CAS Google Scholar
Inaba K, Schuler G, Steinman RM (1993) GM-CSF – a granulocyte/macrophage/dendritic cell stimulating factor. In: Van Furth R (ed) Hemopoietic growth factors and mononuclear phagocytes. Karger, Basel, pp 187–196
Google Scholar
Jakob T, Udey MC (1998) Regulation of E-Cadherin mediated adhesion in Langerhans cell-like dendritic cells by inflammatory mediators that mobilize Langerhans cells in vivo. J Immunol 160:4067–4073
PubMed CAS Google Scholar
Schwarzenberger K, Udey MC (1996) Contact allergens and epidermal proinflammatory cytokines modulate Langerhans cell E-cadherin expression in situ. J Invest Dermatol 106:553–558
Article PubMed CAS Google Scholar
Enk AH, Katz SI (1992) Early molecular events in the induction phase of contact sensitivity. Proc Natl Acad Sci U S A 89:1398–1402
Article PubMed CAS Google Scholar
Enk AH, Angeloni VL, Udey MC, Katz SI (1993) An essential role for Langerhans cell-derived IL-1b in the initiation of primary immune responses in skin. J Immunol 150:3698–3704
PubMed CAS Google Scholar
Iversen L, Johansen C (2008) Inflammasomes and inflammatory caspases in skin inflammation. Expert Rev Mol Diagn 8(6):697–705
Article PubMed CAS Google Scholar
Wang B, Esche C, Mamelak A, Freed I, Watanabe H, Sauder DN (2003) Cytokine knockouts in contact hypersensitivity research. Cytokine Growth Factor Rev 14:381–389
Article PubMed CAS Google Scholar
Tang A, Amagai M, Granger LG, Stanley JR, Udey MC (1993) Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature 361:82–85
Article PubMed CAS Google Scholar
Ma J, Wing J-H, Guo Y-J, Sy M-S, Bigby M (1994) In vivo treatment with anti-ICAM-1 and antiLFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes. Cell Immunol 158:389–399
Article PubMed CAS Google Scholar
Rambukhana A, Bos JD, Irik D, Menko WJ, Kapsenberg ML, Das PK (1995) In situ behaviour of human Langerhans cells in skin organ culture. Lab Invest 73:521–531
Google Scholar
Price AA, Cumberbatch M, Kimber I (1997) α6 integrins are required for Langerhans cell migration from the epidermis. J Exp Med 186:1725–1735
Article PubMed CAS Google Scholar
Weiss JM, Sleeman J, Renkl AC, Dittmar H, Termeer CC, Taxis S, Howells N, Hofmann M, Kohler G, Schöpf E, Ponta H, Herrlich P, Simon JC (1997) An essential role for CD44 variant isoforms in epidermal Langerhans cell and blood dendritic cell function. J Cell Biol 137:1137–1147
Article PubMed CAS Google Scholar
Brand CU, Hunger RE, Yawalkar N, Gerber HA, Schaffner T, Braathen LR (1999) Characterization of human skin-derived CD1a-positive lymph cells. Arch Dermatol Res 291:65–72
Article PubMed CAS Google Scholar
Kobayashi Y (1997) Langerhans cells produce type IV collagenase (MMP-9) following epicutaneous stimulation with haptens. Immunology 90:496–501
Article PubMed CAS Google Scholar
Randolph GJ (2001) Dendritic cell migration to lymph nodes: cytokines, chemokines, and lipid mediators. Semin Immunol 13:267–274
Article PubMed CAS Google Scholar
Sallusto F, Lanzavecchia A, Mackay CR (1998) Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today 19:568–574
Article PubMed CAS Google Scholar
Zlotnik A, Morales J, Hedrick JA (1999) Recent advances in chemokines and chemokine receptors. Crit Rev Immunol 19:1–47
Article PubMed CAS Google Scholar
Caux C, Ait-Yahia S, Chemin K, de Bouteiller O, Dieu-Nosjean MC, Homey B, Massacrier C, Vanbervliet B, Zlotnik A, Vicari A (2000) Dendritic cell biology and regulation of dendritic cell trafficking by chemokines. Springer Semin Immunopathol 22:345–369
Article PubMed CAS Google Scholar
Sallusto F, Palermo B, Lenig D, Miettinen M, Matikainen S, Julkunen I, Forster R, Burgstahler R, Lipp M, Lanzavecchia A (1999) Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur J Immunol 29:1617–1625
Article PubMed CAS Google Scholar
Saeki H, Moore AM, Brown MJ, Hwan ST (1999) Secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol 162:2472–2475
PubMed CAS Google Scholar
Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT (1998) A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naïve T lymphocytes. Proc Natl Acad Sci U S A 95:258–263
Article PubMed CAS Google Scholar
Kim CH, Broxmeyer HE (1999) Chemokines: signal lamps for trafficking of T and B cells for development and effector function. J Leuk Biol 65:6–15
CAS Google Scholar
Robbiani DF, Finch RA, Jager D, Muller WA, Sartorelli AC, Randolph GJ (2000) The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103:757–768
Article PubMed CAS Google Scholar
Honig SM, Fu S, Mao X, Yopp A, Gunn MD, Randolph GJ, Bromberg JS (2003) FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes. J Clin Invest 111:627–637
PubMed CAS Google Scholar
van de Ven R, Scheffer GL, Scheper RJ, de Gruijl TD (2009) The ABC of dendritic cell development and function. Trends Immunol 30(9):421–429
Article PubMed CAS Google Scholar
Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR, Qin S, Lanzavecchia A (1998) Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 28: 2760–2769
Article PubMed CAS Google Scholar
Cumberbatch M, Dearman RJ, Kimber I (1997) Interleukin 1-beta and the stimulation of Langerhans cell migration – comparisons with tumour necrosis factor alpha. Arch Dermatol Res 289:277–284
Article PubMed CAS Google Scholar
Heufler C, Koch F, Schuler G (1988) Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of epidermal Langerhans cells into potent immunostimulatory dendritic cells. J Exp Med 167:700–705
Article PubMed CAS Google Scholar
Steinman RM, Hoffman L, Pope M (1995) Maturation and migration of cutaneous dendritic cells. J Invest Dermatol 105:2S–7S
Article PubMed CAS Google Scholar
Furue M, Chang CH, Tamaki K (1996) Interleukin-1 but not tumor necrosis factor a synergistically upregulates the granulocyte-macrophage colony-stimulating factor-induced B7–1 expression of murine Langerhans cells. Br J Dermatol 135:194–198
Article PubMed CAS Google Scholar
Schuler G, Steinman RM (1985) Murine epidermal Langerhans cells mature into potent immune-stimulatory dendritic cells in vitro. J Exp Med 161:526–546
Article PubMed CAS Google Scholar
Haig DM, Hopkins J, Miller HRP (1999) Local immune responses in afferent and efferent lymph. Immunology 96:155–163
Article PubMed CAS Google Scholar
Altin JG, Sloan EK (1997) The role of CD45 and CD45-associated molecules in T cell activation. Immunol Cell Biol 75:430–445
Article PubMed CAS Google Scholar
Schon MP, Zollner TM, Boehncke WH (2003) The molecular basis of lymphocyte recruitment to the skin: clues for pathogenesis and selective therapies of inflammatory disorders. J Invest Dermatol 121:951–962
Article PubMed Google Scholar
Von Andrian UH, Mrini C (1998) In situ analysis of lymphocyte migration to lymph nodes. Cell Adh Comm 6:85–96
Article Google Scholar
Vestweber D, Blanks JE (1999) Mechanisms that regulate the function of the selectins and their ligands. Physiol Rev 79:181–213
PubMed CAS Google Scholar
Adema GJ, Hartgers F, Verstraten R, de Vries E, Marland G, Menon S, Foster J, Xu Y, Nooyen P, McClanahan T, Bacon KB, Figdor CG (1997) A dendritic-cell-derived C-C chemokine that preferentially attracts naïve T cells. Nature 387:713–717
Article PubMed CAS Google Scholar
Ngo VN, Tang LH, Cyster JG (1998) Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naïve T cells and activated B cells. J Exp Med 188:181–191
Article PubMed CAS Google Scholar
Nagira M, Imai T, Hieshima K, Kusuda J, Ridanpaa M, Takagi S, Nishimura M, Kakizaki M, Nomiyama H, Yoshie O (1997) Molecular cloning of a novel human CC chemokine secondary lymphoid-tissue chemokine that is a potent chemoattractant for lymphocytes and mapped to chromosome 9p13. J Biol Chem 272:19518–19524
Article PubMed CAS Google Scholar
Rustemeyer T, von Blomberg BME, de Ligter S, Frosch PJ, Scheper RJ (1999) Human T lymphocyte priming in vitro by dendritic cells. Clin Exp Immunol 117:209–216
Article PubMed CAS Google Scholar
Crivellato E, Vacca A, Ribatti D (2004) Setting the stage: an anatomist’s view of the immune system. Trends Immunol 25:210–217
Article PubMed CAS Google Scholar
Itano AA, Jenkins MK (2003) Antigen presentation to naive CD4 T cells in the lymph node. Nat Immunol 4:733–739
Article PubMed CAS Google Scholar
Griem P, Wulferink M, Sachs B, Gonzales JB, Gleichmann E (1998) Allergic and autoimmune reactions to xenobiotics: how do they arise? Immunol Today 19:133–141
PubMed CAS Google Scholar
Moulon C, Vollmer J, Weltzien H-U (1995) Characterization of processing requirements and metal crossreactivities in T cell clones from patients with allergic contact dermatitis to nickel. Eur J Immunol 25:3308–3315
Article PubMed CAS Google Scholar
Li QJ, Dinner AR, Qi S, Irvine DJ, Huppa JB, Davis MM, Chakraborty AK (2004) CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nat Immunol 5:791–799
Article PubMed CAS Google Scholar
Schoenberger SP, Toes REM, Vandervoort EIH, Offringa R, Melief CJM (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480–483
Article PubMed CAS Google Scholar
Gascoigne NR, Zal T (2004) Molecular interactions at the T cell-antigen-presenting cell interface. Curr Opin Immunol 16:114–119
Article PubMed CAS Google Scholar
Cantrell D (1996) T cell receptor signal transduction pathways. Annu Rev Immunol 14:259–274
Article PubMed CAS Google Scholar
Kuo CT, Leiden JM (1999) Transcriptional regulation of T lymphocyte development and function. Annu Rev Immunol 17:149–187
Article PubMed CAS Google Scholar
Davis SJ, van der Merwe PA (2003) TCR triggering: co-receptor-dependent or -independent? Trends Immunol 24:624–626
Article PubMed CAS Google Scholar
Trautmann A, Randriamampita C (2003) Initiation of TCR signalling revisited. Trends Immunol 24:425–428
Article PubMed CAS Google Scholar
Acuto O, Michel F (2003) CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3:939–951
Article PubMed CAS Google Scholar
Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ (2004) CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 22:307–328
Article PubMed CAS Google Scholar
Dong C, Nurieva RI, Prasad DV (2003) Immune regulation by novel costimulatory molecules. Immunol Res 28:39–48
Article PubMed Google Scholar
Viola A, Lanzavecchia A (1996) T cell activation determined by T cell receptor number and tunable thresholds. Science 273:104–106
Article PubMed CAS Google Scholar
Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252
Article PubMed CAS Google Scholar
Hommel M (2004) On the dynamics of T-cell activation in lymph nodes. Immunol Cell Biol 82:62–66
Article PubMed Google Scholar
Cella M, Sallusto F, Lanzavecchia A (1997) Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol 9:10–16
Article PubMed CAS Google Scholar
Crispín JC, Tsokos GC (2009) Human TCR-alpha beta+ CD4- CD8- T cells can derive from CD8+ T cells and display an inflammatory effector phenotype. J Immunol 183(7):4675–4678
Article PubMed CAS Google Scholar
Malek TR, Yu A, Zhu L, Matsutani T, Adeegbe D, Bayer AL (2008) IL-2 family of cytokines in T regulatory cell development and homeostasis. J Clin Immunol 28(6):635–639
Article PubMed CAS Google Scholar
Pei Z, Lin D, Song X, Li H, Yao H (2008) TLR4 signaling promotes the expression of VEGF and TGFbeta1 in human prostate epithelial PC3 cells induced by lipopolysaccharide. Cell Immunol 254(1):20–27
Article PubMed CAS Google Scholar
Lan RY, Selmi C, Gershwin ME (2008) The regulatory, inflammatory, and T cell programming roles of interleukin-2 (IL-2). J Autoimmun 31(1):7–12
Article PubMed CAS Google Scholar
Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8(5):337–348
Article PubMed CAS Google Scholar
Zhu J, Paul WE (2008) CD4 T cells: fates, functions, and faults. Blood 112(5):1557–1569
Article PubMed CAS Google Scholar
Sallusto F, Lanzavecchia A (2009) Human Th17 cells in infection and autoimmunity. Microbes Infect 11(5):620–624
Article PubMed CAS Google Scholar
Oboki K, Ohno T, Saito H, Nakae S (2008) Th17 and allergy. Allergol Int 57(2):121–134
Article PubMed CAS Google Scholar
Dabbagh K, Lewis DB (2003) Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis 16:199–204
Article PubMed Google Scholar
Faria AM, Weiner HL (2006) Oral tolerance and TGF-beta-producing cells. Inflamm Allergy Drug Targets 5(3):179–190
Article PubMed CAS Google Scholar
Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517. Review. PubMed PMID: 19132915
Article PubMed CAS Google Scholar
Louten J, Boniface K, de Waal Malefyt R (2009) Development and function of TH17 cells in health and disease. J Allergy Clin Immunol 123(5):1004–1011
Article PubMed CAS Google Scholar
Romagnani S (2006) Regulation of the T cell response. Clin Exp Allergy 36(11):1357–1366
Article PubMed CAS Google Scholar
Feuerer M, Hill JA, Mathis D, Benoist C (2009) Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol 10(7):689–695
Article PubMed CAS Google Scholar
Cavani A (2008) Immune regulatory mechanisms in allergic contact dermatitis and contact sensitization. Chem Immunol Allergy 94:93–100
Article PubMed CAS Google Scholar
Wu K, Bi Y, Sun K, Wang C (2007) IL-10-producing type 1 regulatory T cells and allergy. Cell Mol Immunol 4(4):269–275
PubMed Google Scholar
Shevach EM (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30(5):636–645
Article PubMed CAS Google Scholar
Basso AS, Cheroutre H, Mucida D (2009) More stories on Th17 cells. Cell Res 19(4):399–411
Article PubMed CAS Google Scholar
Zhou L, Littman DR (2009) Transcriptional regulatory networks in Th17 cell differentiation. Curr Opin Immunol 21(2):146–152. Review
Article PubMed CAS Google Scholar
Wilson CB, Rowell E, Sekimata M (2009) Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 9(2):91–105
Article PubMed CAS Google Scholar
Coulter EM, Jenkinson C, Farrell J, Lavergne SN, Pease C, White A, Aleksic M, Basketter D, Williams DP, King C, Pirmohamed M, Park BK, Naisbitt DJ (2010) Measurement of CD4+ and CD8+ T-lymphocyte cytokine secretion and gene expression changes in p-phenylenediamine allergic patients and tolerant individuals. J Invest Dermatol 130(1):161–174
Article PubMed CAS Google Scholar
Nakamura T, Lee RK, Nam SY, Podack ER, Bottomly K, Flavell RA (1997) Roles of IL-4 and IFN-g in stabilizing the T helper cell type-1 and 2 phenotype. J Immunol 158:2648–2653
PubMed CAS Google Scholar
Kang KF, Kubin M, Cooper KD, Lessin SR, Trinchieri G, Rook AH (1996) IL-12 synthesis by human Langerhans cells. J Immunol 156:1402–1407
PubMed CAS Google Scholar
Pulendran B (2004) Modulating TH1/TH2 responses with microbes, dendritic cells, and pathogen recognition receptors. Immunol Res 29:187–196
Article PubMed CAS Google Scholar
Kubo M, Ransom J, Webb D, Hashimoto Y, Tada T, Nakayama T (1997) T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6. EMBO J 16(13):4007–4020
Article PubMed CAS Google Scholar
Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F (1997) Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med 185:825–831
Article PubMed CAS Google Scholar
Zhou L, Chong MM, Littman DR (2009) Plasticity of CD4+ T cell lineage differentiation. Immunity 30(5):646–655. Review. PubMed PMID: 19464987
Article PubMed CAS Google Scholar
Nakamura T, Kamogawa Y, Bottomly K, Flavell RA (1997) Polarization of IL-4- and IFN-gamma-producing CD4(⁺) T cells following activation of naive CD4(⁺) T cells. J Immunol 158:1085–1094
PubMed CAS Google Scholar
Orange JS, Biron CA (1996) An absolute and restricted requirement for IL-12 in natural killer cell IFN-g production and antiviral defense. J Immunol 156:1138–1142
PubMed CAS Google Scholar
Groux H, Sornasse T, Cottrez F, de Vries JE, Coffman RL, Roncarolo MG, Yssel H (1997) Induction of human T helper cell type-1 differentiation results in loss of IFN-g receptor b-chain expression. J Immunol 158:5627–5631
PubMed CAS Google Scholar
Gajewski TF, Fitch FW (1988) Antiproliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol 140:4245–4252
PubMed CAS Google Scholar
Takatori H, Kanno Y, Chen Z, O’Shea JJ (2008) New complexities in helper T cell fate determination and the implications for autoimmune diseases. Mod Rheumatol 18(6):533–541
Article PubMed CAS Google Scholar
Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G (1996) Ligation of CD40 on dendritic cells triggers production of high levels of interleukin 12 and enhances T cell stimulatory capacity. J Exp Med 184:747–752
Article PubMed CAS Google Scholar
Ohshima Y, Tanaka Y, Tozawa H, Takahashi Y, Maliszewski C, Delespesse C (1997) Expression and function of OX40 ligand on human dendritic cells. J Immunol 159:3838–3848
PubMed CAS Google Scholar
Croft M (2009) The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 9(4):271–278
Article PubMed CAS Google Scholar
Iliev ID, Mileti E, Matteoli G, Chieppa M, Rescigno M (2009) Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol 2(4):340–350
Article PubMed CAS Google Scholar
Izcue A, Coombes JL, Powrie F (2009) Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27:313–338
Article PubMed CAS Google Scholar
Hoyer KK, Dooms H, Barron L, Abbas AK (2008) Interleukin-2 in the development and control of inflammatory disease. Immunol Rev 226:19–28
Article PubMed CAS Google Scholar
Létourneau S, Krieg C, Pantaleo G, Boyman O (2009) IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets. J Allergy Clin Immunol 123(4):758–762
Article PubMed CAS Google Scholar
Oukka M (2008) Th17 cells in immunity and autoimmunity. Ann Rheum Dis 67(suppl 3):iii26–iii29
Article PubMed CAS Google Scholar
Larsen JM, Bonefeld CM, Poulsen SS, Geisler C, Skov L (2009) IL-23 and T(H)17-mediated inflammation in human allergic contact dermatitis. J Allergy Clin Immunol 123(2):486–492
Article PubMed CAS Google Scholar
Edele F, Esser PR, Lass C, Laszczyk MN, Oswald E, Strüh CM, Rensing-Ehl A, Martin SF (2007) Innate and adaptive immune responses in allergic contact dermatitis and autoimmune skin diseases. Inflamm Allergy Drug Targets 6(4):236–244
Article PubMed CAS Google Scholar
Fyhrquist-Vanni N, Alenius H, Lauerma A (2007) Contact dermatitis. Dermatol Clin 25(4):613–623
Article PubMed CAS Google Scholar
Werfel T, Hentschel M, Kapp A, Renz H (1997) Dichotomy of blood- and skin-derived IL-4-producing allergen-specific T cells and restricted V beta repertoire in nickel-mediated contact dermatitis. J Immunol 158:2500–2505
PubMed CAS Google Scholar
Probst P, Küntzlin D, Fleischer B (1995) T_H2-type infiltrating T cells in nickel-induced contact dermatitis. Cell Immunol 165:134–140
Article PubMed CAS Google Scholar
Grewe M, Bruijnzeel-Koomen CA, Schöpf E, Thepen T, Langeveld-Wildschut AG, Ruzicka T, Krutmann J (1998) A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis. Immunol Today 19(8):359–361
Article PubMed CAS Google Scholar
Perez VL, Lederer JA, Lichtman AH, Abbas AK (1995) Stability of Th1 and Th2 populations. Int Immunol 7:869–875
Article PubMed CAS Google Scholar
Ulrich P, Grenet O, Bluemel J, Vohr HW, Wiemann C, Grundler O, Suter W (2001) Cytokine expression profiles during murine contact allergy: T helper 2 cytokines are expressed irrespective of the type of contact allergen. Arch Toxicol 75(8):470–479
Article PubMed CAS Google Scholar
van Beelen AJ, Teunissen MB, Kapsenberg ML, de Jong EC (2007) Interleukin-17 in inflammatory skin disorders. Curr Opin Allergy Clin Immunol 7(5):374–381
Article PubMed Google Scholar
Mucida D, Salek-Ardakani S (2009) Regulation of TH17 cells in the mucosal surfaces. J Allergy Clin Immunol 123(5):997–1003
Article PubMed CAS Google Scholar
Constant SL, Bottomly K (1997) Induction of Th1 and Th2 CD4⁺ T cell responses: the alternate approaches. Annu Rev Immunol 15:297–322
Article PubMed CAS Google Scholar
Constant SL, Pfeiffer C, Woodard A, Pasqualini T, Bottomly K (1995) Extent of T cell receptor ligation can determine the functional differentiation of naïve CD4⁺ T cells. J Exp Med 5:1591–1596
Article Google Scholar
Bretscher PA, Ogunremi O, Menon JN (1997) Distinct immunological states in murine cutaneous leishmaniasis by immunizing with different amounts of antigen: the generation of beneficial, potentially harmful, harmful and potentially extremely harmful states. Behring Inst Mitt 98: 153–159
PubMed CAS Google Scholar
Toebak MJ, Moed H, von Blomberg MB, Bruynzeel DP, Gibbs S, Scheper RJ, Rustemeyer T (2006) Intrinsic characteristics of contact and respiratory allergens influence production of polarizing cytokines by dendritic cells. Contact Dermatitis 55(4):238–245
Article PubMed CAS Google Scholar
Watanabe H, Gehrke S, Contassot E, Roques S, Tschopp J, Friedmann PS, French LE, Gaide O (2008) Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization. J Immunol 180(9):5826–5832
PubMed CAS Google Scholar
Kanerva L, Hyry H, Jolanki R, Hytonen M, Estlander T (1997) Delayed and immediate allergy caused by methylhexahydrophthalic anhydride. Contact Dermatitis 36:34–38
Article PubMed CAS Google Scholar
Geenen V, Brilot F (2003) Role of the thymus in the development of tolerance and autoimmunity towards the neuroendocrine system. Ann N Y Acad Sci 992:186–195
Article PubMed CAS Google Scholar
Luger TA, Lotti T (1998) Neuropeptides: role in inflammatory skin diseases. J Eur Acad Derm Venereol 10:207–211
Article CAS Google Scholar
Luger TA (2002) Neuromediators – a crucial component of the skin immune system. J Dermatol Sci 30(2):87–93
Article PubMed CAS Google Scholar
Lord GM, Matarese G, Howard LK, Baker RJ, Bloom SR, Lechler RI (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394:897–901
Article PubMed CAS Google Scholar
Morfin R, Lafaye P, Cotillon AC, Nato F, Chmielewski V, Pompon D (2000) 7 alpha-hydroxy-dehydroepiandrosterone and immune response. Ann N Y Acad Sci 917: 971–982
Article PubMed CAS Google Scholar
Cutolo M, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A (2002) Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis. Ann N Y Acad Sci 966:131–142
Article PubMed CAS Google Scholar
Kidd P (2003) Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 8:223–246
PubMed Google Scholar
Piccinni MP, Giudizi MG, Biagiotti R, Beloni L, Giannarini L, Sampognaro S, Parronchi P, Manetti R, Annuziato F, Livi C, Romagnani S, Maggi E (1995) Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 155:128–133
PubMed CAS Google Scholar
Vieira PL, Kalinski P, Wierenga EA, Kapsenberg ML, Dejong EC (1998) Glucocorticoids inhibit bioactive IL-12P70 production by in vitro-generated human dendritic cells without affecting their T cell stimulatory potential. J Immunol 161:5245–5251
PubMed CAS Google Scholar
Calder PC, Bevan SJ, Newsholme EA (1992) The inhibition of T-lymphocyte proliferation by fatty acids is via an eicosanoid-independent mechanism. Immunology 75: 108–115
PubMed CAS Google Scholar
Uotila P (1996) The role of cyclic AMP and oxygen intermediates in the inhibition of cellular immunity in cancer. Cancer Immunol Immunother 43:1–9
PubMed CAS Google Scholar
Demeure CE, Yang LP, Desjardins C, Raynauld P, Delespesse G (1997) Prostaglandin E-2 primes naïve T cells for the production of anti-inflammatory cytokines. Eur J Immunol 27:3526–3531
Article PubMed CAS Google Scholar
Abe N, Katamura K, Shintaku N, Fukui T, Kiyomasu T, Lio J, Ueno H, Tai G, Mayumi M, Furusho K (1997) Prostaglandin E2 and IL-4 provide naïve CD4⁺ T cells with distinct inhibitory signals for the priming of IFN-gamma production. Cell Immunol 181:86–92
Article PubMed CAS Google Scholar
Kalinski P, Hilkens CMU, Snijders A, Snijdewint FGM, Kapsenberg ML (1997) IL-12 deficient dendritic cells, generated in the presence of prostaglandin E₂, promote type-2 cytokine production in maturing human naïve T helper cells. J Immunol 159:28–35
PubMed CAS Google Scholar
Edele F, Molenaar R, Gütle D, Dudda JC, Jakob T, Homey B, Mebius R, Hornef M, Martin SF (2008) Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns. J Immunol 181(6):3745–3749
PubMed CAS Google Scholar
Woodland DL, Kohlmeier JE (2009) Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol 9(3):153–156
Article PubMed CAS Google Scholar
Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS (1997) Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 389:978–981
Article PubMed CAS Google Scholar
Sigmundsdottir H, Butcher EC (2008) Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat Immunol 9(9):981–987
Article PubMed CAS Google Scholar
Miles A, Liaskou E, Eksteen B, Lalor PF, Adams DH (2008) CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow. Am J Physiol Gastrointest Liver Physiol 294(5):G1257–G1267
Article PubMed CAS Google Scholar
Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22:745–763
Article PubMed CAS Google Scholar
Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401(6754):708–712
Article PubMed CAS Google Scholar
Austrup F, Vestweber D, Borges E, Lohning M, Brauer R, Herz U, Renz H, Hallmann R, Scheffold A, Radbruch A, Hamann A (1997) P- and E selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature 385:81–83
Article PubMed CAS Google Scholar
Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10(8):857–863
Article PubMed CAS Google Scholar
Borges E, Tietz W, Steegmaier M, Moll T, Hallmann R, Hamann A, Vestweber D (1997) P-selectin glycoprotein ligand-1 (PSGL-1) on T helper 1 but not on T helper 2 cells binds to P-selectin and supports migration into inflamed skin. J Exp Med 185:573–578
Article PubMed CAS Google Scholar
Ward SG, Marelli-Berg FM (2009) Mechanisms of chemokine and antigen-dependent T-lymphocyte navigation. Biochem J 418(1):13–27
Article PubMed CAS Google Scholar
Hudak S, Hagen M, Liu Y, Catron D, Oldham E, McEvoy LM, Bowman EP (2002) Immune surveillance and effector functions of CCR10(+) skin homing T cells. J Immunol 169(3):1189–1196
PubMed CAS Google Scholar
Kitagaki H, Ono N, Hayakawa K, Kitazawa T, Watanabe K, Shiohara T (1997) Repeated elicitation of contact hypersensitivity induces a shift in cutaneous cytokine milieu from a T helper cell type 1 to a T helper cell type 2 profile. J Immunol 159(5):2484–2491
PubMed CAS Google Scholar
Cavani A, Mei D, Guerra E, Corinti S, Giani M, Pirrotta L, Puddu P, Girolomoni G (1998) Patients with allergic contact dermatitis to nickel and nonallergic individuals display different nickel-specific T cell responses. Evidence for the presence of effector CD8⁺ and regulatory CD4⁺ T cells. J Invest Dermatol 111:621–628
Article PubMed CAS Google Scholar
Lindemann M, Rietschel F, Zabel M, Grosse-Wilde H (2008) Detection of chromium allergy by cellular in vitro methods. Clin Exp Allergy 38(9):1468–1475
Article PubMed CAS Google Scholar
Kalish RS (1990) The use of human T-lymphocyte clones to study T-cell function in allergic contact dermatitis to urushiol. J Invest Dermatol 94(6 suppl):108S–111S
Article PubMed CAS Google Scholar
von Blomberg BME, Bruynzeel DP, Scheper RJ (1991) Advances in mechanisms ofallergic contact dermatitis: in vitro and in vivo research. In: Marzulli FN, Maibach HI (eds) Dermatotoxicology, 4th edn. Hemisphere Publishing Corporation, New York, pp 255–362
Google Scholar
Bordignon V, Palamara F, Cordiali-Fei P, Vento A, Aiello A, Picardo M, Ensoli F, Cristaudo A (2008) Nickel, palladium and rhodium induced IFN-gamma and IL-10 production as assessed by in vitro ELISpot-analysis in contact dermatitis patients. BMC Immunol 9:19
Article PubMed CAS Google Scholar
Minang JT, Troye-Blomberg M, Lundeberg L, Ahlborg N (2005) Nickel elicits concomitant and correlated in vitro production of Th1-, Th2-type and regulatory cytokines in subjects with contact allergy to nickel. Scand J Immunol 62(3):289–296
Article PubMed CAS Google Scholar
Moed H, von Blomberg BM, Bruynzeel DP, Scheper RJ, Gibbs S, Rustemeyer T (2005) Regulation of nickel-induced T-cell responsiveness by CD4+CD25+ cells in contact allergic patients and healthy individuals. Contact Dermatitis 53(2):71–74
Article PubMed CAS Google Scholar
Rustemeyer T, von Blomberg BME, van Hoogstraten IMW, Bruynzeel DP, Scheper RJ (2004) Analysis of effector and regulatory immune-reactivity to nickel. Clin Exp Allergy 34(9):1458–1466
Article PubMed CAS Google Scholar
Spiewak R, Moed H, von Blomberg BM, Bruynzeel DP, Scheper RJ, Gibbs S, Rustemeyer T (2007) Allergic contact dermatitis to nickel: modified in vitro test protocols for better detection of allergen-specific response. Contact Dermatitis 56(2):63–69
Article PubMed CAS Google Scholar
Minang JT, Areström I, Ahlborg N (2008) ELISpot displays a better detection over ELISA of T helper (Th) 2-type cytokine-production by ex vivo-stimulated antigen-specific T cells from human peripheral blood. Immunol Invest 37(4):279–291
Article PubMed CAS Google Scholar
Minang JT, Areström I, Troye-Blomberg M, Lundeberg L, Ahlborg N (2006) Nickel, cobalt, chromium, palladium and gold induce a mixed Th1- and Th2-type cytokine response in vitro in subjects with contact allergy to the respective metals. Clin Exp Immunol 146(3):417–426
Article PubMed CAS Google Scholar
Wahlkvist H, Masjedi K, Gruvberger B, Zuber B, Karlberg AT, Bruze M, Ahlborg N (2008) The lipophilic hapten parthenolide induces interferon-gamma and interleukin-13 production by peripheral blood-derived CD8+ T cells from contact allergic subjects in vitro. Br J Dermatol 158(1):70–77
PubMed CAS Google Scholar
Skazik C, Grannemann S, Wilbers L, Merk HF, Coenraads PJ, Breuer S, Blömeke B (2008) Reactivity of in vitro activated human T lymphocytes to p-phenylenediamine and related substances. Contact Dermatitis 59(4):203–211
Article PubMed CAS Google Scholar
Boyman O, Létourneau S, Krieg C, Sprent J (2009) Homeostatic proliferation and survival of naïve and memory T cells. Eur J Immunol 39(8):2088–2094
Article PubMed CAS Google Scholar
Rustemeyer T, von Blomberg BME, de Ligter S, Frosch PJ, Scheper RJ (1999) Human T lymphocyte priming in vitro by haptenated autologous dendritic cells. Clin Exp Immunol 117:209–216
Article PubMed CAS Google Scholar
Goebeler M, Meinardus-Hager G, Roth J, Goerdt S, Sorg C (1993) Nickel chloride and cobalt chloride, two common contact sensitizers, directly induce expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule (ELAM-1) by endothelial cells. J Invest Dermatol 100:759–765
Article PubMed CAS Google Scholar
Goebeler M, Roth J, Brocker EB, Sorg C, Schulze-Osthoff K (1995) Activation of nuclear factor-kappa B and gene expression in human endothelial cells by the common haptens nickel and cobalt. J Immunol 155:2459–2467
PubMed CAS Google Scholar
Walsh LJ, Lavker RM, Murphy GF (1990) Determinants of immune cell trafficking in the skin. Lab Invest 63: 592–600
PubMed CAS Google Scholar
Waldorf HA, Walsh LJ, Schechter NM, Murphy GF (1991) Early molecular events in evolving cutaneous delayed hypersensitivity in humans. Am J Pathol 138:477–486
PubMed CAS Google Scholar
Meller S, Lauerma AI, Kopp FM, Winterberg F, Anthoni M, Müller A, Gombert M, Haahtela A, Alenius H, Rieker J, Dieu-Nosjean MC, Kubitza RC, Gleichmann E, Ruzicka T, Zlotnik A, Homey B (2007) Chemokine responses distinguish chemical-induced allergic from irritant skin inflammation: memory T cells make the difference. J Allergy Clin Immunol 119(6):1470–1480
Article PubMed CAS Google Scholar
Bangert C, Friedl J, Stary G, Stingl G, Kopp T (2003) Immunopathologic features of allergic contact dermatitis in humans: participation of plasmacytoid dendritic cells in the pathogenesis of the disease? J Invest Dermatol 121: 1409–1418
Article PubMed CAS Google Scholar
Houck G, Saeed S, Stevens GL, Morgan MB (2004) Eczema and the spongiotic dermatoses: a histologic and pathogenic update. Semin Cutan Med Surg 23:39–45
Article PubMed Google Scholar
Silberberg-Sinakin I, Thorbecke GJ, Baer RL, Rosenthal SA, Berezowsky V (1976) Antigen-bearing Langerhans cells in skin, dermal lymphatics, and in lymph nodes. Cell Immunol 25:137–151
Article PubMed CAS Google Scholar
Hill S, Edwards AJ, Kimber I, Knight SC (1990) Systemic migration of dendritic cells during contact sensitization. Immunology 71:277–281
PubMed CAS Google Scholar
Toebak MJ, Gibbs S, Bruynzeel DP, Scheper RJ, Rustemeyer T (2009) Dendritic cells: biology of the skin. Contact Dermatitis 60(1):2–20
Article PubMed CAS Google Scholar
Sterry W, Künne N, Weber-Matthiesen K, Brasch J, Mielke V (1991) Cell trafficking in positive and negative patch test reactions: demonstration of a stereotypic migration pathway. J Invest Dermatol 96:459–462
Article PubMed CAS Google Scholar
Herzog WR, Meade R, Pettinicchi A, Ptak W, Askenase PW (1989) Nude mice produce a T cell-derived antigen-binding factor that mediates the early component of delayed-type hypersensitivity. J Immunol 142:1803–1812
PubMed CAS Google Scholar
Willis CM, Young E, Brandon DR, Wilkinson JD (1986) Immunopathological and ultrastructural findings in human allergic and irritant contact dermatitis. Br J Dermatol 115:305–316
Article PubMed CAS Google Scholar
Brasch J, Burgard J, Sterry W (1992) Common pathways in allergic and irritant contact dermatitis. J Invest Dermatol 98:166–170
Article PubMed CAS Google Scholar
Hoefakker S, Caubo M, van ‘t Herve EHM, Roggeveen MJ, Boersma WJA, van Joost TH, Notten WRF, Claassen E (1995) In vivo cytokine profiles in allergic and irritant contact dermatitis. Contact Dermatitis 33:258–266
Article PubMed CAS Google Scholar
Flier J, Boorsma DM, Bruynzeel DP, van Beek PJ, Stoof TJ, Scheper RJ, Willemze R, Tensen CP (1999) The CXCR3 activating chemokines IP-10, MIG and IP-9 are expressed in allergic but not in irritant patch test reactions. J Invest Dermatol 113:574–578
Article PubMed CAS Google Scholar
Kondo S, Sauder DN (1995) Epidermal cytokines in allergic contact dermatitis. J Am Acad Dermatol 33:786–800
Article PubMed CAS Google Scholar
Wardorf HA, Walsh LJ, Schechter NM (1991) Early cellular events in evolving cutaneous delayed hypersensitivity in humans. Am J Pathol 138:477–486
Google Scholar
Pober JS, Bevilacqua MP, Mendrick DL, Lapierre LA, Fiers W, Gimbrone MA Jr (1986) Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 136:1680–1687
PubMed CAS Google Scholar
Shimizu Y, Newman W, Gopal TV, Horgan KJ, Graber N, Beall LD, van Seventer GA, Shaw S (1991) Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions. J Cell Biol 113:1203–1212
Article PubMed CAS Google Scholar
Ross R, Gilitzer C, Kleinz R, Schwing J, Kleinert H, Forstermann U, Reske-Kunz AB (1998) Involvement of NO in contact hypersensitivity. Int Immunol 10:61–69
Article PubMed CAS Google Scholar
Rowe A, Farrell AM, Bunker CB (1997) Constitutive endothelial and inducible nitric oxide synthase in inflammatory dermatoses. Br J Dermatol 136:18–23
Article PubMed CAS Google Scholar
Szepietowski JC, McKenzie RC, Keohane SG, Walker C, Aldridge RD, Hunter JA (1997) Leukaemia inhibitory factor: induction in the early phase of allergic contact dermatitis. Contact Dermatitis 36:21–25
Article PubMed CAS Google Scholar
Yu X, Barnhill RL, Graves DT (1994) Expression of monocyte chemoattractant protein-1 in delayed type hypersensitivity reactions in the skin. Lab Invest 71:226–235
PubMed CAS Google Scholar
Buchanan KL, Murphy JW (1997) Kinetics of cellular infiltration and cytokine production during the efferent phase of a delayed-type hypersensitivity reaction. Immunology 90:189–197
Article PubMed CAS Google Scholar
Kish DD, Li X, Fairchild RL (2009) CD8 T cells producing IL-17 and IFN-gamma initiate the innate immune response required for responses to antigen skin challenge. J Immunol 182(10):5949–5959
Article PubMed CAS Google Scholar
Toebak MJ, Pohlmann PR, Sampat-Sardjoepersad SC, von Blomberg BM, Bruynzeel DP, Scheper RJ, Rustemeyer T, Gibbs S (2006) CXCL8 secretion by dendritic cells predicts contact allergens from irritants. Toxicol In Vitro 20(1):117–124
Article PubMed CAS Google Scholar
Askenase PW, Kawikova I, Paliwal V, Akahira-Azuma M, Gerard C, Hugli T, Tsuji R (1999) A new paradigm of T cell allergy: requirement for the B-1 cell subset. Int Arch Allergy Immunol 118(2–4):145–149
Article PubMed CAS Google Scholar
Van Loweren H, Meade R, Askenase PW (1983) An early component of delayed type hypersensitivity mediated by T cells and mast cells. J Exp Med 157:1604–1617
Article Google Scholar
Foreman KE, Vaporciyan AA, Bonish BK, Jones ML, Johnson KJ, Glovsky MM, Eddy SM, Ward PA (1994) C5a-induced expression of P-selectin in endothelial cells. J Clin Invest 94:1147–1155
Article PubMed CAS Google Scholar
Groves RW, Allen MH, Ross EL, Barker JN, MacDonald DM (1995) Tumor necrosis factor alpha is pro-inflammatory in normal human skin and modulates cutaneous adhesion molecule expression. Br J Dermatol 132:345–352
Article PubMed CAS Google Scholar
Tsuji RF, Geba GP, Wang Y, Kawamoto K, Matis LA, Askenase PW (1997) Required early complement activation in contact sensitivity with generation of local C5-dependent chemotactic activity, and late T cell interferon g: a possible initiating role of B cells. J Exp Med 186:1015–1026
Article PubMed CAS Google Scholar
Nataf S, Davoust N, Ames RS, Barnum SR (1999) Human T cells express the C5a receptor and are chemoattracted to C5a. J Immunol 162:4018–4023
PubMed CAS Google Scholar
Wilkinson SM, Mattey DL, Beck MH (1994) IgG antibodies and early intradermal reactions to hydrocortisone in patients with cutaneous delayed-type hypersensitivity to hydrocortisone. Br J Dermatol 131:495–498
Article PubMed CAS Google Scholar
Shirakawa T, Kusaka Y, Morimoto K (1992) Specific IgE antibodies to nickel in workers with known reactivity to cobalt. Clin Exp Allergy 22:213–218
Article PubMed CAS Google Scholar
Redegeld FA, Nijkamp FP (2003) Immunoglobulin free light chains and mast cells: pivotal role in T-cell-mediated immune reactions? Trends Immunol 24:181–185
Article PubMed CAS Google Scholar
O’Leary JG, Goodarzi M, Drayton DL, von Andrian UH (2006) T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat Immunol 7(5): 507–516
Article PubMed CAS Google Scholar
Nieuwenhuis P, Ford WL (1976) Comparative migration of B- and T-Lymphocytes in the rat spleen and lymph nodes. Cell Immunol 23(2):254–267
Article PubMed CAS Google Scholar
Gober MD, Fishelevich R, Zhao Y, Unutmaz D, Gaspari AA (2008) Human natural killer T cells infiltrate into the skin at elicitation sites of allergic contact dermatitis. J Invest Dermatol 128(6):1460–1469
Article PubMed CAS Google Scholar
Dieli F, Ptak W, Sireci G, Romano GC, Potestio M, Salerno A, Asherson GL (1998) Cross-talk between V-beta-8(⁺) and gamma-delta(⁺) T lymphocytes in contact sensitivity. Immunology 93:469–477
Article PubMed CAS Google Scholar
Milon G, Marchal G, Seman M, Truffa-Bachi P (1981) A delayed-type hypersensitivity reaction initiated by a single T lymphocyte. Agents Actions 11:612–614
Article PubMed CAS Google Scholar
Marchal G, Seman M, Milon G, Truffa-Bachi P, Zilberfarb V (1982) Local adoptive transfer of skin delayed-type hypersensitivity initiated by a single T lymphocyte. J Immunol 129:954–958
PubMed CAS Google Scholar
Scheper RJ, van Dinther-Janssen AC, Polak L (1985) Specific accumulation of hapten-reactive T cells in contact sensitivity reaction sites. J Immunol 134:1333–1336
PubMed CAS Google Scholar
Macatonia SE, Knight SC, Edwards AJ, Griffiths S, Fryer P (1987) Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. Functional and morphological studies. J Exp Med 166:1654–1667
Article PubMed CAS Google Scholar
Lappin MB, Kimber I, Norval M (1996) The role of dendritic cells in cutaneous immunity. Arch Dermatol Res 288:109–121
Article PubMed CAS Google Scholar
Moed H, Boorsma DM, Stoof TJ, von Blomberg BM, Bruynzeel DP, Scheper RJ, Gibbs S, Rustemeyer T (2004) Nickel-responding T cells are CD4+ CLA+ CD45RO+ and express chemokine receptors CXCR3, CCR4 and CCR10. Br J Dermatol 151:32–41
Article PubMed CAS Google Scholar
Vocanson M, Hennino A, Cluzel-Tailhardat M, Saint-Mezard P, Benetiere J, Chavagnac C, Berard F, Kaiserlian D, Nicolas JF (2006) CD8+ T cells are effector cells of contact dermatitis to common skin allergens in mice. J Invest Dermatol 126(4):815–820
Article PubMed CAS Google Scholar
Abe M, Kondo T, Xu H, Fairchild RL (1996) Interferon-gamma inducible protein (IP-10) expression is mediated by CD8⁺ T cells and is regulated by CD4+ T cells during the elicitation of contact hypersensitivity. J Invest Dermatol 107:360–366
Article PubMed CAS Google Scholar
Saulnier M, Huang S, Aguet M, Ryffel B (1995) Role of interferon-gamma in contact hypersensitivity assessed in interferon-gamma receptor-deficient mice. Toxicology 102(3):301–312
Article PubMed CAS Google Scholar
Rowe A, Bunker CB (1998) Interleukin-4 and the interleukin-4 receptor in allergic contact dermatitis. Contact Dermatitis 38:36–39
Article PubMed CAS Google Scholar
Asherson GL, Dieli F, Sireci G, Salerno A (1996) Role of IL-4 in delayed type hypersensitivity. Clin Exp Immunol 103:1–4
Article PubMed CAS Google Scholar
Asada H, Linton J, Katz SI (1997) Cytokine gene expression during the elicitation phase of contact sensitivity – regulation by endogenous IL-4. J Invest Dermatol 108:406–411
Article PubMed CAS Google Scholar
Kitagaki H, Fujisawa S, Watanabe K, Hayakawa K, Shiohara T (1995) Immediate-type hypersensitivity response followed by late reaction is induced by repeated epicutaneous application of contact sensitizing agents in mice. J Invest Dermatol 105:749–755
Article PubMed CAS Google Scholar
Carroll JM, Crompton T, Seery JP, Watt FM (1997) Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss. J Invest Dermatol 108:412–422
Article PubMed CAS Google Scholar
Lider O, Cahalon L, Gilat D, Hershkoviz R, Siegel D, Margalit R, Shoseyov O, Cohen IR (1995) A disaccharide that inhibits tumor necrosis factor alpha is formed from the extracellular matrix by the enzyme heparinase. Proc Natl Acad Sci U S A 92:5037–5041
Article PubMed CAS Google Scholar
Kothny-Wilkes G, Kulms D, Poppelmann B, Luger TA, Kubin M, Schwarz T (1998) Interleukin-1 protects transformed keratinocytes from tumor necrosis factor-related apoptosis-inducing ligand. J Biol Chem 273:29247–29253
Article PubMed CAS Google Scholar
Orteu CH, Poulter LW, Rustin MHA, Sabin CA, Salmon M, Akbar AN (1998) The role of apoptosis in the resolution of T cell-mediated cutaneous inflammation. J Immunol 161:1619–1629
PubMed CAS Google Scholar
Zhang X, Brunner T, Carter L, Dutton RW, Rogers P, Bradley L, Sato T, Reed JC, Green D, Swain SL (1997) Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J Exp Med 185:1837–1849
Article PubMed CAS Google Scholar
Enk AH, Katz SI (1992) Identification and induction of keratinocyte-derived IL-10. J Immunol 149:92–95
PubMed CAS Google Scholar
Schwarz A, Grabbe S, Riemann H, Aragane Y, Simon M, Manon S, Andrade S, Luger TA, Zlotnik A, Schwarz T (1994) In vivo effects of interleukin-10 on contact hypersensitivity and delayed-type hypersensitivity reactions. J Invest Dermatol 103:211–216
Article PubMed CAS Google Scholar
Berg DJ, Leach MW, Kuhn R, Rajewsky K, Muller W, Davidson NJ, Rennick D (1995) Interleukin 10 but not interleukin 4 is a natural suppressant of cutaneous inflammatory responses. J Exp Med 182:99–108
Article PubMed CAS Google Scholar
Morel PA, Oriss TB (1998) Crossregulation between Th1 and Th2 cells. Crit Rev Immunol 18:275–303
Article PubMed CAS Google Scholar
Lalani I, Bhol K, Ahmed AR (1997) Interleukin-10 biology, role in inflammation and autoimmunity. Ann Allergy Asthma Immunol 79:469–484
Article PubMed CAS Google Scholar
Epstein SP, Baer RL, Thorbecke GJ, Belsito DV (1991) Immunosuppressive effects of transforming growth factor beta: inhibition of the induction of Ia antigen on Langerhans cells by cytokines and of the contact hypersensitivity response. J Invest Dermatol 96:832–837
Article PubMed CAS Google Scholar
Lawrence JN, Dickson FM, Benford DJ (1997) Skin irritant-induced cytotoxicity and prostaglandin E-2 release in human skin keratinocyte cultures. Toxicol Vitro 11:627–631
Article CAS Google Scholar
Walker C, Kristensen F, Bettens F, deWeck AL (1983) Lymphokine regulation of activated (G1) lymphocytes. I. Prostaglandin E₂-induced inhibition of interleukin 2 production. J Immunol 130:1770–1773
PubMed CAS Google Scholar
Weston MC, Peachell PT (1998) Regulation of human mast cell and basophil function by cAMP. Gen Pharmacol 31:715–719
Article PubMed CAS Google Scholar
Dvorak HF, Mihm MC Jr, Dvorak AM (1976) Morphology of delayed-type hypersensitivity reactions in man. J Invest Dermatol 64:391–401
Article Google Scholar
Marone G, Spadaro G, Patella V, Genovese A (1994) The clinical relevance of basophil releasability. J Aller Clin Immunol 94:1293–1303
Article CAS Google Scholar
Lundeberg L, Mutt V, Nordlind K (1999) Inhibitory effect of vasoactive intestinal peptide on the challenge phase of allergic contact dermatitis in humans. Acta Derm Venereol 79:178–182
Article PubMed CAS Google Scholar
Boerrigter GH, Scheper RJ (1987) Local and systemic desensitization induced by repeated epicutaneous hapten application. J Invest Dermatol 88:3–7
Article PubMed CAS Google Scholar
Jensen CS, Menne T, Lisby S, Kristiansen J, Veien NK (2003) Experimental systemic contact dermatitis from nickel: a dose-response study. Contact Dermatitis 49:124–132
Article PubMed CAS Google Scholar
Hindsen M, Bruze M, Christensen OB (2001) Flare-up reactions after oral challenge with nickel in relation to challenge dose and intensity and time of previous patch test reactions. J Am Acad Dermatol 44:616–623
Article PubMed CAS Google Scholar
Larsson A, Moller H, Björkner B, Bruze M (1997) Morphology of endogenous flare-up reactions in contact allergy to gold. Acta Derm Venereol 77:474–479
PubMed CAS Google Scholar
Skog E (1976) Spontaneous flare-up reactions induced by different amounts of 1, 3-dinitro-4-chlorobenzene. Acta Derm Venereol 46:386–395
Google Scholar
Scheper RJ, von Blomberg BME, Boerrigter GH, Bruynzeel D, van Dinther A, Vos A (1983) Induction of local memory in the skin. Role of local T cell retention. Clin Exp Immunol 51:141–148
PubMed CAS Google Scholar
Moed H, Boorsma DM, Tensen CP, Flier J, Jonker MJ, Stoof TJ, Von Blomberg BM, Bruynzeel DP, Scheper RJ, Rustemeyer T, Gibbs S (2004) Increased CCL27-CCR10 expression in allergic contact dermatitis: implications for local skin memory. J Pathol 204:39–46
Article PubMed CAS Google Scholar
Christensen OB, Beckstead JH, Daniels TE, Maibach HI (1985) Pathogenesis of orally induced flare-up reactions at old patch sites in nickel allergy. Acta Derm Venereol 65:298–304
PubMed CAS Google Scholar
Hindsen M, Christensen OB (1992) Delayed hypersensitivity reactions following allergic and irritant inflammation. Acta Derm Venereol 72:220–221
PubMed CAS Google Scholar
Gawkrodger DJ, McVittie E, Hunter JA (1987) Immunophenotyping of the eczematous flare-up reaction in a nickel-sensitive subject. Dermatology 175:171–177
Article CAS Google Scholar
Polak L, Turk JL (1968) Studies on the effect of systemic administration of sensitizers in guinea-pigs with contact sensitivity to inorganic metal compounds.II. The flare-up of previous test sites of contact sensitivity and the development of a generalized rash. Clin Exp Immunol 3:253–262
PubMed CAS Google Scholar
Moser B, Loetscher M, Piali L, Loetscher P (1998) Lymphocyte responses to chemokines. Int Rev Immunol 16:323–3244
Article PubMed CAS Google Scholar
Rustemeyer T, de Groot J, von Blomberg BME, Frosch PJ, Scheper RJ (2002) Assessment of contact allergen cross-reactivity by retesting. Exp Dermatol 11:257–265
Article PubMed Google Scholar
Matura M (1998) Contact allergy to locally applied corticosteroids. Thesis, Leuven, Belgium
Google Scholar
Inerot A, Moller H (2000) Symptoms and signs reported during patch testing. Am J Contact Dermatol 11:49–52
Article CAS Google Scholar
Isaksson M, Bruze M (2003) Late patch-test reactions to budesonide need not be a sign of sensitization induced by the test procedure. Am J Contact Dermatol 14:154–156
Google Scholar
Zinkernagel RM (2004) On “reactivity” versus “tolerance”. Immunol Cell Biol 82:343–352
Article PubMed Google Scholar
Piccirillo CA, Thornton AM (2004) Cornerstone of peripheral tolerance: naturally occurring CD4+CD25+ regulatory T cells. Trends Immunol 25:374–380
Article PubMed CAS Google Scholar
Benson JM, Whitacre CC (1997) The role of clonal deletion and anergy in oral tolerance. Res Immunol 148:533–541
Article PubMed CAS Google Scholar
Ferber I, Schönrich G, Schenkel J, Mellor AL, Hämmerling GJ, Arnold B (1994) Levels of peripheral T cell tolerance induced by different doses of tolerogen. Science 263:674–676
Article PubMed CAS Google Scholar
Morgan DJ, Kreuwel HTC, Sherman LA (1999) Antigen concentration and precursor frequency determine the rate of CD8(⁺) T cell tolerance to peripherally expressed antigens. J Immunol 163:723–727
PubMed CAS Google Scholar
Shreedhar V, Giese T, Sung VW, Ullrich SE (1998) A cytokine cascade including prostaglandin E2, IL-4, and IL-10 is responsible for UV-induced systemic immune suppression. J Immunol 160:3783–3789
PubMed CAS Google Scholar
Semma M, Sagami S (1981) Induction of suppressor T cells to DNFB contact sensitivity by application of sensitizer through Langerhans cell-deficient skin. Arch Dermatol Res 271:361–364
Article PubMed CAS Google Scholar
Taams LS, van Eden W, Wauben MHM (1999) Dose-dependent induction of distinct anergic phenotypes: multiple levels of T cell anergy. J Immunol 162:1974–1981
PubMed CAS Google Scholar
Girolomoni G, Gisondi P, Ottaviani C, Cavani A (2004) Immunoregulation of allergic contact dermatitis. J Dermatol 31:264–270
PubMed CAS Google Scholar
Mayer L, Sperber K, Chan L, Child J, Toy L (2001) Oral tolerance to protein antigens. Allergy 56:12–15
Article PubMed Google Scholar
Weiner HL, Gonnella PA, Slavin A, Maron R (1997) Oral tolerance: cytokine milieu in the gut and modulation of tolerance by cytokines. Res Immunol 148:528–533
Article PubMed CAS Google Scholar
Wang YH, Liu YJ (2008) The IL-17 cytokine family and their role in allergic inflammation. Curr Opin Immunol 20(6):697–702
Article PubMed CAS Google Scholar
Rustemeyer T, de Groot J, von Blomberg BME, Frosch PJ, Scheper RJ (2001) Induction of tolerance and cross-tolerance to methacrylate contact sensitizers. Toxicol Appl Pharmacol 176:195–202
Article PubMed CAS Google Scholar
Miller SD, Sy M-S, Claman HN (1977) The induction of hapten-specific T cell tolerance using hapten-modified lymphoid membranes. II. Relative roles of suppressor T cells and clone inhibition in the tolerant state. Eur J Immunol 7:165–170
Article PubMed CAS Google Scholar
Polak L (1980) Immunological aspects of contact sensitivity. An experimental study. Monogr Allergy 15:4–60
Google Scholar
Weiner HL (1997) Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 18:335–343
Article PubMed CAS Google Scholar
Weigle WO, Romball CG (1997) CD4⁺ T-cell subsets and cytokines involved in peripheral tolerance. Immunol Today 18:533–538
Article PubMed CAS Google Scholar
Arnaboldi PM, Roth-Walter F, Mayer L (2009) Suppression of Th1 and Th17, but not Th2, responses in a CD8(+) T cell-mediated model of oral tolerance. Mucosal Immunol 2(5):427–438
Article PubMed CAS Google Scholar
Zembala M, Ashershon GL (1973) Depression of T cell phenomenon of contact sensitivity by T cells from unresponsive mice. Nature 244:227–228
Article PubMed CAS Google Scholar
Boerrigter GH, Scheper RJ (1984) Local administration of the cytostatic drug 4-hydroperoxy-cyclophosphamde (4-HPCY) facilitates cell mediated immune reactions. Clin Exp Immunol 58:161–166
PubMed CAS Google Scholar
Boerrigter GH, de Groot J, Scheper RJ (1986) Intradermal administration of 4-hydoperoxy-cyclophosphamde during contact sensitization potentiates effector T cell responsiveness in draining lymph nodes. Immunopharmacology 1:13–20
Article Google Scholar
Mokyr MB, Kalinichenko T, Gorelik L, Bluestone JA (1998) Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice. Cancer Res 58:5301–5304
PubMed CAS Google Scholar
Knop J, Stremmer R, Neumann C, Dc Maeyer D, Macher E (1982) Interferon inhibits the suppressor T cell response of delayed-type hypersensitivity. Nature 296:775–776
Article Google Scholar
Zhang ZY, Michael JG (1990) Orally inducible immune unresponsiveness is abrogated by IFN-gamma treatment. J Immunol 144:4163–4165
PubMed CAS Google Scholar
Claessen AME, von Blomberg BME, de Groot J, Wolvers DAE, Kraal G, Scheper RJ (1996) Reversal of mucosal tolerance by subcutaneous administration of interleukin-12 at the site of attempted sensitization. Immunology 88:363–367
Article PubMed CAS Google Scholar
Bridoux F, Badou A, Saoudi A, Bernard L, Druet E, Pasquier R, Druet P, Pelletier L (1997) Transforming growth factor beta (TGF-beta)-dependent inhibition of T helper cell 2 (Th2)-induced autoimmunity by self-major histocompatibility complex (MHC) class II-specific, regulatory CD4+ T cell lines. J Exp Med 185:1769–1775
Article PubMed CAS Google Scholar
Cavani A, Nasorri F, Ottaviani C, Sebastiani S, De Pita O, Girolomoni G (2003) Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J Immunol 171:5760–5768
PubMed CAS Google Scholar
Hafler DA, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Fukaura H (1997) Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis. Ann N Y Acad Sci 835:120–131
Article PubMed CAS Google Scholar
Lonati A, Licenziati S, Marcelli M, Canaris D, Pasolini G, Caruso A, de Panfilis G (1998) Quantitative analysis “at the single cell level” of the novel CD28^-CD11b^- subpopulation of CD8⁺ T lymphocytes. ESDR meeting at Cologne
Google Scholar
De Panfilis G (1998) CD8⁺ cytolytic T lymphocytes and the skin. Exp Dermatol 7:121–131
Article PubMed Google Scholar
Ilan Y (2009) Oral tolerance: can we make it work? Hum Immunol 70(10):768–776
Article PubMed CAS Google Scholar
Kuchroo VK, Byrne MC, Atsumi Y, Greenfeld E, Connol JH, Whitters MJ, O’Hara RM, Collins M, Dorf ME (1991) T cell receptor alpha chain plays a critical role in antigen-specific suppressor cell function. Proc Natl Acad Sci U S A 88:8700–8704
Article PubMed CAS Google Scholar
Taams LS, Boot EPJ, van Eden W, Wauben MHM (2000) “Anergic” T cells modulate the T-cell activating capacity of antigen-presenting cells. J Autoimmun 14:335–341
Article PubMed CAS Google Scholar
Taams LS, van Rensen AJML, Poelen MC, van Els CACM, Besseling AC, Wagenaar JPA, van Eden W, Wauben MHM (1998) Anergic T cells actively suppress T cell responses via the antigen presenting cell. Eur J Immunol 28:2902–2912
Article PubMed CAS Google Scholar
Kalinski P, Schuitemaker JH, Hilkens CM, Kapsenberg ML (1998) Prostaglandin E₂ induces the final maturation of IL-12 deficient CD1a⁺CD83⁺ dendritic cells. J Immunol 161:2804–2809
PubMed CAS Google Scholar
Steinbrink K, Wolf M, Jonuleit H, Knop J, Enk AH (1997) Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159:4772–4780
PubMed CAS Google Scholar
Steinbrink K, Jonuleit H, Muller G, Schuler G, Knop J, Enk AH (1999) Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(⁺) T cells resulting in a failure to lyse tumor cells. Blood 93:1634–1642
PubMed CAS Google Scholar
Van Hoogstraten IMW, Andersen JE, von Blomberg BME, Boden D, Bruynzeel DP, Burrows D, Camarasa JMG, Dooms-Goossens A, Lahti A, Menné T, Rycroft R, Todd D, Vreeburg KJJ, Wilkinson JD, Scheper RJ (1989) Preliminary results of a multicenter study on the incidence of nickel allergy in relationship to previous oral and cutaneous contacts. In: Frosch PJ, Dooms-Goossens A, Lachapelle JM, Rycroft RJG, Scheper RJ (eds) Current topics in contact dermatitis. Springer, Berlin, pp 178–184
Google Scholar
Strobel S, Mowat AM (1998) Immune responses to dietary antigens: oral tolerance. Immunol Today 19:173–181
Article PubMed CAS Google Scholar
von Herrath MG (1997) Bystander suppression induced by oral tolerance. Res Immunol 148:541–554
Article Google Scholar
Fowler E, Weiner HL (1997) Oral tolerance: elucidation of mechanisms and application to treatment of autoimmune diseases. Biopolymers 43:323–335
Article PubMed CAS Google Scholar
Van Hoogstraten IMW, von Blomberg BME, Boden D, Kraal G, Scheper RJ (1994) Non-sensitizing epicutaneous skin tests prevent subsequent induction of immune tolerance. J Invest Dermatol 102:80–83
Article PubMed Google Scholar
Epstein WL (1987) The poison ivy picker of Pennypack Park: the continuing saga of poison ivy. J Invest Dermatol 88:7–9
Article Google Scholar
Morris DL (1998) Intradermal testing and sublingual in desensitization for nickel. Cutis 61:129–132
PubMed CAS Google Scholar
Wendel GD, Stark BJ, Jamison RB, Molina RD, Sullivan TJ (1985) Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 312: 1229–1232
Article PubMed Google Scholar
Panzani RC, Schiavino D, Nucera E, Pellegrino S, Fais G, Schinco G, Patriarca G (1995) Oral hyposensitization to nickel allergy: preliminary clinical results. Int Arch Allergy Immunol 107:251–254
Article PubMed CAS Google Scholar
Troost RJ, Kozel MM, van Helden-Meeuwsen CG, van Joost T, Mulder PG, Benner R, Prens EP (1995) Hyposensitization in nickel allergic contact dermatitis: clinical and immunologic monitoring. J Am Acad Dermatol 32:576–583
Article PubMed CAS Google Scholar
Chase MW (1946) Inhibition of experimental drug allergy by prior feeding of the sensitizing agent. Proc Soc Exp Biol Med 61:257–259
PubMed CAS Google Scholar
Polak L, Turk SL (1968) Studies on the effect of systemic administration of sensitizers in guinea pigs with contact sensitivity to inorganic metal compounds. I. The induction of immunological unresponsiveness in already sensitized animals. Clin Exp Immunol 3:245–251
PubMed CAS Google Scholar
Polak L, Rinck C (1978) Mechanism of desensitization in DNCH-contact sensitive guinea pigs. J Invest Dermatol 70:98–104
Article PubMed CAS Google Scholar
Gaspari AA, Jenkins MK, Katz SI (1988) Class II MCH-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific TH1 clones. J Immunol 141:2216–2220
PubMed CAS Google Scholar
Murphy K, Travers P, Walport M (eds) (2008) Janeway’s immunobiology, 7th edn. Garland Science, Taylor & Francis Group, US, UK
Google Scholar
Gaga M, Ong YE, Benyahia F, Aizen M, Barkans J (2008) Kay AB.Skin reactivity and local cell recruitment in human atopic and nonatopic subjects by CCL2/MCP-1 and CCL3/MIP-1alpha. Allergy 63(6):703–711
Article PubMed CAS Google Scholar
Homey B, Alenius H, Müller A, Soto H, Bowman EP, Yuan W, McEvoy L, Lauerma AI, Assmann T, Bünemann E, Lehto M, Wolff H, Yen D, Marxhausen H, To W, Sedgwick J, Ruzicka T, Lehmann P, Zlotnik A (2002) CCL27-CCR10 interactions regulate T cell-mediated skin inflammation. Nat Med 8(2):157–165
Article PubMed CAS Google Scholar
Kagami S, Saeki H, Tsunemi Y, Nakamura K, Kuwano Y, Komine M, Nakayama T, Yoshie O, Tamaki K (2008) CCL27-transgenic mice show enhanced contact hypersensitivity to Th2, but not Th1 stimuli. Eur J Immunol 38(3):647–657
Article PubMed CAS Google Scholar
Grimm MC, Ng WS (2008) Road most traveled: gut-specific migration signals and leucocyte entry to the intestine. J Gastroenterol Hepatol 23(12):1775
Article PubMed Google Scholar
Gomez J, Gonzalez A, Martinez-A C, Rebollo A (1998) IL-2-induced cellular events. Crit Rev Immunol 18:185–220
Article PubMed CAS Google Scholar
Berridge MJ (1997) Lymphocyte activation in health and disease. Crit Rev Immunol 17:155–178
Article PubMed CAS Google Scholar
Theze J, Alzari PM, Bertoglio J (1996) Interleukin 2 and its receptors: recent advances and new immunological functions. Immunol Today 17:481–486
Article PubMed CAS Google Scholar
Lacour M, Arrighi J-F, Müller KM, Carlberg C, Saurat J-H, Hauser C (1994) cAMP up-regulates IL-4 and IL-5 production from activated CD4⁺ T cells while decreasing IL-2 release and NF-AT induction. Int Immunol 6:1333–1343
Article PubMed CAS Google Scholar
Linsley PS, Ledbetter JA (1993) The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 11:191–212
Article PubMed CAS Google Scholar
Mazzoni A, Segal DM (2004) Controlling the Toll road to dendritic cell polarization. J Leukoc Biol 75:721–730
Article PubMed CAS Google Scholar
O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275–283
Article PubMed Google Scholar
Santana MA, Rosenstein Y (2003) What it takes to become an effector T cell: the process, the cells involved, and the mechanisms. J Cell Physiol 195:392–401
Article PubMed CAS Google Scholar
Burkett PR, Koka R, Chien M, Boone DL, Ma A (2004) Generation, maintenance, and function of memory T cells. Adv Immunol 83:191–231
Article PubMed CAS Google Scholar
Spahn TW, Kucharzik T (2004) Modulating the intestinal immune system: the role of lymphotoxin and GALT organs. Gut 53:456–465
Article PubMed CAS Google Scholar
Bour H, Peyron E, Gaucherand M, Garrigue JL, Desvignes C, Kaiserlian D, Revillard JP, Nicolas JF (1995) Major histocompatibility complex class I-restricted CD8⁺ T cells and class II-restricted CD4⁺ T cells, respectively, mediate and regulate contact sensitivity to dinitrofluorobenzene. Eur J Immunol 25:3006–3010
Article PubMed CAS Google Scholar
Paul WE, Ohara J (1987) B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol 5:429–459
Article PubMed CAS Google Scholar
Mackey MF, Barth RJ, Noelle RJ (1998) The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cell. J Leuk Biol 63:418–428
CAS Google Scholar
Kuchroo V, Prabhu Das M, Brown JA, Ranger A, Zamvill MSS, Sobel RA, Weiner HL, Nabavi N, Glimcher LH (1995) B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways. Application to autoimmune disease therapy. Cell 80: 707–718
CAS Google Scholar
Ranger AM, Prabhu Das M, Kuchroo VK, Glimcher LH (1996) B7–2 (CD86) is essential for the development of IL-4 producing cells. Int Immunol 153:1549–1560
Article Google Scholar
Schweitzer AN, Borriello F, Wong RCK, Abbas AK, Sharpe AH (1997) Role of costimulators in T cell differentiation – studies using antigen-presenting cells lacking expression of CD80 or CD86. J Immunol 158:2713–2722
PubMed CAS Google Scholar
Rulifson IC, Sperling AI, Fields PE, Fitch FW, Bluestone JA (1997) CD28 costimulation promotes the production of Th2 cytokines. J Immunol 158:658–665
PubMed CAS Google Scholar
Pernis A, Gupta S, Gollob KJ, Garfein E, Coffman RL, Schindler C, Rothman P (1995) Lack of interferon gamma receptor beta chain and the prevention of interferon signaling in Th1 cells. Science 269:245–247
Article PubMed CAS Google Scholar
Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K (1998) IL-12 up-regulates IL-18 receptor expression on T cells, TH1 cells, and B cells – synergism with IL-18 for IFN-gamma production. J Immunol 161:3400–3407
PubMed CAS Google Scholar
Zanni MP, Mauri-Hellweg D, Brander C, Wendland T, Schnyder B, Frei E, von Greyerz S, Bircher A, Pichler WJ (1997) Characterization of lidocaine-specific T cells. J Immunol 158:1139–1148
PubMed CAS Google Scholar
Rincon M, Anguita J, Nakamura T, Fikrig E, Flavell RA (1997) Interleukin (IL)-6 directs the differentiation of IL-4 producing CD4⁺ T cells. J Exp Med 182:1591–1596
Google Scholar
Yoshimoto T, Bendelac A, Watson C, Hu-Li J, Paul WE (1995) Role of NK1.1⁺ T cells in a TH2 response and in immunoglobulin E production. Science 270:1845–1847
Article PubMed CAS Google Scholar
Hiroi T, Iwatani K, Iijima H, Kodama S, Yanagita M, Kiyono H (1998) Nasal immune system – distinctive Th0 and Th1/Th2 type environments in murine nasal-associated lymphoid tissues and nasal passage, respectively. Eur J Immunol 28:3346–3353
Article PubMed CAS Google Scholar
Banchereau J (1995) Converging and diverging properties of human interleukin-4 and interleukin-10. Behr Inst Mitteil 96:58–77
CAS Google Scholar
Itoh K, Hirohata S (1995) The role of IL-10 in human B cell activation, proliferation, and differentiation. J Immunol 154:4341–4350
PubMed CAS Google Scholar
Napolitano LM, Buzdon MM, Shi HJ, Bass BL (1997) Intestinal epithelial cell regulation cell regulation of macrophage and lymphocyte interleukin 10 expression. Arch Surg 132:1271–1276
Article PubMed CAS Google Scholar
Xu H, Banerjee A, Diulio NA, Fairchild RL (1996) T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: interferon gamma-producing (Tc1) effector CD8⁺ T cells and interleukin (IL)-4/IL-10-producing (Th2) negative regulatory CD4⁺ T cells. J Exp Med 183: 1001–1012
Article PubMed CAS Google Scholar
Letterio JL, Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16:137–161
Article PubMed CAS Google Scholar
Hosken NA, Shibuya K, Heath AW, Murphy KM, O’Garra A (1995) The effect of antigen dose on CD4⁺ T helper cell phenotype development in a T cell receptor phenotype development in a T cell receptor alpha/beta-transgenic model. J Exp Med 182:1579–1584
Article PubMed CAS Google Scholar
Scholzen T, Armstrong CA, Bunnett NW, Luger TA, Olerud JE, Ansel JC (1998) Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems. Exp Dermatol 7:81–96
Article PubMed CAS Google Scholar
Westerman J, Geismar U, Sponholz A, Bode U, Sparshott BEB (1997) CD4⁺ T cells of both the naive and the memory phenotype enter rat lymph nodes and Peyer’s patches via high endothelial venules: within the tissue their migratory behaviour differs. Eur J Immunol 27:3174–3181
Article Google Scholar
Marshall D, Haskard DO (2002) Clinical overview of leukocyte adhesion and migration: where are we now? Semin Immunol 14:133–140
Article PubMed CAS Google Scholar
Hall JG, Morris B (1965) The origin of cells in the efferent lymph from a single lymph node. J Exp Med 121:901–910
Article PubMed CAS Google Scholar
Hwang ST (2001) Mechanisms of T-cell homing to skin. Adv Dermatol 17:211–241
PubMed CAS Google Scholar
Pober JS, Kluger MS, Schechner JS (2001) Human endothelial cell presentation of antigen and the homing of memory/effector T cells to skin. Ann N Y Acad Sci 941:12–25
Article PubMed CAS Google Scholar
Mackay CR (1993) Homing of naïve, memory and effector lymphocytes. Curr Opin Immunol 5:423–427
Article PubMed CAS Google Scholar
Tietz W, Allemand Y, Borges E, Vonlaer D, Hallmann R, Vestweber D, Hamann A (1998) CD4(⁺) T cells migrate into inflamed skin only if they express ligands for E- and P-selectin. J Immunol 16:963–970
Google Scholar
Rosen Homey B (2004) Chemokines and chemokine receptors as targets in the therapy of psoriasis. Curr Drug Targets Inflamm Allergy 3:169–174
Article Google Scholar
Homey B, Bunemann E (2004) Chemokines and inflammatory skin diseases. Ernst Schering Res Found Workshop 4:69–83
Google Scholar
Tanchot C, Rocha B (1998) The organization of mature T-cell pools. Immunol Today 19:575–579
Article PubMed CAS Google Scholar
Williams IR (2004) Chemokine receptors and leukocyte trafficking in the mucosal immune system. Immunol Res 29:283–292
Article PubMed CAS Google Scholar
Telemo E, Korotkova M, Hanson LA (2003) Antigen presentation and processing in the intestinal mucosa and lymphocyte homing. Ann Allergy Asthma Immunol 90:28–33
Article PubMed CAS Google Scholar
Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LWMM (1993) Control of lymphocyte recirculation in man: II. Differential regulation of the cutaneous lymphocyte associated antigen, a tissue-selective homing receptor for skin homing T cells. J Immunol 150:1122–1136
PubMed CAS Google Scholar
Sunderkötter C, Steinbrink K, Henseleit U, Bosse R, Schwarz A, Vestweber D, Sorg C (1996) Activated T cells induce expression of E-selectin in vitro and in an antigen-dependent manner in vivo. Eur J Immunol 26:1571–1579
Article PubMed Google Scholar
Tensen CP, Flier J, Rampersad SS, Sampat-Sardjoerpersad A, Scheper RJ, Boorsma DM, Willemze R (1999) Genomic organization, sequence and transcriptional regulation of the human CXCL 11 gene. Biochim Biophys Acta 1446:167–172
Article PubMed CAS Google Scholar
Sallusto F, Kremmer E, Palermo B, Hoy A, Ponath P, Qin SX, Forster R, Lipp M, Lanzavecchia A (1999) Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur J Immunol 29:2037–2045
Article PubMed CAS Google Scholar
Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392:565–568
Article PubMed CAS Google Scholar
Bell EB, Sparshott SM, Bunce C (1998) CD4⁺ T-cell memory, CD45R subsets and the persistence of antigen – a unifying concept. Immunol Today 19:60–64
Article PubMed CAS Google Scholar
Bell EB, Sparshott SM, Ager A (1995) Migration pathways of CD4 T cell subsets in vivo: the CD45RC- subset enters the thymus via alpha 4 integrin- VCAM-1 interaction. Int Immunol 11:1861–1871
Article Google Scholar
Stoof TJ, Boorsma DM, Nickoloff BJ (1994) Keratinocytes and immunological cytokines. In: Leigh I, Lane B, Watt F (eds) The keratinocyte handbook. Cambridge University Press, Cambridge, pp 365–399
Google Scholar
Tensen CP, Flier J, van der Raaij-Helmer EM, Sampat-Sardjoepersad S, van den Schors RC, Leurs R, Scheper RJ, Boorsma DM, Willemze R (1999) Human IP-9: a keratinocyte derived high affinity CXC-chemokine ligand for the IP-10/Mig receptor (CXCR3). J Invest Dermatol 112:716–722
Article PubMed CAS Google Scholar
Virag L, Szabo E, Bakondi E, Bai P, Gergely P, Hunyadi J, Szabo C (2002) Nitric oxide-peroxynitrite-poly(ADP-ribose) polymerase pathway in the skin. Exp Dermatol 11:189–202
Article PubMed CAS Google Scholar
Ptak W, Askenase PW, Rosenstein RW, Gershon RK (1982) Transfer of an antigen-specific immediate hypersensitivity-like reaction with an antigen-binding factor produced by T cells. Proc Natl Acad Sci U S A 79:1969–1973
Article PubMed CAS Google Scholar
Van Loveren H, Ratzlaff RE, Kato K, Meade R, Ferguson TA, Iverson GM, Janeway CA, Askenase PW (1986) Immune serum from mice contact-sensitized with picryl chloride contains an antigen-specific T cell factor that transfers immediate cutaneous reactivity. Eur J Immunol 16:1203–1208
Article PubMed Google Scholar
Ptak W, Herzog WR, Askenase PW (1991) Delayed-type hypersensitivity initiation by early-acting cells that are antigen mismatched or MHC incompatible with late-acting, delayed-type hypersensitivity effector T cells. J Immunol 146:469–475
PubMed CAS Google Scholar
Askenase PW, Kawikova I, Paliwal V, Akahira-Azuma M, Gerard C, Hugli T, Tsuji R (1999) A new paradigm of T cell allergy: requirement for the B-1 B cell subset. Int Arch All Appl Immunol 118:145–149
Article CAS Google Scholar
Hardy RR, Hayakawa K (1994) CD5⁺ B cells, a fetal B cell lineage. Adv Immunol 55:297–339
Article PubMed CAS Google Scholar
Feinstein A, Richardson N, Taussig MJ (1986) Immunoglobulin flexibility in complement activation. Immunol Today 7:169–173
Article CAS Google Scholar
Geba GP, Ptak W, Anderson GA, Ratzlaff RE, Levin J, Askenase PW (1996) Delayed-type hypersensitivity in mast cell deficient mice: dependence on platelets for expression on contact sensitivity. J Immunol 157:557–565
PubMed CAS Google Scholar
Salerno A, Dieli F (1998) Role of gamma delta T lymphocytes in immune response in humans and mice. Crit Rev Immunol 18:327–357
Article PubMed CAS Google Scholar
Szczepanik M, Lewis J, Geba GP, Ptak W, Askenase PW (1998) Positive regulatory gamma-delta T cells in contact sensitivity – augmented responses by in vivo treatment with anti-gamma-delta monoclonal antibody, or anti-V-gamma-5 or V-delta-4. Immunol Invest 27:1–15
Article PubMed CAS Google Scholar
Tang HL, Cyster JG (1999) Chemokine up-regulation and activated T cell attraction by maturing dendritic cells. Science 284:819–822
Article PubMed CAS Google Scholar
Vana G, Meingassner JG (2000) Morphologic and immunohistochemical features of experimentally induced allergic contact dermatitis in Gottingen minipigs. Vet Pathol 37:565–580
Article PubMed CAS Google Scholar
Teraki Y, Picker LJ (1997) Independent regulation of cutaneous lymphocyte-associated antigen expression and cytokine synthesis phenotype during human CD4⁺ memory T cell differentiation. J Immunol 159:6018–6029
PubMed CAS Google Scholar
Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272:60–66
Article PubMed CAS Google Scholar
Strunk D, Egger C, Leitner G, Hanau D, Stingl G (1997) A skin homing molecule defines the Langerhans cell progenitor in human peripheral blood. J Exp Med 185:1131–1136
Article PubMed CAS Google Scholar
Wroblewski M, Hamann A (1997) CD45-mediated signals can trigger shedding of lymphocyte L-selectin. Int Immunol 9:555–562
Article PubMed CAS Google Scholar
Burastero SE, Rossi GA, Crimi E (1998) Selective differences in the expression of the homing receptors of helper lymphocyte subsets. Clin Immunol Immunopathol 89:110–116
Article PubMed CAS Google Scholar
Wahbi A, Marcusson JA, Sundqvist KG (1996) Expression of adhesion molecules and their ligands in contact allergy. Exp Dermatol 5:12–19
Article PubMed CAS Google Scholar
Dailey MO (1998) Expression of T lymphocyte adhesion molecules: regulation during antigen-induced T cell activation and differentiation. Crit Rev Immunol 18:153–184
Article PubMed CAS Google Scholar
Oppenheimer-Marks N, Lipsky PE (1997) Migration of naïve and memory T cells. Immunol Today 18:456–457
Article PubMed CAS Google Scholar
Romanic AM, Graesser D, Baron JL, Visintin I, Janeway CA Jr, Madri JA (1997) T cell adhesion to endothelial cells and extracellular matrix is modulated upon transendothelial cell migration. Lab Invest 76:11–23
PubMed CAS Google Scholar
Zanni MP, von Greyerz S, Schnyder B, Brander KA, Frutig K, Hari Y, Valitutti S, Pichler WJ (1998) HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes. J Clin Invest 102:1591–1598
Article PubMed CAS Google Scholar
Akdis CA, Akdis M, Simon HU, Blaser K (1999) Regulation of allergic inflammation by skin-homing T cells in allergic eczema. Int Arch Allergy Immunol 118:140–144
Article PubMed CAS Google Scholar
Okazaki F, Kanzaki H, Fujii K, Arata J, Akiba H, Tsujii K, Iwatsuki K (2002) Initial recruitment of interferon-gamma-producing CD8+ effector cells, followed by infiltration of CD4+ cells in 2, 4, 6-trinitro-1-chlorobenzene (TNCB)-induced murine contact hypersensitivity reactions. J Dermatol 29:699–708
PubMed Google Scholar
Pichler WJ, Schnyder B, Zanni MP, Hari Y, von Greyerz S (1998) Role of T cells in drug allergies. Allergy 53:225–232
Article PubMed CAS Google Scholar
Kehren J, Desvignes C, Krasteva M, Ducluzeau MT, Assossou O, Horand F, Hahne M, Kagi D, Kaiserlian D, Nicolas JF (1999) Cytotoxicity is mandatory for CD8⁺ T cell mediated contact hypersensitivity. J Exp Med 189:779–786
Article PubMed CAS Google Scholar
Mauri-Hellweg D, Bettens F, Mauri D, Brander C, Hunziker T, Pichler WJ (1995) Activation of drug-specific CD4⁺ and CD8⁺ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol 155:462–472
PubMed CAS Google Scholar
Stark GR, Kerr IM, Williams BRG, Silverman RH, Schreiber RD (1998) How cells respond to interferons. Annu Rev Biochem 67:227–264
Article PubMed CAS Google Scholar
Yamada H, Matsukura M, Yudate T, Chihara J, Stingl G, Tezuka T (1997) Enhanced production of RANTES, an eosinophil chemoattractant factor, by cytokine-stimulated epidermal keratinocytes. Int Arch Aller Immunol 114:28–32
Article CAS Google Scholar
Siveke JT, Hamann A (1998) T helper 1 and T helper 2 Cells respond differentially to chemokines. J Immunol 160:550–554
PubMed CAS Google Scholar
Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR (1998) The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101:746–754
Article PubMed CAS Google Scholar
Rocha B, von Boehmer H (1991) Peripheral selection of the T cell repertoire. Science 251:1225–1228
Article PubMed CAS Google Scholar
Arnold B, Schönrich G, Hämmerling GJ (1993) Multiple levels of peripheral tolerance. Immunol Today 14:12–14
Article PubMed CAS Google Scholar
Pozzilli P, Gisella Cavallo M (2000) Oral insulin and the induction of tolerance in man: reality or fantasy? Diabetes Metab Res Rev 16:306–307
Article PubMed CAS Google Scholar
Röcken M, Shevach EM (1996) Immune deviation – the third dimension of nondeletional T cell tolerance. Immunol Rev 149:175–194
Article PubMed Google Scholar
Kumar V, Sercarz E (1998) Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells. J Immunol 161:6585–6591
PubMed CAS Google Scholar
Strober W, Kelsall B, Marth T (1998) Oral tolerance. J Clin Immunol 18:1–30
Article PubMed CAS Google Scholar
Inobe J, Slavin AJ, Komagata Y, Chen Y, Liu L, Weiner HL (1998) IL-4 is a differentiation factor for transforming growth factor-beta secreting Th3 cells and oral administration of IL-4 enhances oral tolerance in experimental allergic encephalomyelitis. Eur J Immunol 28:2780–2790
Article PubMed CAS Google Scholar
Allan SE, Broady R, Gregori S, Himmel ME, Locke N, Roncarolo MG, Bacchetta R, Levings MK (2008) CD4+ T-regulatory cells: toward therapy for human diseases. Immunol Rev 223:391–421
Article PubMed CAS Google Scholar
Croft M, So T, Duan W, Soroosh P (2009) The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev 229(1):173–191
Article PubMed CAS Google Scholar

Download references

Author information

Authors and Affiliations

Department of Dermatology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands
Thomas Rustemeyer & Sue Gibbs
Department of Pathology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands
Ingrid M. W. van Hoogstraten, B. Mary E. von Blomberg & Rik J. Scheper

Authors

Thomas Rustemeyer
View author publications
You can also search for this author in PubMed Google Scholar
Ingrid M. W. van Hoogstraten
View author publications
You can also search for this author in PubMed Google Scholar
B. Mary E. von Blomberg
View author publications
You can also search for this author in PubMed Google Scholar
Sue Gibbs
View author publications
You can also search for this author in PubMed Google Scholar
Rik J. Scheper
View author publications
You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Rustemeyer .

Editor information

Editors and Affiliations

Dept. Dermatology, Amtssygehuset Gentofte, Niels Andersens Vej 65, Hellerup, 2900, Denmark
Jeanne Duus Johansen
Klinikzentrum Mitte, Hautklinik, Städtische Kliniken Dortmund, Beurhausstr. 40, Dortmund, 44137, Germany
Peter J. Frosch
Labo. Dermatochimie, Institut le Bel, rue Blaise Pascal 4, Strasbourg CX, 67070, France
Jean-Pierre Lepoittevin

Rights and permissions

Reprints and permissions

Copyright information

About this chapter

Cite this chapter

Rustemeyer, T., van Hoogstraten, I.M.W., von Blomberg, B.M.E., Gibbs, S., Scheper, R.J. (2011). Mechanisms of Irritant and Allergic Contact Dermatitis. In: Johansen, J., Frosch, P., Lepoittevin, JP. (eds) Contact Dermatitis. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-03827-3_3

Download citation

DOI: https://doi.org/10.1007/978-3-642-03827-3_3
Published: 12 August 2010
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-03826-6
Online ISBN: 978-3-642-03827-3
eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Mechanisms of Irritant and Allergic Contact Dermatitis

Abstract

Similar content being viewed by others

Contact Dermatitis Due to Irritation

Contact Dermatitis due to Irritation

Pathophysiology of Allergic and Irritant Contact Dermatitis

1 Introduction

2 Irritant Contact Dermatitis

2.1 Skin Barrier Perturbation Can Lead to Irritant Contact Dermatitis

2.2 Pathogenesis of Acute Irritant Contact Dermatitis

2.3 Development of Chronic Irritant Contact Dermatitis

2.4 Genetic Risk Factors in Irritant Contact Dermatitis and Atopic Dermatitis

2.5 Cellular Immunological Changes in Irritant Contact Dermatitis

3 Introduction Allergic Contact Dermatitis

3.1 Binding of Contact Allergens to Skin Components

3.1.1 Chemical Nature of Contact Allergens

3.1.2 Hapten Presentation by Langerhans Cells (LC)

3.1.3 Pre and Prohaptens

3.2 Hapten-Induced Activation of Allergen-Presenting Cells

3.2.1 Physiology of Langerhans Cells

3.2.2 Hapten-Induced LC Activation

3.3 Recognition of Allergen-Modified Langerhans’ Cells by Specific T Cells

3.3.1 Homing of Naive T Cells Into Lymph Nodes

3.3.2 Activation of Hapten-Specific T Cells

3.4 Proliferation and Differentiation of Specific T Cells

3.4.1 T-Cell Proliferation

3.4.2 T-Cell Differentiation

3.4.3 Cytokine Environment

3.4.4 Nature of the Allergen

3.4.5 Neuroendocrine Factors

3.5 Systemic Propagation of the Specific T-Cell Progeny

3.5.1 T-Cell Recirculation

3.5.2 Allergen-Specific T-Cell Recirculation: Options for In Vitro Testing

3.6 The Effector Phase of Allergic Contact Dermatitis

3.6.1 Elicitation of ACD

3.6.2 Irritant Properties of Allergens

3.6.3 Early Phase Reactivity

3.6.4 T-Cell Patrol and Specificity of T-Cell Infiltrates

3.6.5 Effector T-Cell Phenotypes

3.6.6 Downregulatory Processes

3.7 Flare-Up and Retest Reactivity

3.7.1 Local Allergen Retention

3.7.2 Local T-Cell Retention

3.8 Hyporeactivity: Tolerance and Desensitization

3.8.1 Regulation of Immune Responses

3.8.2 Cellular Basis of Active Tolerance

3.8.3 Regulatory Mechanisms of the Effector Phase

3.8.4 Redundancy of Tolerance Mechanisms

3.8.5 Induction of Lasting Tolerance Only in Naive Individuals

3.8.6 Transient Desensitization in Primed Individuals

4 Summary and Conclusions

References

Author information

Authors and Affiliations

Corresponding author

Editor information

Editors and Affiliations

Rights and permissions

Copyright information

About this chapter

Cite this chapter

Download citation

Share this chapter

Publish with us

Search

Navigation