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1 Introduction

The etiology of autoimmune diseases remains unknown; even if many studies have investigated it in the past and are still exploring it, until now no unique genetic or environmental risk factor has been identified to be responsible for the onset of autoimmune diseases. We now consider autoimmune diseases to be induced by multiple factors, genetic and environmental, and this is well supported by the fact that no direct genetic transmission of the same autoimmune disease has yet been found in a familiar group, even if different expressions of autoimmunity (organ specific or systemic) are found in families with affected individuals. An important observation comes from the incomplete concordance rate for autoimmune diseases in couples of monozygotic twins, in which only one twin expresses the rheumatic disease, despite the identical genomic sequences (Miller et al. 2012b; Selmi et al. 2012a). Twin studies are indicated in the study of autoimmune diseases as these allow also the possibility to calculate the genetic heritability of each condition, i.e., the proportion of observable differences in a phenotype between individuals that is due to genetic differences (Bogdanos et al. 2012; Christensen et al. 2011; De Santis and Selmi 2012). Since heritability is a proportion, its value ranges from 0 (when genes do not contribute to phenotypic differences) to 1 (when the environment does not contribute to phenotypic differences). This estimate depends on numerous variables, including the prevalence of the disease in the general population, and does not reflect the risk of getting a disease but the variance between twins. The term “heritability” defines the proportion of the phenotypic variance attributable to genetics (A + D), while the less known term “environmentability” represents the proportion of phenotypic variance attributable to environmental features (or 1-heritability). Of particular importance in the discussion of environmental factors is the fact that “environmentability” includes environmental influences that are the sum of common/shared environmental factors and individual environmental variance, while also including the differences due to measurement errors or observation bias. In specific autoimmune diseases, genetic heritability estimates are summarized in Table 13.1 and demonstrate that the weight of genetic influences is mostly observed in some conditions (as for Crohn’s disease or ankylosing spondylitis) while being almost negligible in others (as for systemic sclerosis) (Selmi et al. 2004, 2011). To tackle this complex view in which causality is difficult to prove, the National Institute of Environmental Health Sciences (NIEHS) organized an expert workshop in September 2010 to provide a consensus on the definition of environmentally induced autoimmune diseases (Parks et al. 2014). The results of the expert panel were reported in three comprehensive articles on the mechanisms, epidemiology, and animal models, while a consensus statement was later reported (Miller et al. 2012a, b; Parks et al. 2014; Selmi et al. 2012a). The Delphi exercise results are summarized for immune or other mechanisms (Table 13.2), animal studies (Table 13.3), and factor-specific mechanisms (Table 13.4).

Table 13.1 Genetic heritability based on twin concordance rates for specific autoimmune diseases (Selmi et al. 2012b)
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Table 13.2 The 2010 NIEHS expert workshop and panel findings on mechanisms involved in the role of environmental factors and development of autoimmune disease (Parks et al. 2014)
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Table 13.3 The 2010 NIEHS expert workshop and panel finding studies of animal models in the role of environmental factors and development of autoimmune disease (Parks et al. 2014)
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Table 13.4 The 2010 NIEHS expert workshop and panel findings on mechanisms involved in the role of environmental factors and development of autoimmune disease (Parks et al. 2014)
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Based on these observations, it is now commonly accepted that multiple genetic predisposition factors must interact with epigenetic and environmental triggers to induce the clinical expression of autoimmune diseases , such as rheumatic ones (Ehrenfeld 2010). This could explain why some diseases develop mainly in some geographic areas (usually industrial zones), and they seem to have a seasonal concentration, maybe related to viral infections , as in the case of dermatomyositis (Tanaka and Takikawa 2013; Invernizzi 2010; Shapira et al. 2010; Chandran and Raychaudhuri 2010; Zeki et al. 2010; Moroni et al. 2012; Selmi and Tsuneyama 2010; Prieto and Grau 2010). Despite the increasing interest about environmental risk factors, the recommendations and the ongoing growth of pathophysiological data about autoimmune diseases, there are still numerous gaps in our knowledge. The aim of this chapter is to describe the environmental factors and the general and specific mechanisms that are considered to play a role in the onset of autoimmune diseases.

2 Environment and Autoimmune Diseases : The Role of Chemicals, Xenobiotics, and Adjuvants

Every day an increasing number of factors responsible for autoimmune diseases are under evaluation, and in particular growing evidence for a pathogenic role is associated to chemicals, xenobiotics, and adjuvants (Chandran and Raychaudhuri 2010; Costenbader et al. 2012; Hemminki et al. 2010; Miller et al. 2012a, b). In the case of chemicals, some studies have demonstrated that aryl hydrocarbon receptor (AhR) can induce Th17 cell to differentiate with their activity exacerbating autoimmune diseases in animal models (Veldhoen et al. 2008), while others have shown that AhR promotes the expansion of regulatory T-cell (Treg) populations, decreases Th17 frequency, and limits the clinical symptoms of disease (Quintana et al. 2008). Mechanisms linking nicotine, inflammation, and interleukin-17 (IL-17) production were studied in a rat adjuvant-induced arthritis model of human rheumatoid arthritis (RA). In this model, nicotine pretreatment aggravates arthritis increasing interferon (IFN) and IL-17 production, whereas posttreatment nicotine suppressed the disease (Yu et al. 2011).

Moreover, toxicological factors, such as silica, have been recently considered as triggering factors for autoimmune diseases based on both epidemiological and experimental evidences. The observation of a possible link between chemicals and disease onset is based on epidemiological studies that associate chemical exposure with biological markers of autoimmunity and also by laboratory studies that identify plausible biological mechanisms through which environmental agents can influence autoimmunity (Miller et al. 2012a, b). As for the role of xenobiotics in autoimmune diseases, recent works showed that the activation of toll-like receptors (TLR) in macrophages predisposes the cells to produce toxin-induced inflammatory cytokines. In fact, co-exposure to nickel and TLR2 agonists induces the release of IL-6 by lung fibroblasts in a protein kinase-dependent pathway (Gao et al. 2010). Because TLR signaling and IL-6 production are key elements in autoimmune diseases, they may be involved in the onset and perpetuation of an autoimmune response in the long term. In mouse models undergoing mercury exposure later developing an autoimmune disease, lipopolysaccharide (LPS) exposure has been shown to trigger the disease onset. Similarly, studies performed in vitro on human peripheral blood mononuclear cells stimulated with mercuric chloride showed that proinflammatory cytokines were induced only when the cells were co-exposed to LPS (Gardner et al. 2009). Similarly to chemicals and xenobiotics, adjuvants can stimulate the immune system even without having an antigenic effect per se. Adjuvants such as pristane , squalene , and mineral oil are capable of activating the immune response and can induce the release of chemokines and proinflammatory cytokines. Some studies, mainly performed on animal models, showed that adjuvants can activate the innate immune system mainly by binding to TLR and inducing dendritic cells or macrophage function, and moreover, they can modulate the release of chemokines and the recruitment of immune cells. Based on these data, we assume that environmental adjuvants can stimulate the innate immune response and then activate the adaptive response, which finally leads to chronic arthritis and production of autoantibodies such as lupus-related anti-Sm/RNP or Su antibodies (Rose 2008; Meroni 2011). Beside adjuvants that can be traced because of their use in experimental models, no specific autoimmune-associated biomarker of adjuvant exposure is currently used to identify and design studies of specific biomarkers of adjuvant exposure.

Another mechanism through which dietary components and environmental toxins can influence autoimmune disease onset is through the modification of the Th17 response in susceptible individuals. This has been evaluated and supported by scientific evidence in autoimmune diseases such as RA, Crohn’s disease, and psoriasis, where Th17 cells seem to be involved in the development and in the relapse of the diseases (Di Cesare et al. 2009; Sarkar and Fox 2010; Segal 2010). In the last decade, several reports showed that vitamin A and vitamin D can exert an immune modulatory effect by controlling the Th17 and Treg balance, and also they play a hormonal role linked not only to bone health but also to immune homeostasis (Quintana and Weiner 2009).

Several studies have indicated that mercury -induced cell death leads to the formation of a unique 19 kDa cleavage fragment of fibrillarin, which cannot be detected in cells died from other causes. These mercury modifications of fibrillarin appear to increase its immunogenicity, and it is unclear whether this process is limited to fibrillarin itself or whether nontargeted cellular proteins are left intact following mercury exposure (Havarinasab and Hultman 2005; Pollard et al. 1997).

Recent reports suggest that environmental chemicals could influence the autoimmune response through the alteration of Treg production or function mediated by multiple intracellular receptors. But new studies are necessary to analyze the assumption that exposure to environmental chemicals, capable of modulating intracellular receptor signaling, is associated with the risk or severity of autoimmune diseases in humans.

3 Environment and Autoimmune Diseases : The Role of Physical Elements

Among many environmental factors that can play a role in autoimmune diseases , receptor-independent stressor-mediated environmental effects have been reported. Among these factors, ultraviolet B (UVB) light is able to induce Treg cell differentiation to produce IL-10 for antigen-specific immunosuppression (Maeda et al. 2008; Shintani et al. 2008). This process mediated by UV light may represent an immunosuppressive response to UV-mediated epithelial cell death and autoantigen presentation by Langerhans cells (Lehmann and Homey 2009). Ionizing radiations are also likely to contribute to the onset of autoimmune diseases, especially thyroid diseases, such as Hashimoto thyroiditis and Graves’ disease, even if research bias (i.e., few studies of medical radiation therapy and inconsistency in findings from nuclear testing fallout and accidental radiation contamination) is still present. Another important field of investigation that deserves further development is the role of UV exposure as risk factor for dermatomyositis and systemic lupus erythematosus (SLE), as suggested by prospectively collected and preclinical data on sun sensitivity.

4 Environment and Autoimmune Disease: The Role of Infectious Agents

Infectious agents are one of the most studied environmental factors in the etiopathogenesis of autoimmune diseases . A well-known example is represented by rheumatic fever, caused by streptococcal antigens that can induce systemic symptoms such as fever, arthritis, and also heart disease (Malkiel et al. 2000). Other infections, mainly mediated by viruses such as Epstein-Barr virus (EBV), are linked to the development of autoimmune diseases such as SLE (Barzilai et al. 2007) but also RA (Balandraud et al. 2004), and Sjögren’s syndrome (Padalko and Bossuyt 2001). Besides EBV, a potential role for cytomegalovirus (CMV ) in the development of SLE has been suggested (Su et al. 2007), similarly to antiphospholipid syndrome (Blank et al. 2004; Blank and Shoenfeld 2004; Shoenfeld and Blank 2004).

The mainly accepted hypothesis assumes that genetically predisposed individuals with a normal immune system who develop a viral infection (probably with other concomitant environmental factors) activate autoimmunity through the action of viral superantigens, molecular mimicry, polyclonal activation, epitope spreading, and bystander activation (Barzilai et al. 2007). This uncontrolled activation leads to autoimmunity, which we can detect through sera autoantibodies, even before the onset of the clinical symptoms of the disease. Whether these are stochastic associations or significant pathogenetic links remains to be clarified in most cases; however, the time lapse between induction of infection and clinical manifestations will make a direct proof poorly feasible in humans, maybe in animal models.

5 Conclusions

The data reported in this chapter show that multiple agents are under investigation for their capacity to lead to multiple modifications (i.e., phosphorylation, glycosylation, acetylation, deamidation) in response to self-antigens, with the breakdown of tolerance and the onset of autoimmune reactions and diseases. Beside cellular mechanisms of innate and adaptive immunity, also autoantibodies to modified self-antigens can be crucial to the effector immune reaction against target tissues, as well represented in RA.

The lack of epidemiological data reflects that main difficulties and gaps are still present in this field, such as quantifying the exposure to environmental chemicals and analyzing multiple cellular subsets and their functions in human populations. A few recommendations for future research include (i) analysis of multiple chemical mixtures , reflecting the real-life complexity of human life in contact with the environment; (ii) exposure-related risks within specific disease phenotypes and in the context of genetic risk factors, such as the smoking associated with RA-defined anti-citrullinated peptide antibody positivity; and (iii) the definition of critical “windows of opportunity” in the timing of exposure and latency relative to age/developmental stage, understanding dose-response relationship, and identifying mechanisms that lead to autoimmunity.

More “translational” epidemiological studies of environmental autoimmunity are needed and should be guided by mechanisms defined in animal model systems and vice versa. An integrated, multidisciplinary approach is critical, and programs should be established to provide opportunities for collaboration and improve communication between epidemiologists, exposure scientists, and basic cellular/molecular biologists, i.e., fostering of interdisciplinary research through forums, funding, and training. Moreover, funding opportunities need to be specifically addressed toward autoimmunity and environmental factor research studies. In fact, a better coordination across the different disciplines and agencies conducting autoimmune research may help to encourage collaborations. Such coordinated efforts may also promote a more cohesive body of knowledge through studies of multiple autoimmune diseases with similar underlying mechanisms and shared genetic or environmental risk factors.

An important need for human autoimmune research is, for example, the availability of high-quality, validated measurement tools. As to the efforts to characterize the genome, new technologies should be harnessed to address the critical need to characterize human environmental exposures. An environment-wide association (exposure/EWAS) study database (complementing PHENX) would facilitate future epidemiological studies. More data are also needed to establish the contribution of psychosocial factors, infections, complex mixtures, and susceptibility factors to the development and severity of autoimmune diseases . Biomarkers identified by mechanistic studies should be applied to epidemiological research in the context of relevant exposure measures. Investments in high-quality exposure measures and biological markers will increase the ability to identify environmental contributions to the etiopathogenesis of autoimmune diseases.

Finally, a consensus-based approach should be established to define autoimmune phenotypes (rather than diseases), which may improve comparability between human studies and animal models. The focus on studying diseases defined by classification criteria may limit interpretation of animal model data and the ability to identify human exposure cohorts using the broadest disease definitions. Conversely, there is a need for animal models to better represent phenotypes that occur in human diseases (e.g., CNS -SLE). Some environmental exposures may cause diseases characterized by a mixture of outcomes or multiple phenotypes that do not fit the standard diagnostic criteria. Outbreak investigations should collect data to characterize the emerging phenotypes and include the preservation and archiving of biological specimens. Long-term follow-up of affected individuals is critical to assess phenotypes that might develop with long latency.