Abstract
Down syndrome (DS) is the most common genetic cause of learning difficulties and intellectual disabilities. DS patients often present with several congenital defects and chronic diseases, including immunity disorders. Elevated levels of pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) have been seen, which appear to vary with age. At birth, patients present with combined immunodeficiency, with frequent infections that decrease with age. Furthermore, high levels of IL-4 and IL-10 with anti-inflammatory properties and low levels of IL-6 and TNF-α are described in children. The immune system is believed to play an essential role in SARS-CoV-2 pathogenesis, and it has been associated with elevated levels of pro-inflammatory cytokines and an exaggerated cytokine release syndrome (CRS) that may eventually trigger a severe situation called cytokine storm. On the other hand, genetic features seem to be involved in the predisposition to illness and its severity. Overexpression of DSCR1 and ZAKI-4 inhibits the translocation of activated T lymphocyte nuclear factor (NF-AT) to the nucleus, a main step in the inflammatory responsiveness. We discuss here the possible role of immunology and genetic features of DS in the infection and prognosis in COVID-19.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Coronavirus (Coronaviridae), one of the most contagious viruses, is primarily targeting the human respiratory system and infecting the epithelial cells of the respiratory tract, but it also has neuroinvasive capabilities to spread from the respiratory tract to the central nervous system (CNS) [1]. More than one-third of COVID-19 patients present neuropsychiatric symptoms during the course of the disease. Even in some patients, neurologic symptoms may be the initial or only presentations of the COVID-19 [2]. An association between major depressive disorder (MDD), alexithymia, and negative complications such as suicidal behavior in COVID-19 patients has been described. There is an increasing evidence that alexithymia may be considered a risk factor for suicide, even simply increasing the risk of development of depressive symptoms or per se [3]. The prevalence of alexithymia is quite high in subjects with psychiatric disorders [4]. Therefore, the studies on relationships between alexithymia and suicide risk on clinical samples of patients with psychiatric disorders are very interesting as alexithymia may predispose to their development or worsen an existing one [3].
Previous studies highlighted the involvement of sensory perception in emotional processes as well as its prognosis. Engel-Yeger et al. examined the unique sensory processing patterns of individuals with major affective disorders and their relationship with psychiatric symptomatology. They have shown that hyposensitivity or hypersensitivity may be “trait” markers of individuals with major affective disorders. Thus, interventions should refer to the individual unique sensory profiles and their behavioral and functional impact in the context of real life [5].
Down syndrome (DS), initially described by John Langdon Down in 1866 [6], is the most frequent aneuploidy characterized by a genetic disorder that results from the triplication of human chromosome 21 [7, 8], also related to chromosomal abnormalities such as translocation and mosaicism [8, 9]. There are three main types of DS: trisomy 21 (most common form, all cells have a triple copy of the 21st chromosome), mosaicism (some cells have three copies of chromosome 21 and some cells have two copies of chromosome 21), and translocation (a third copy of chromosome 21 is translocated to another acrocentric chromosome). It is also the most common genetic cause of learning difficulties and intellectual disabilities [7]. The incidence in Europe is about 1.1 per 1000 live births [10] and in the USA about 1.42 in 1000 live births [11], calculating that in the world there are around 6 million people affected [12]. The survival of individuals with Down syndrome has increased in recent decades (owing mainly to improved management of congenital heart defects), resulting in large numbers of adults with DS.
DS is characterized by developmental delay, with typical dysmorphic characteristics and mild intellectual involvement [13], showing CI punctuations between 37 and 70 with an average of 50, while in the general population, it ranges from 85 to 115 with an average of 100 CI [14].
Many conditions can occur in DS, such as congenital heart problems present in 50% of cases [15], gastrointestinal problems [16], and hypothyroidism [17]. It should also be noted that in DS, the immune system is usually compromised, which makes this population more exposed to infections and autoimmune conditions such as celiac disease, thyroid disease, or type I diabetes mellitus, in addition to autoinflammatory conditions [18]. DS is also related to eating problems with overweight, obesity, hypercholesterolemia, and vitamin and mineral deficiencies [19].
Concerning neuronal aspects, there are generalized alterations in neurogenesis, an excessive number of astrocytes, dendritic atrophy, and problems in establishing new neuronal connections [20]. It has also been related to a smaller brain volume, maturation disorders, and reduced neurotransmitter release. The lower brain volume is related to psychomotor impairment, which affects cognition, gait quality, and voluntary movement [21]. Moreover, hypoplasia that mainly affects the cerebellum in addition produces speech balance and coordination problems [22].
Regarding neurodegenerative processes, DS is associated with the presence of early Alzheimer’s, between the age of 40 and 50 years [23]. DS dementia is the most common form of dementia in individuals under 50 years of age [24]. However, the causes of this early deterioration are currently under discussion, being attributed to neuronal changes associated with insulin levels [25], which plays a neuroprotective role against ischemia, oxidative stress, apoptosis, and toxicity of amyloid-β(Aβ) [26]. Besides, the association between Alzheimer’s disease (AD) and DS has been described, together with high levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, which are pro-inflammatory cytokines [27, 28]. Parkinson’s and Huntington diseases have also been correlated with DS [7]. Down syndrome (DS) is also characterized by overexpression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by amyloid-β(Aβ) overproduction and tau hyperphosphorylation as early as the age of 40, and it has been speculated DS individuals may benefit from active immunotherapy against Aβ from a young age [29].
In addition, killer-specific secretory (Ksp37) gene is commonly expressed by NK, CD8(+) T, γδ T, and CD4(+) T cells, suggesting that Ksp37 has cytotoxic properties. An increase of Ksp37 protein serum levels has been shown during the acute phase of Epstein-Barr virus (EBV), and chronic infection by EBV is frequently present in subjects with Down syndrome. Salemi et al. showed that in fibroblasts and leukocytes of Down syndrome subjects, the KSP37 gene expression was increased compared with control subjects. The results of this study suggest that the expression of Ksp37 gene might be associated with increased susceptibility of individuals with Down syndrome to EBV infections and autoimmune problems [30].
Nuclear factor-kB1(NF-kB1) regulates the transcription of many genes involved in immune response, cell adhesion, differentiation, proliferation, angiogenesis, and apoptosis, and increased NF-kB1 activation is involved in inflammatory response [31]. Regarding immune activity in subjects with DS, another study has found down-expression of NF-kB1 in cells from DS patients compared to normal subjects. The minor expression of NF-kB1 may relate to the association of this gene to the same pathway of expression that in this case favors the activation of the pro-apoptotic mechanisms in DS. In fact, inhibition of NF-kB1 has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth [32].
In February 2020, the World Health Organization named COVID-19 disease, which means coronavirus disease 2019 [33]. The virus that causes COVID-19 is called SARS-CoV-2 (severe acute respiratory syndrome coronavirus); previously, it was called 2019-nCoV [34, 35]. The World Health Organization (WHO) announced the new disease’s official name as “coronavirus disease 2019” (COVID-19), and the International Committee on Virus Taxonomy named it SARS-CoV-2. On March 11, 2020, the WHO declared the pandemic [33]. Since the start of the pandemic until July 14, 2020, more than thirteen million cases have been reported worldwide [36]. Currently, its genomic sequence has already been made public (Wuhan-Hu-1, GenBank Accession No. MN908947). However, the pathogenic mechanisms and the genetic role in them are not yet fully understood.
Immunology
SARS-CoV-2 infection activates the innate immune system, generating an excessive response that could be related to more significant lung injury. Pro-inflammatory cytokines (IL-2R, IL-6, IL8, IL10, and TNFα) have been also found to be associated with a hypercoagulability state [37] leading to the development of vascular disorders such as hearth [38] and cerebrovascular diseases [39], and worse clinical evolution. Clinical observations suggest that when the immune response is unable to effectively control the virus, as in older people with a weakened immune system, the virus would spread more efficiently, causing lung tissue damage, which would activate macrophages and granulocytes and could lead to the massive release of pro-inflammatory cytokines [40]. A Chinese research team has described the activation circuit of this immune pathway from the activation of aberrant CD4+ and CD8+ T helper (Th) lymphocytes (with higher expression of inflammatory markers, compared to healthy controls). In patients with SARS-CoV-2 pneumonia admitted to the intensive care unit (ICU) compared to those not admitted to the ICU, and with healthy controls, they observed a correlation with a higher proportion of CD4+ T cells that produce IL-6 and GM-CSF (granulocyte-macrophage colony-stimulating factor) with the severity of COVID-19 cases [41]. Other studies have observed the presence of elevated levels of IL-6 and other pro-inflammatory cytokines in patients with severe COVID-19 [42]. This activation could carry cytokine release syndrome (CRS), which can trigger a positive feedback loop that overwhelms counter-regulatory homeostatic mechanisms and results in a cytokine storm [43] (Fig. 1). It would be associated with acute respiratory failure syndrome or adult respiratory distress syndrome (ARDS), which has been described as the main cause of death from COVID-19 [44]. CRS occurs when large numbers of leukocytes (neutrophils, macrophages, and mast cells) are activated and release large amounts of pro-inflammatory cytokines [45]. The central cytokines involved in CRS pathogenesis include IL-6, IL-10, interferon (IFN), monocyte chemotactic protein 1 (MCP-1), and GM-CSF. Other cytokines such as tumor necrosis factor (TNF), IL-1, IL-2, and IL-8 have also been described during the CRS. This syndrome has been observed in other viral infections such as SARS, MERS, or Ebola, although through the alteration of different pathways. Furthermore, an increased plasma concentration of various cytokines has been observed (IL-1β, IL-6, IL2, IL-2R, IL7, IL10, GSCF, IP10, MCP1 MIP1A, TNFα, etc.) in patients with COVID-19 mainly in patients with more severe symptoms [46].
Over the past decades, the immune system in DS has been studied extensively. DS patients have been reported to have an increase in circulating cytokines other than TNF-α, including interleukin β and interleukin γ levels, and impaired cell-mediated immune function. These anomalies might cause an abnormal exacerbated inflammatory response and more severe disease in response to viral infection, as described in COVID-19 [47]. Enhanced expression of pro-inflammatory mediators (IFNγ, IL1β, IL15, MIP3α, G-CSF, and IL17A) has been observed in the hippocampi of animal models of DS significantly reduced by the chronic administration of an anti-IL17 mAb [48].
In the other hand, Cetiner et al. suggest that a poor anti-inflammatory state with low IL-6 and TNF-α would explain the cause of susceptibility to infections in DS children [47]. They found reduced levels of IL-6 and TNF-α, and higher levels of anti-inflammatory cytokines IL-10 and IL-4, which inhibit the synthesis of pro-inflammatory cytokines such as IL-6 and TNF-α. It has been known that subjects with DS have an increased susceptibility to bacterial and viral infections, and autoimmune disorders according to healthy population, due to the impairment of the immune system [49,50,51].
In addition, individuals with trisomy 21 show more severe consequences during viral lung infections, such as increased rates of hospitalization during respiratory syncytial virus (RSV) and H1N1 influenza A infections [52, 53]. The results of the study from Cetiner et al. might suggest that continuing anti-inflammatory state in DS is the cause of recurrent infections in DS child. In a recent study with 3 cases of DS infected by SARS-CoV-2, Krishnan et al. have speculated that repeated viral infections in the first years of life may boost natural humoral and cellular immunity explaining decreasing infections with age [54]. Patients who had a history of repeated viral infections had milder clinical courses in response to SARS-CoV-2 infection. And those who did not have frequent viral infections as a child had a more severe and prolonged course of SARS-CoV-2 infection [54]. Then, the variable levels of circulating cytokines reported probably reflect the ages of the patients studied, their environment, and associated disorders as well as previous exposure to infections. Thus, DS could be a risk factor for infection and COVID-19 in the child, while in older adults, high levels of pro-inflammatory cytokines (IL-6 and TNF-α) could produce an exaggerated response to SARS-CoV-2 infection, leading to poor prognosis.
How trisomy 21 produces an alteration in the immune system is not yet completely known. However, there are several genes involved in the immune response whose overexpression could contribute to these abnormalities. Mainly the immune regulators encoded on chromosome 21 are four of the six interferon receptors: the two type I interferon (IFN) receptors IFNAR1 and IFNAR2, the type II IFN receptor IFNGR2, and IL10RB, which serve as receptor subunits not only for type III IFNs but also for cytokines IL-10, IL-22 and IL-2 [55,56,57]. These genes are overexpressed in all individuals with Down syndrome, regardless of sex, age, or ethnicity [58, 59]. Furthermore, a positive feedback mechanism likely exists between pro-inflammatory cytokine production, the Aβ burden, and the APP level, present in DS and AD [48].
Several lines of evidence demonstrate the hyperactivation of IFN signaling in DS [55]. Previous epidemics of coronavirus (SARS) and influenza (bird flu and Spanish flu) produced a high number of deaths. The cytokine storm is believed to be the cause. Preliminary studies conducted in Hong Kong [57] indicated that this was probably the leading cause of death during the 2003 SARS epidemic, as was the 2019–2020 coronavirus (SARS-CoV-2) [60].
Genetics
Solid malignancies (apart from testicular cancer) are less common, resulting in a lower overall risk for malignancies in Down syndrome [58, 61, 62]. Overexpression of DSCR1 and ZAKI-4 inhibits the transcription of calcineurin-dependent genes, by inhibiting the translocation of activated T lymphocyte nuclear factor (NF-AT) to the nucleus [63]. Precisely the non-structural protein SARS-CoV 1 (Nsp1) induces the expression of IL-2 through the activation of NF-AT [64, 65] which could trigger the cytokine storm observed in patients. Therefore, over-activation of the DSCR1 protein, in addition to protecting against cancer, might be expected to do so in the effects of COVID-19. Prefferle et al. identified redundant interactions between SARS-CoV non-structural protein Nsp1 and a group of host proteins with peptidyl-prolylcis-trans-isomerase activity, including the cyclophilins/immunophilins PPIA, PPIG, PPIH, FKBP1A, and FKBP1B [65]. These modulate the calcineurin/NFAT pathway that plays an important role in immune cell activation [66, 67]. They showed that SARS-CoV non-structural protein Nsp1, as well as full replicating SARS-CoV, enhances the CnA/NFAT pathway and induces NFAT-responsive promoters. This point could be a target for ciclosporin A in treatment of the infection [65]. Like DSCR1, it inhibits this pathway in BS.
In addition, increased neuroinflammation in DS brains appears to be mainly mediated by the exacerbation of macrophage activation state 1 (M1) cells due to the triplication of some critical inflammatory-associated genes, including RCAN1, CXADR, ADAMTS1, ADAMTS5, TIAM1, and IFNGR2 [48].
The SARS-CoV-2 genome is made up of a single positively polarized single-stranded RNA chain (+ ssRNA) of approximately 30,000 base pairs. This RNA chain structurally resembles a messenger RNA (mRNA) of eukaryotic cells. However, unlike eukaryotic mRNAs, this viral genome contains at least six open reading frames (ORFs) [68,69,70]. Thus, the first two-thirds (closer to the 5′ end) code for the viral replicating gene. This gene is made up of two ORFs (ORF 1a and ORF 1b) [68], which, at the beginning of the infection, will be directly translated into two large polyproteins called pp1a and pp1ab. These polyproteins will subsequently be proteolytically processed to generate 16 non-structural proteins (NSPs), which will be involved in the replication of the viral genome and the transcription of subgenomic mRNAs (sgRNAs) [71,72,73,74].
Conclusion
Even though the effects of DSCR1 overexpression are contradicted by the increase in IL-2 levels in DS and the probability of an exacerbated immune response, it could be explained by the differences between the infant and adult stages. That is, in children, there would be an immunodeficiency as already described in the last decades that would facilitate infections, with decreased levels of pro-inflammatory interleukins such as IL-2. However, in adults, there would be a pro-inflammatory state with elevated pro-inflammatory cytokine levels, such as IL-2, IL-6, and TNF-α, as described in DS (also related to AD).
According to this hypothesis, DS could be a risk factor for suffering COVID-19 in the child, while in adulthood, DS would protect against SARS-CoV-19 infection, but with a worse prognosis due to an exaggerated immune response (cytokine storm).
Although DS cases have already been described with COVID-19, finding that on average they are admitted up to 10 years younger than the general population, and with greater severity of symptoms [75], this does not allow us to conclude that it is a risk factor, but those who have been hospitalized showed more severe symptoms, without knowing their clinical history and comorbidities.
Therefore, with all the aforementioned, COVID-19 would not only affect depending on the person’s state of health or age but could also be affected by genetic components such as the alteration of chromosome 21 present in Down syndrome.
On the other hand, it must be taken into account that despite the considerable increase in life expectancy in the case of DS [10], one of the characteristics of this group is accelerated and premature aging [76], so if we were to attend to the age of the organism, people over 40 would be in the highest risk group, as are those over sixty in the general population.
In brief, different pro-inflammatory and anti-inflammatory cytokine levels have been shown in DS from child to adulthood. Neuroinflammation would play a main role in the DS and other neurodegenerative disorders such as AD. It is postulated a hyperresponsiveness of the immune system involved in the neuropathogenesis of COVID-19 and related severity. Genetics and age could modify the infection response to SARS-CoV-2 in DS, with different features from COVID-19 patients without DS.
However, several limitations are present in this article. Here we describe only some characteristics of the immune system and genetics consequences from the triplication of human chromosome 21, but there are myriads of cross talking pathways that differ from healthy controls in addition to the mentioned. Besides, these molecular links determine a panoply of processes that change throughout the age of the controls, COVID-19 patients, and DS subjects.
References
Kumar M, Thakur AK (2020) Neurological manifestations and comorbidity associated with COVID-19: an overview. Neurol Sci. https://doi.org/10.1007/s10072-020-04823-6
Sultana S, Ananthapur V (2020)COVID-19 and its impact on neurological manifestations and mental health: the present scenario. Neurol Sci 41:3015–3020. https://doi.org/10.1007/s10072-020-04695-w
De Berardis D, Fornaro M, Orsolini L, Valchera A, Carano A, Vellante F et al (2017) Alexithymia and suicide risk in psychiatric disorders: a mini-review. Front Psychiatry 8:148. https://doi.org/10.3389/fpsyt.2017.00148
Leweke F, Leichsenring F, Kruse J, Hermes S (2011) Is alexithymia associated with specific mental disorders? Psychopathology 45:22–28. https://doi.org/10.1159/000325170
Engel-Yeger B, Muzio C, Rinosi G, Solano P, Geoffroy PA, Pompili M, Amore M, Serafini G (2016) Extreme sensory processing patterns and their relation with clinical conditions among individuals with major affective disorders. Psychiatry Res 236:112–118. https://doi.org/10.1016/j.psychres.2015.12.022
Langdon-Down JLH. On some of the mental affections of childhood and youth being The Lettsomian Lectures delivered before The Medical Society of London in 1887 together with other papers. Ment Affect Child Youth Being Lettsomian Lect Deliv before Med Soc London 1887 Together with Other Pap 1990:1–84
Ballard C, Mobley W, Hardy J, Williams G, Corbett A (2016) Dementia in Down’s syndrome. Lancet Neurol 15:622–636. https://doi.org/10.1016/S1474-4422(16)00063-6
Moreira L, El-Hani CN, Gusmão FAF (2000) A síndrome de Down e sua patogênese: considerações sobre o determinismo genético. Braz J Psychiatry 22:96–99
Chapman RS, Hesketh LJ (2000) Behavioral phenotype of individuals with Down syndrome. Ment Retard Dev Disabil Res Rev 6:84–95
Loane M, Morris JK, Addor MC, Arriola L, Budd J, Doray B, Garne E, Gatt M, Haeusler M, Khoshnood B, Klungsøyr Melve K, Latos-Bielenska A, McDonnell B, Mullaney C, O’Mahony M, Queißer-Wahrendorf A, Rankin J, Rissmann A, Rounding C, Salvador J, Tucker D, Wellesley D, Yevtushok L, Dolk H (2013)Twenty-year trends in the prevalence of Down syndrome and other trisomies in Europe: impact of maternal age and prenatal screening. Eur J Hum Genet 21:27–33. https://doi.org/10.1038/ejhg.2012.94
Presson AP, Partyka G, Jensen KM, Devine OJ, Rasmussen SA, McCabe LL et al (2013) Current estimate of Down syndrome population prevalence in the United States. J Pediatr 163:1163–1168
FAQ and facts about down syndrome-Global Down Syndrome Foundation n.d. https://www.globaldownsyndrome.org/about-down-syndrome/facts-about-down-syndrome/ (accessed 12 July 2020)
Lott IT, Dierssen M (2010) Cognitive deficits and associated neurological complications in individuals with Down’s syndrome. Lancet Neurol 9:623–633. https://doi.org/10.1016/S1474-4422(10)70112-5
Vicari S, Marotta L, Carlesimo GA (2004) Verbal short-term memory in Down’s syndrome: an articulatory loop deficit? J Intellect Disabil Res 48:80–92. https://doi.org/10.1111/j.1365-2788.2004.00478.x
Asim A, Kumar A, Muthuswamy S, Jain S, Agarwal S. Down syndrome: an insight of the disease. J Biomed Sci 2015;22. https://doi.org/10.1186/s12929-015-0138-y, 22
Holmes G (2014) Gastrointestinal disorders in Down syndrome. Gastroenterol Hepatol Bed Bench 7:6
Amr NH (2018) Thyroid disorders in subjects with down syndrome: an update. Acta Biomed 89:132–139. https://doi.org/10.23750/abm.v89i1.7120
Verstegen RHJ, Chang KJJ, Kusters MAA (2020) Clinical implications of immune-mediated diseases in children with Down syndrome. Pediatr Allergy Immunol 31:117–123. https://doi.org/10.1111/pai.13133
Matuszak K, Bryl W, Pupek-Musialik D (2010) Obesity in children and adolescents with mental retardation. Forum Zab Metab 1:55–63
Bartesaghi R, Guide S, Ciani E (2011) Is it possible to improve neurodevelopmental abnormalities in Down syndrome? Rev Neurosci 22:419–455. https://doi.org/10.1515/RNS.2011.037
Teipel SJ, Alexander GE, Schapiro MB, Möller H-J, Rapoport SI, Hampel H (2004)Age-related cortical grey matter reductions in non-demented Down’s syndrome adults determined by MRI with voxel-based morphometry. Brain 127:811–824
Šveljo O, Ćulić M, Koprivšek K, Lučić M (2014) The functional neuroimaging evidence of cerebellar involvement in the simple cognitive task. Brain Imaging Behav 8:480–486. https://doi.org/10.1007/s11682-014-9290-3
Wiseman FK, Al-Janabi T, Hardy J, Karmiloff-Smith A, Nizetic D, Tybulewicz VLJ et al (2015) A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci 16:564–574
Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, Lawrence D, Yu LM, Tyrer S, Francis PT, Johnson T, Bullock R, Ballard C (2012) Memantine for dementia in adults older than 40 years with Down’s syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet 379:528–536. https://doi.org/10.1016/S0140-6736(11)61676-0
Tramutola A, Lanzillotta C, Di Domenico F, Head E, Butterfield DA, Perluigi M et al (2020) Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome. Neurobiol Dis 137:104772. https://doi.org/10.1016/j.nbd.2020.104772
Ferreira LSS, Fernandes CS, Vieira MNN, De Felice FG (2018) Insulin resistance in Alzheimer’s disease. Front Neurosci 12:830
Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, de Felice FG (2012) An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease-associated Aβ oligomers. J Clin Invest 122:1339–1353. https://doi.org/10.1172/JCI57256
Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, Sathler LB, Brito-Moreira J, Amaral OB, Silva CA, Freitas-Correa L, Espírito-Santo S, Campello-Costa P, Houzel JC, Klein WL, Holscher C, Carvalheira JB, Silva AM, Velloso LA, Munoz DP, Ferreira ST, de Felice FG (2013)TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s β-amyloid oligomers in mice and monkeys. Cell Metab 18:831–843. https://doi.org/10.1016/j.cmet.2013.11.002
Illouz T, Madar R, Biragyn A, Okun E (2019) Restoring microglial and astroglial homeostasis using DNA immunization in a Down syndrome mouse model. Brain Behav Immun 75:163–180. https://doi.org/10.1016/j.bbi.2018.10.004
Salemi M, Barone C, Morale MC, Caniglia S, Romano C, Salluzzo MG, Rando RGG, Ragalmuto A, Bosco P, Romano C (2016)Killer-specific secretory (Ksp37) gene expression in subjects with Down’s syndrome. Neurol Sci 37:793–795. https://doi.org/10.1007/s10072-016-2554-5
Beinke S, Ley SC (2004) Functions of NF-κB1 and NF-κB2 in immune cell biology. Biochem J 382:393–409. https://doi.org/10.1042/BJ20040544
Salemi M, Barone C, Romano C, Scillato F, Ragalmuto A, Caniglia S, Salluzzo MG, Sciuto G, Ridolfo F, Romano C, Bosco P (2015)NF-kB1 gene expression in Down syndrome patients. Neurol Sci 36:1065–1066. https://doi.org/10.1007/s10072-014-1981-4
WHO | World Health Organization n.d. https://www.who.int/ (accessed 13 July 2020)
Tikellis C, Thomas MC (2012)Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept 2012:1–8
Ministerio de Sanidad, Consumo y Bienestar Social - Profesionales - Información científico-técnica, enfermedad por coronavirus, COVID-19 n.d. https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActual/nCov-China/ITCoronavirus/home.htm (accessed 13 July 2020)
Johns Hopkins CSSE. Coronavirus COVID-19(2019-nCoV) 2020. https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6 (accessed 7 Mar 2020)
Hornstein NL, Putnam FW (1992) Clinical phenomenology of child and adolescent dissociative disorders. J Am Acad Child Adolesc Psychiatry 31:1077–1085. https://doi.org/10.1097/00004583-199211000-00013
Boukhris M, Hillani A, Moroni F, Annabi MS, Addad F, Ribeiro MH, Mansour S, Zhao X, Ybarra LF, Abbate A, Vilca LM, Azzalini L (2020) Cardiovascular implications of the COVID-19 pandemic: a global perspective. Can J Cardiol 36:1068–1080. https://doi.org/10.1016/j.cjca.2020.05.018
Altable M, de la Serna JM (2020) Cerebrovascular disease in COVID-19: is there a higher risk of stroke? Brain Behav Immun Health 6:100092. https://doi.org/10.1016/j.bbih.2020.100092
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ (2020) COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395:1033–1034. https://doi.org/10.1016/S0140-6736(20)30628-0
Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y et al (2020) Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. BioRxiv. https://doi.org/10.1101/2020.02.12.945576
Conti P, Ronconi G, Caraffa AL, Gallenga CE, Ross R, Frydas I et al (2020) Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 34:1
Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B, von Bergwelt-Baildon MS (2018) Cytokine release syndrome. J Immunother Cancer 6:56. https://doi.org/10.1186/s40425-018-0343-9
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z et al (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395:1054–1062. https://doi.org/10.1016/S0140-6736(20)30566-3
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188–195. https://doi.org/10.1182/blood-2014-05-552729
Mei H, Hu Y (2020) Characteristics, causes, diagnosis and treatment of coagulation dysfunction in patients with COVID-19. Zhonghua Xue Ye Xue Za Zhi 41:185–191. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0002
Cetiner S, Demirhan O, Inal TC, Tastemir D, Sertdemir Y (2010) Analysis of peripheral blood T-cell subsets, natural killer cells and serum levels of cytokines in children with Down syndrome. Int J Immunogenet 37:233–237. https://doi.org/10.1111/j.1744-313X.2010.00914.x
Rueda N, Vidal V, García-Cerro S, Narcís JO, Llorens-Martín M, Corrales A, Lantigua S, Iglesias M, Merino J, Merino R, Martínez-Cué C (2018)Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice. Brain Behav Immun 73:235–251. https://doi.org/10.1016/j.bbi.2018.05.008
Castro M, Crinò A, Papadatou B, Purpura M, Giannotti A, Ferretti F, Colistro F, Mottola L, Digilio MC, Lucidi V, Borrelli P (1993) Down’s syndrome and celiac disease: the prevalence of high IgA-antigliadin antibodies and HLA-DR and DQ antigens in trisomy 21. J Pediatr Gastroenterol Nutr 16:265–268
NESPOLI L, BURGIO GR, UGAZIO AG, MACCARIO R (1993) Immunological features of Down’s syndrome: a review. J Intellect Disabil Res 37:543–551. https://doi.org/10.1111/j.1365-2788.1993.tb00324.x
Scotese I, Gaetaniello L, Matarese G, Lecora M, Racioppi L, Pignata C (1998) T cell activation deficiency associated with an aberrant pattern of protein tyrosine phosphorylation after CD3 perturbation in Down’s syndrome. Pediatr Res 44:252–258. https://doi.org/10.1203/00006450-199808000-00019
Beckhaus AA, Castro-Rodriguez JA (2018) Down syndrome and the risk of severe RSV infection: a meta-analysis. Pediatrics 142:e20180225. https://doi.org/10.1542/peds.2018-0225
Pérez-Padilla R, Fernández R, García-Sancho C, Franco-Marina F, Aburto O, López-Gatell H, Bojórquez I (2010) Pandemic (H1N1) 2009 virus and Down syndrome patients. Emerg Infect Dis 16:1312–1314. https://doi.org/10.3201/eid1608.091931
Krishnan US, Krishnan SS, Jain S, Chavolla-Calderon MB, Lewis M, Chung WK, Rosenzweig EB (2020)SARS-CoV-2 infection in patients with Down syndrome, congenital heart disease, and pulmonary hypertension: is Down syndrome a risk factor? J Pediatr 225:246–248. https://doi.org/10.1016/j.jpeds.2020.06.076
Espinosa JM (2020) Down syndrome and COVID-19: a perfect storm? Cell Rep Med 1:100019. https://doi.org/10.1016/j.xcrm.2020.100019
De Weerd NA, Nguyen T (2012) The interferons and their receptors-distribution and regulation. Immunol Cell Biol 90:483–491. https://doi.org/10.1038/icb.2012.9
Duan ZP, Chen Y, Zhang J, Zhao J, Lang ZW, Meng FK et al (2003) Clinical characteristics and mechanism of liver injury in patients with severe acute respiratory syndrome. Zhonghua Gan Zang Bing Za Zhi= Zhonghua Ganzangbing Zazhi= Chin J Hepatol 11:493
Verstegen RHJ, Kusters MAA (2020) Inborn errors of adaptive immunity in Down syndrome. J Clin Immunol 40:791–806. https://doi.org/10.1007/s10875-020-00805-7
Sullivan KD, Lewis HC, Hill AA, Pandey A, Jackson LP, Cabral JM, Smith KP, Liggett LA, Gomez EB, Galbraith MD, DeGregori J, Espinosa JM (2016) Trisomy 21 consistently activates the interferon response. Elife 5. https://doi.org/10.7554/eLife.16220
Cytokine storm and the H5N1 influenza pandemic: the bird flu n.d. http://www.cytokinestorm.com/ (accessed 13 July 2020)
Hasle H, Friedman JM, Olsen JH, Rasmussen SA (2016) Low risk of solid tumors in persons with Down syndrome. Genet Med 18:1151–1157. https://doi.org/10.1038/gim.2016.23
Satgé D, Seidel MG (2018) The pattern of malignancies in down syndrome and its potential context with the immune system. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.03058
Strippoli P, Lenzi L, Petrini M, Carinci P, Zannotti M (2000) A new gene family including DSCR1 (Down syndrome candidate region 1) and ZAKI-4: characterization from yeast to human and identification of DSCR1-like 2, a novel human member (DSCR1L2). Genomics 64:252–263. https://doi.org/10.1006/geno.2000.6127
Liddicoat AM, Lavelle EC (2019) Modulation of innate immunity by cyclosporine A. Biochem Pharmacol 163:472–480. https://doi.org/10.1016/j.bcp.2019.03.022
Pfefferle S, Schöpf J, Kögl M, Friedel CC, Müller MA, Carbajo-Lozoya J, Stellberger T, von Dall’Armi E, Herzog P, Kallies S, Niemeyer D, Ditt V, Kuri T, Züst R, Pumpor K, Hilgenfeld R, Schwarz F, Zimmer R, Steffen I, Weber F, Thiel V, Herrler G, Thiel HJ, Schwegmann-Weßels C, Pöhlmann S, Haas J, Drosten C, von Brunn A (2011) The SARS-Coronavirus-host interactome: identification of cyclophilins as target for pan-Coronavirus inhibitors. PLoS Pathog 7:e1002331. https://doi.org/10.1371/journal.ppat.1002331
Feske S, Giltnane J, Dolmetsch R, Staudt LM, Rao A (2001) Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol 2:316–324. https://doi.org/10.1038/86318
Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17:2205–2232. https://doi.org/10.1101/gad.1102703
Mousavizadeh L, Ghasemi S (2020) Genotype and phenotype of COVID-19: their roles in pathogenesis. J Microbiol Immunol Infect. https://doi.org/10.1016/j.jmii.2020.03.022
Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, Pan P, Wang W, Hu D, Liu X, Zhang Q, Wu J (2020) Coronavirus infections and immune responses. J Med Virol 92:424–432
Rabaan AA, Al-Ahmed SH, Haque S, Sah R, Tiwari R, Malik YS et al (2020) SARS-CoV-2, SARS-CoV, and MERS-CoV: a comparative overview. Infez Med 28:174–184
Ahn DG, Shin HJ, Kim MH, Lee S, Kim HS, Myoung J, Kim BT, Kim SJ (2020) Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-19). J Microbiol Biotechnol 30:313–324. https://doi.org/10.4014/jmb.2003.03011
Chen Y, Liu Q, Guo D (2020) Emerging coronaviruses: genome structure, replication, and pathogenesis. J Med Virol 92:418–423. https://doi.org/10.1002/jmv.25681
Rokni M, Ghasemi V, Tavakoli Z (2020) Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: comparison with SARS and MERS. Rev Med Virol 30:e2107. https://doi.org/10.1002/rmv.2107
Han Q, Lin Q, Jin S, You L (2020) Coronavirus 2019-nCoV: a brief perspective from the front line. J Inf Secur 80:373–377. https://doi.org/10.1016/j.jinf.2020.02.010
Malle L, Gao C, Bouvier N, Percha B (2020) Bogunovic D (2020)COVID-19 hospitalization is more frequent and severe in Down syndrome. MedRxiv 05(26):20112748. https://doi.org/10.1101/2020.05.26.20112748
Zigman WB (2013) Atypical aging in down syndrome. Dev Disabil Res Rev 18:51–67. https://doi.org/10.1002/ddrr.1128
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This research is not involving human participants.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Altable, M., de la Serna, J.M. Down’s syndrome and COVID-19: risk or protection factor against infection? A molecular and genetic approach. Neurol Sci 42, 407–413 (2021). https://doi.org/10.1007/s10072-020-04880-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-020-04880-x