Human Endogenous Retroviruses in Neurological Diseases
Authors: Patrick Küry, Avindra Nath, Alain Créange, Antonina Dolei, Patrice Marche, Julian Gold, Gavin Giovannoni, Hans-Peter Hartung, Hervé Perron
Journal: Trends in Molecular Medicine (2018)

HERVs, retroviral sequences integrated into the genome during evolution, are now known to represent 8% of the human genome. These were recently shown to comprise copies that retain potential to express retroviral proteins or particles, and can be abnormally expressed in autoimmune, neurodegenerative, chronic inflammatory diseases, and cancer. Environmental factors such as specific viral infections were shown to potently activate HERVs under tissue-specific and temporal conditions. Of several diseases in which abnormal activation and expression of HERV proteins have been reported, studies over recent decades have led to a proof of concept that HERVs play a key role in the pathogenesis of MS and ALS. HERV-W and HERV-K Env proteins induce pathogenic effects in vitro and in vivo that are relevant to the pathognomonic features of these diseases. These endogenous retroviruses are potential novel therapeutic targets that are now being addressed with innovative therapeutic strategies in clinical trials. The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches. The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches. A new comprehensive approach to the etiopathogenesis of some diseases is emerging from studies on genomic remnants of mobile genetic elements (see Glossary) that are known for their role in the molecular evolution of genomes [1Hayes M. et al.Pathological and evolutionary implications of retroviruses as mobile genetic elements.Genes. 2013; 4: 573-582Crossref PubMed Google Scholar, 2Babatz T.D. Burns K.H. Functional impact of the human mobilome.Curr. Opin. Genet. Dev. 2013; 23: 264-270Crossref PubMed Scopus (20) Google Scholar, 3Pace 2nd, J.K. Feschotte C. The evolutionary history of human DNA transposons: evidence for intense activity in the primate lineage.Genome Res. 2007; 17: 422-432Crossref PubMed Scopus (224) Google Scholar, 4Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6e1001191Crossref PubMed Scopus (473) Google Scholar], with a particular focus on human endogenous retroviruses (HERVs). This domain cannot be appropriately understood through classical virology or genetics because it deals with entities that are neither viruses nor physiological genes [5Feschotte C. Gilbert C. Endogenous viruses: insights into viral evolution and impact on host biology.Nat. Rev. Genet. 2012; 13: 283-296Crossref PubMed Scopus (479) Google Scholar]. In the present review we discuss recent scientific discoveries of these long-misunderstood elements, previously considered to be junk DNA but which, in some instances, are now known to contribute to physiological functions ('domesticated copies') [5Feschotte C. Gilbert C. Endogenous viruses: insights into viral evolution and impact on host biology.Nat. Rev. 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Immunol. 2014; 15: 415-422Crossref PubMed Scopus (208) Google Scholar]. We attempt to explain how these peculiar genetic elements may provide missing keys to understanding complex multifactorial diseases. The best-studied diseases where consistent scientific data support an involvement of HERV genetic elements in their pathogenesis are MS (Box 1) and amyotrophic lateral sclerosis (ALS), but we also introduce chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In addition, we discuss novel HERV-targeted therapeutic avenues that are starting to be evaluated in MS and ALS. Moreover, HERVs have also been associated with other diseases such as schizophrenia and bipolar disorder [10Perron H. et al.Molecular characteristics of human endogenous retrovirus type-W in schizophrenia and bipolar disorder.Transl. Psychiatry. 2012; 2: e201Crossref PubMed Scopus (92) Google Scholar], as well as with type 1 diabetes [11Levet S. et al.An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes.JCI Insight. 2017; 294387Crossref PubMed Scopus (31) Google Scholar], but much less data are available for these disorders.Box 1Viruses in MSAn infectious origin of MS was suggested for the first time by Pierre Marie in 1884, but was rejected by the contemporary medical community. The evidence that viruses may contribute to MS comes from the accumulation of immune cells within the brain and CSF, local immune reactivity to specific viruses, and the presence of oligoclonal bands. MS epidemiology indicates some triggers during adolescence, an unusual geographic distribution (a gradient with latitude, but with exceptions: e.g., contrasting patterns in Sardinia and Japan), and epidemic clusters in previously isolated islands. Over time, several viruses have been proposed as causative agents of MS. From the 1940s onward they included rabies virus, herpes simplex virus (HSV), scrapie prion, an unidentified MS-associated agent, parainfluenza virus 1, measles virus, simian virus 5, chimpanzee cytomegalovirus, coronavirus, EBV, an unidentified SMON-like virus (subacute myelo-opticoneuropathy virus), tick-borne encephalitis virus, HTLV-1, HSV-1, VZV, and HHV-6. The proposed mechanisms were direct brain or peripheral infection, activation of autoreactive T cells against nerve myelin, bystander activation, epitope spreading, molecular mimicry, and virus–virus interactions. However, the link to MS was shown to be weak for the majority of the above viruses. The most consistent and independently confirmed studies for viral involvement in MS are for EBV. They appear to be confirmed, but only with indirect links, by history of infectious mononucleosis (IM; primary infection with EBV causes IM), and high anti-EBNA-1 (EBV nuclear antigen 1) IgG titers before MS onset. However, a new concept arose with the discovery that HERVs express pathogenic proteins in disease, and the best evidence of an association and pathogenic involvement is for HERV-W/MSRV (detected in MS blood, spinal fluid, and brain, in parallel with MS stages, active/remission phases, and therapy outcome). EBV is known to activate HERV-W/MSRV in vitro and in vivo (in IM patients and in healthy humans with high anti-EBNA1 IgG titers). This suggests that EBV could be an initial trigger, and that HERV-W/MSRV is a direct neuropathogenic contributor, before and during MS, in addition to its known contribution to promoting autoreactive T cells, immunoinflammation, and remyelination blockade. An infectious origin of MS was suggested for the first time by Pierre Marie in 1884, but was rejected by the contemporary medical community. The evidence that viruses may contribute to MS comes from the accumulation of immune cells within the brain and CSF, local immune reactivity to specific viruses, and the presence of oligoclonal bands. MS epidemiology indicates some triggers during adolescence, an unusual geographic distribution (a gradient with latitude, but with exceptions: e.g., contrasting patterns in Sardinia and Japan), and epidemic clusters in previously isolated islands. Over time, several viruses have been proposed as causative agents of MS. From the 1940s onward they included rabies virus, herpes simplex virus (HSV), scrapie prion, an unidentified MS-associated agent, parainfluenza virus 1, measles virus, simian virus 5, chimpanzee cytomegalovirus, coronavirus, EBV, an unidentified SMON-like virus (subacute myelo-opticoneuropathy virus), tick-borne encephalitis virus, HTLV-1, HSV-1, VZV, and HHV-6. The proposed mechanisms were direct brain or peripheral infection, activation of autoreactive T cells against nerve myelin, bystander activation, epitope spreading, molecular mimicry, and virus–virus interactions. However, the link to MS was shown to be weak for the majority of the above viruses. The most consistent and independently confirmed studies for viral involvement in MS are for EBV. They appear to be confirmed, but only with indirect links, by history of infectious mononucleosis (IM; primary infection with EBV causes IM), and high anti-EBNA-1 (EBV nuclear antigen 1) IgG titers before MS onset. However, a new concept arose with the discovery that HERVs express pathogenic proteins in disease, and the best evidence of an association and pathogenic involvement is for HERV-W/MSRV (detected in MS blood, spinal fluid, and brain, in parallel with MS stages, active/remission phases, and therapy outcome). EBV is known to activate HERV-W/MSRV in vitro and in vivo (in IM patients and in healthy humans with high anti-EBNA1 IgG titers). This suggests that EBV could be an initial trigger, and that HERV-W/MSRV is a direct neuropathogenic contributor, before and during MS, in addition to its known contribution to promoting autoreactive T cells, immunoinflammation, and remyelination blockade. The eukaryotic genome is composed of a large set of DNA sequences, many of which derive from mobile genetic elements [1Hayes M. et al.Pathological and evolutionary implications of retroviruses as mobile genetic elements.Genes. 2013; 4: 573-582Crossref PubMed Google Scholar, 12Criscione S.W. et al.Transcriptional landscape of repetitive elements in normal and cancer human cells.BMC Genomics. 2014; 15: 583Crossref PubMed Scopus (189) Google Scholar]. These were estimated to account for about 50% of the human genome [13Liang P. Tang W. Database documentation of retrotransposon insertion polymorphisms.Front. Biosci. 2012; 4: 1542-1555Crossref Scopus (6) Google Scholar, 14Hedges D.J. Belancio V.P. Restless genomes: humans as a model organism for understanding host–retrotransposable element dynamics.Adv. Genet. 2011; 73: 219-262Crossref PubMed Scopus (17) Google Scholar, 15Medina J. Perron H. DNA sequences from mobile genetic elements, a hidden half of the human genome.Med. 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Two types of transposable elements can be distinguished: (i) elements that can be transposed via a DNA intermediate and a cut-and-paste mechanism (transposons) [18Campos-Sanchez R. et al.Genomic landscape of human, bat, and ex vivo DNA transposon integrations.Mol. Biol. Evol. 2014; 31: 1816-1832Crossref PubMed Scopus (17) Google Scholar], and (ii) those using a RNA and a copy-paste mechanism (retrotransposons) [16Hancks D.C. Kazazian Jr., H.H. Roles for retrotransposon insertions in human disease.Mob. DNA. 2016; 7: 9Crossref PubMed Scopus (434) Google Scholar]. Retrotransposons comprise endogenous retroviruses (ERVs), for which the current literature presents incomplete data as well as several classifications and nomenclatures, leading to ambiguities [15Medina J. Perron H. DNA sequences from mobile genetic elements, a hidden half of the human genome.Med. Sci. 2017; 33: 151-158Google Scholar]. The term 'HERV' refers to the sequences of human ERV families. HERVs retain structural features of retroviral genomes (Figure 1B), and originally entered the genome of species through repeated infections of germ cells over millions of years (Figure 2) [5Feschotte C. Gilbert C. Endogenous viruses: insights into viral evolution and impact on host biology.Nat. Rev. Genet. 2012; 13: 283-296Crossref PubMed Scopus (479) Google Scholar, 19Belshaw R. et al.Long-term reinfection of the human genome by endogenous retroviruses.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4894-4899Crossref PubMed Scopus (314) Google Scholar]. The question of why and how HERV copies that have retained coding potential may become expressed is now addressed. The ability of HERVs to become activated is linked to the chromatin state where a given copy is located [20van de Lagemaat L.N. et al.Multiple effects govern endogenous retrovirus survival patterns in human gene introns.Genome Biol. 2006; 7: R86Crossref PubMed Scopus (73) Google Scholar]. DNA methylation and histone modifications are essential to the epigenetic control of human genes, including HERV elements. The prerequisite for functional transcription is that HERV sequences must retain functional long terminal repeats (LTRs), or become controlled by another promoter, without deletions or nucleotide substitutions that disrupt their open reading frames (ORFs). Because the nuclear microenvironment including the chromatin accessibility of coding regions differs between tissues, the baseline predisposition of a HERV copy to be activated can be tissue-, cell-, or maturation stage-specific. Inflammatory stimuli may activate HERVs via epigenetic dysregulation. For instance, transcription of HERV-W sequences has been reported to be upregulated by proinflammatory cytokines in cultured cells from MS patients [21Serra C. et al.In vitro modulation of the multiple sclerosis (MS)-associated retrovirus by cytokines: implications for MS pathogenesis.J. Neurovirol. 2003; 9: 637-643PubMed Google Scholar], and this was shown to correlate with increased differentiation of peripheral blood mononuclear cells from MS patients [22Uleri E. et al.HIV Tat acts on endogenous retroviruses of the W family and this occurs via Toll-like receptor 4: inference for neuroAIDS.AIDS. 2014; 28: 2659-2670Crossref PubMed Scopus (40) Google Scholar]. By contrast, reductionof anti-Env antibody reactivity for HERV-H and HERV-W [23Petersen T. et al.Effects of interferon-beta therapy on innate and adaptive immune responses to the human endogenous retroviruses HERV-H and HERV-W, cytokine production, and the lectin complement activation pathway in multiple sclerosis.J. Neuroimmunol. 2009; 215: 108-116Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] and MS-associated retrovirus (MSRV) load [24Mameli G. et al.Inhibition of multiple-sclerosis-associated retrovirus as biomarker of interferon therapy.J. Neurovirol. 2008; 14: 73-77Crossref PubMed Scopus (53) Google Scholar] in the blood have been in seen in MS patients treated with IFN-β, suggesting efficacy of the therapy or low disease activity. After an initial study, which first presented evidence that herpesviruses might trigger HERVs in patients with MS as part of the retrovirus hypothesis for MS etiology [25Perron H. et al.Herpes simplex virus ICP0 and ICP4 immediate early proteins strongly enhance expression of a retrovirus harboured by a leptomeningeal cell line from a patient with multiple sclerosis.J. Gen. Virol. 1993; 74: 65-72Crossref PubMed Scopus (74) Google Scholar], several teams showed that transcription of HERV genes and/or reverse transcriptase (RT) activity is increased in various human cells in vitro by Herpesviridae with tropism for nervous cell. This includes herpes simplex virus type 1 (HSV-1) in lymphocytes from MS patients [26Brudek T. et al.Activation of endogenous retrovirus reverse transcriptase in multiple sclerosis patient lymphocytes by inactivated HSV-1, HHV-6 and VZV.J. Neuroimmunol. 2007; 187: 147-155Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar] and in neuronal or in brain endothelial cell lines [27Ruprecht K. et al.Regulation of human endogenous retrovirus W protein expression by herpes simplex virus type 1: implications for multiple sclerosis.J. Neurovirol. 2006; 12: 65-71Crossref PubMed Scopus (90) Google Scholar]; varicella-zoster virus (VZV) in lymphocytes from MS patients [26Brudek T. et al.Activation of endogenous retrovirus reverse transcriptase in multiple sclerosis patient lymphocytes by inactivated HSV-1, HHV-6 and VZV.J. 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Virol. 2009; 46: 47-48Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]; and Epstein–Barr virus (EBV) in T cell lines [30Sutkowski N. et al.Epstein–Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen.Immunity. 2001; 15: 579-589Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar] and in peripheral blood mononuclear cells from MS patients as well as in astrocyte cell lines [31Mameli G. et al.Expression and activation by Epstein–Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis.PLoS One. 2012; 7e44991Crossref PubMed Scopus (129) Google Scholar]. Many of these viruses have been implicated in MS (reviewed in [32Leibovitch E.C. Jacobson S. Viruses in chronic progressive neurologic disease.Mult. Scler. 2018; 24: 48-52Crossref PubMed Scopus (17) Google Scholar]). Herpesviridae may invade brain parenchyma and induce local proinflammatory responses, but these pathogens are normally intercepted by perivascular macrophages (Figure 3). Macrophages are not permissive for their replication but may allow expression of HERV-transactivating Herpesviridae immediate-early genes [33Morahan P.S. et al.Molecular localization of abortive infection of resident peritoneal macrophages by herpes simplex virus type 1.J. Virol. 1989; 63: 2300-2307PubMed Google Scholar]. The EBV gp350 protein has been shown to activate HERV-W in vitro in B cells and monocytes, but not in T cells, whereas monocyte/macrophage cells appear to be most susceptible [31Mameli G. et al.Expression and activation by Epstein–Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis.PLoS One. 2012; 7e44991Crossref PubMed Scopus (129) Google Scholar]. Because EBV has also been shown to potently modify epigenetic traits of host cell DNA (reviewed in [34Hammerschmidt W. The epigenetic life cycle of Epstein–Barr virus.Curr. Top. Microbiol. Immunol. 2015; 390: 103-117PubMed Google Scholar]), the reported association with infectious mononucleosis, in addition to the elevated anti-EBV nuclear antigen-1 IgG titers in patients with MS [35Ascherio A. Munger K.L. Epstein–Barr virus infection and multiple sclerosis: a review.J. Neuroimmune Pharmacol. 2010; 5: 271-277Crossref PubMed Scopus (221) Google Scholar], might support the hypothesis that EBV acts as a priming trigger. However, this has not been directly demonstrated. Nevertheless, Herpesviridae (or other environmental activating factors) are now suggested to upregulate HERV-W expression, with its Env protein acting as a pathogenic effector in MS [36Mameli G. et al.Activation of MSRV-type endogenous retroviruses during infectious mononucleosis and Epstein–Barr virus latency: the missing link with multiple sclerosis?.PLoS One. 2013; 8e78474Crossref PubMed Scopus (66) Google Scholar]. Other viruses reported to transactivate HERVs are the exogenous retroviruses HTLV-1 and HIV-1. Specifically, the HTLV-1 Tax transactivator potently increased the transcriptional activity of HERV-W, HERV-H, HERV-K, and HERV-E families in T cells [37Toufaily C. et al.Activation of LTRs from different human endogenous retrovirus (HERV) families by the HTLV-1 tax protein and T-cell activators.Viruses. 2011; 3: 2146-2159Crossref PubMed Scopus (47) Google Scholar]. Moreover, effects of HIV on HERV-K and on HERV-W in astrocyte cell lines and peripheral blood cells in vitro have been reported to be mediated by the HIV Tat protein, which can indirectly activate HERV-W through Toll-like receptor-4 (TLR4) along with TNF-α and NF-κB. Thus, by this pathway, HIV Tat could influence non HIV-infected cells [22Uleri E. et al.HIV Tat acts on endogenous retroviruses of the W family and this occurs via Toll-like receptor 4: inference for neuroAIDS.AIDS. 2014; 28: 2659-2670Crossref PubMed Scopus (40) Google Scholar]. This indirect mechanism suggests that the HIV-driven activation pathway requires persisting Tat stimulation for HERV activation. This differs from Herpesviridae in that self-sustained HERV expression may be induced following specific triggering events, which could explain the lifelong progression of MS and the multiple triggering events that are required before a pathogenic threshold leading to disease onset can be passed. Nonetheless, if HERV proteins are not expressed, HERV RNA expression (transcription alone) does not seem to have biological effects per se in humans. Moreover, when produced, HERV proteins are not implicitly pathogenic. An example is provided by the gag (group-specific antigen)-encoded capsid protein of HERV-W which had no immunopathogenic effect on peripheral blood lymphocyte cultures from healthy donors, whereas the Env protein of HERV-W particles (previously termed MSRV) induced proinflammatory and superantigen (SAg)-like effects [38Perron H. et al.Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation.Virology. 2001; 287: 321-332Crossref PubMed Scopus (171) Google Scholar]. Abnormal activation of some HERVs is thought to have proinflammatory effects, leading to dysregulation of the immune system, as we will now illustrate with relevant examples. HERV-K and HERV-W families share an interesting common feature in that the protein encoded by their env gene has been shown to trigger responses in T lymphocyte cells expressing a specific variable region of the T cell receptor (TCR) β chain in vitro [30Sutkowski N. et al.Epstein–Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen.Immunity. 2001; 15: 579-589Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 38Perron H. et al.Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation.Virology. 2001; 287: 321-332Crossref PubMed Scopus (171) Google Scholar]. Usually, T lymphocytes recognize their target antigen through a combination of variable domains in TCR chains that define the antigen-binding site of specific T cell clones. The interaction of these HERV Env proteins with another TCR region, which is known to be independent of the antigen-binding site and present on numerous T cells, is known to activate multiple clones irrespective of their antigen specificity. Molecules inducing such polyclonal activation are SAgs. An inflammatory loop also likely contributes to HERV pathogenicity: following initial priming and induction of specific HERV copies, macrophages and/or B cells produce HERV Env proteins that might fuel local innate inflammation and upregulate major histocompatibility complex (MHC) expression, causing further polyclonal activation of tissue-attracted T cells and therefore of B cells. This potential inflammatory loop could result in the development of devastating local lesions, while antigen-presenting cells stimulated via TLR and polyclonal activation of lymphocytes might promote breaks in immune tolerance that lead to autoimmunity, as was observed in a mouse model of experimental autoimmune encephalomyelitis (EAE) treated with HERV-W Env protein [39Perron H. et al.Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice.PLoS One. 2013; 8e80128Crossref PubMed Scopus (90) Google Scholar]. MS is an inflammatory disease of the central nervous system (CNS) and a major cause of neurological impairment in young adults. There is no available cure for MS, and current therapies can only limit the number of relapses and slow disease progression. The most common symptoms include chronic fatigue, paresthesia with acute and chronic pain, optic neuritis, paresis, gait disturbance, incoordination, sphincter problems, and cognitive impairment, altogether leading to progressive disability. Histopathologically, MS is characterized by demyelinating lesions that predominantly expand in the white matter, causing destruction of myelin and oligodendrocytes and leading to axonal disruption in the brain and spinal cord. Lesions spread to cortical regions, affecting grey matter and neurons. Active lesions also show blood–brain barrier (BBB) breakdown, with infiltration of macrophages and lymphocytes, whereas activated microglia represent the hallmark of regions within active and chronic lesions, where ongoing demyelination and axonal loss are now understood to cause functional impairment (reviewed in [40Dendrou C.A. et al.Immunopathology of multiple sclerosis.Nat. Rev. Immunol. 2015; 15: 545-558Crossref PubMed Scopus (1532) Google Scholar]). Immunological dysfunctions in MS are characterized by multifocal CNS hyperinflammatory reactions, and systemic autoimmune reactivity of B and/or T cells towards myelin autoantigens, with evidence of intrathecal chronic IgG production as revealed by the presence of oligoclonal bands in the cerebrospinal fluid (CSF) [41Petereit H.F. Reske D. Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients – follow-up and clinical implications.Cerebrospinal Fluid Res. 2005; 2: 3Crossref PubMed Scopus (34) Google Scholar]. Whereas initial disease stages may present reversible phases with remission following relapse, evolution towards progressive forms generally follows [42Mahad D.H. et al.Pathological mechanisms in progressive multiple sclerosis.Lancet Neurol. 2015; 14: 183-193Abstract Full Text Full Text PDF PubMed Scopus (851) Google Scholar]. The relapsing forms are dominated by aberrant inflammatory responses, whereas in progressive stages neurodegenerative features take precedence. This may be paralleled by repeated abnormal lymphocyte stimulation that is known to lead to T cell exhaustion, anergy, or depletion [43Rocha B. et al.Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance.J. Exp. Med. 1995; 181: 993-1003Crossref PubMed Scopus (194) Google Scholar], and which implicitly downregulates T cell-driven activation of B cells [44Illingworth J. et al.Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion.J. Immunol. 2013; 190: 1038-1047Crossref PubMed Google Scholar]. The underlying etiology of MS is still not fully understood, but multiple disease-associated loci confer genetic predisposition to develop MS [45Hollenbach J.A. Oksenberg J.R. The immunogenetics of multiple sclerosis: a comprehensive review.J. 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