Immune System In Multiple Sclerosis Research Articles

A Targeted Literature Search and Phenomenological Review of Perspectives of People with Multiple Sclerosis and Healthcare Professionals of the Immunology of Disease-Modifying Therapies

IntroductionThe mechanisms of action of disease-modifying therapies (DMTs) for multiple sclerosis (MS) are complex and involve an interplay of immune system components. People with MS (PwMS) may lack a clear understanding of the immunological pathways involved in MS and its treatment; effective communication between healthcare professionals (HCPs) and PwMS is needed to facilitate shared decision-making when discussing the disease and selecting DMTs and is particularly important in the coronavirus disease 2019 (COVID-19) era.MethodsIn this patient-authored two-part review, we performed a targeted literature search to assess the need for better communication between HCPs and PwMS regarding treatment selection, and also conducted a qualitative survey of four patient and care-partner authors to obtain insights regarding their understanding of and preferences for the treatment and management of MS.ResultsFollowing a search of the Embase and MEDLINE databases using Ovid in June 2020, an analysis of 40 journal articles and conference abstracts relating to patient empowerment and decision-making in DMT selection for MS showed a preference for safety and efficacy of treatments, followed by autonomy and convenience of administration. A need for better communication between HCPs and PwMS during treatment selection to improve patient satisfaction was also identified. The open survey responses from the patient authors revealed a need for greater involvement in decision-making processes and desire for improved communication and information tools.ConclusionsThis targeted literature search and phenomenological review confirms PwMS preferences for empowered decision-making in disease management and treatment selection, to optimize independence, safety, and efficacy. It also identifies an unmet need for improved communication and information tools that convey MS information in a relatable manner. Furthermore, this review seeks to address this unmet need by providing plain language figures and descriptions of MS immune mechanisms that can be used to facilitate discussions between HCPs and PwMS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-022-00349-5.

Molecular Mechanisms of Immunosenescene and Inflammaging: Relevance to the Immunopathogenesis and Treatment of Multiple Sclerosis.

Aging is characterized, amongst other features, by a complex process of cellular senescence involving both innate and adaptive immunity, called immunosenescence and associated to inflammaging, a low-grade chronic inflammation. Both processes fuel each other and partially explain increasing incidence of cancers, infections, age-related autoimmunity, and vascular disease as well as a reduced response to vaccination. Multiple sclerosis (MS) is a lifelong disease, for which considerable progress in disease-modifying therapies (DMTs) and management has improved long-term survival. However, disability progression, increasing with age and disease duration, remains. Neurologists are now involved in caring for elderly MS patients, with increasing comorbidities. Aging of the immune system therefore has relevant implications for MS pathogenesis, response to DMTs and the risks mediated by these treatments. We propose to review current evidence regarding markers and molecular mechanisms of immunosenescence and their relevance to understanding MS pathogenesis. We will focus on age-related changes in the innate and adaptive immune system in MS and other auto-immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The consequences of these immune changes on MS pathology, in interaction with the intrinsic aging process of central nervous system resident cells will be discussed. Finally, the impact of immunosenescence on disease evolution and on the safety and efficacy of current DMTs will be presented.

Review: The Nutritional Management of Multiple Sclerosis With Propionate.

Over the last 15 years there has been an accumulation of data supporting the concept of a gut-brain axis whereby dysbiosis of the gut microbiota can impact neurological function. Such dysbiosis has been suggested as a possible environmental exposure triggering multiple sclerosis (MS). Dysbiosis has been consistently shown to result in a reduction in short-chain fatty acid (SCFA) producing bacteria and a reduction in stool and plasma levels of propionate has been shown for MS patients independent of disease stage and in different geographies. A wealth of evidence supports the action of propionate on T-cell activity, resulting in decreased T-helper cell 1 (Th1) and T-helper cell 17 (Th17) numbers/activity and increased regulatory T cell (Treg cell) numbers/activity and an overall anti-inflammatory profile. These different T-cell populations play various roles in the pathophysiology of MS. A recent clinical study in MS patients demonstrated that supplementation of propionate reduces the annual relapse rate and slows disease progression. This review discusses this data and the relevant mechanistic background and discusses whether taming of the overactive immune system in MS is likely to allow easier bacterial and viral infection.

The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View.

Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease that leads to demyelination and neurodegeneration. The third trimester of pregnancy, which is characterized by high levels of estrogens, has been shown to be associated with reduced relapse rates compared with the rates before pregnancy. These effects could be related to the anti-inflammatory properties of estrogens, which orchestrate the reshuffling of the immune system toward immunotolerance to allow for fetal growth. The action of these hormones is mediated by the transcriptional regulation activity of estrogen receptors (ERs). Estrogen levels and ER expression define a specific balance of immune cell types. In this review, we explore the role of estradiol (E2) and ERs in the adaptive immune system, with a focus on estrogen-mediated cellular, molecular, and epigenetic mechanisms related to immune tolerance and neuroprotection in MS. The epigenome dynamics of immune systems are described as key molecular mechanisms that act on the regulation of immune cell identity. This is a completely unexplored field, suggesting a future path for more extensive research on estrogen-induced coregulatory complexes and molecular circuitry as targets for therapeutics in MS.

Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.

IL-15 expression on B cells and myeloid cells is distinctly modulated by inflammatory factors in MS and healthy donors

Abstract Although the salience of the immune system in multiple sclerosis (MS) pathology has been established, the mechanisms involved are incompletely characterized. We have identified IL-15 as a relevant contributor to MS neuropathology; a greater proportion of antigen presenting cells (APC) (B cells and myeloid cells) from MS patients express IL-15 vs. controls. Our aim is to identify factors and mechanisms that contribute to elevated IL-15 levels in the context of MS. The addition of CpG, a TLR9 agonist, to CD40L-cultured human B cells increased the proportion of IL-15+ B cells. Whereas other TLR ligands (e.g. polyI:C) did not alter B cell IL-15 levels, they nevertheless increased CD40 expression. Monocytes from MS patients and age/sex-matched healthy controls (HC) were differentiated into M0 macrophages prior to M1 or M2 polarization. M2 polarization significantly enhanced the percentage of IL-15+macrophages; in contrast, M1 polarization did not. GM-CSF, which is produced by encephalitogenic T cells, induced a major increase in the proportion of IL-15+ M0 and M1 macrophages and decreased the proportion of IL-15+ monocytes from HC and MS donors. While IL-15+ M2 macrophages from HC are increased upon GM-CSF stimulation, IL-15+ M2 from MS donors are not. GM-CSF did not alter IL-15 expression on microglia. Pharmacological inhibitors of STAT5 (Pimozide) and JAK2 (AG490) phosphorylation decreased the GM-CSF-induced increase of IL-15 on M0 macrophages. Thus, GM-CSF is a potent trigger for IL-15 expression on human M0, M1 and M2 macrophages, but not monocytes or microglia. Our data suggest that specific stimuli mediate IL-15 expression on human APC and that cells from MS donors exhibit altered susceptibility to IL-15 modulators compared to HC.

Dynamics of oligodendrocyte generation in multiple sclerosis

Oligodendrocytes wrap nerve fibers in the central nervous system with layers of specialized cell membrane to form myelin sheaths1. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not appear to contribute to this process2–4. Considering the major differences in oligodendrocyte generation dynamics and adaptive myelination between rodents and humans5–9, it is uncertain how well experimental animals reflect the situation in multiple sclerosis. We have assessed the generation dynamics of oligodendrocytes in multiple sclerosis patients by measuring the integration of nuclear bomb test derived 14C in genomic DNA10. The generation of new oligodendrocytes was increased several-fold in normal appearing white matter in a subset of individuals with very aggressive disease, but not in the majority of subjects with multiple sclerosis, demonstrating an inherent potential to substantially increase oligodendrocyte generation but that this fails in most patients. Oligodendrocytes in shadow plaques, thinly myelinated lesion that are thought to represent remyelinated areas, were old in multiple sclerosis patients. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occur transiently or not at all, or that myelin is regenerated by preexisting, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, which should guide the use of current, and the development of new, therapies.

Dimethyl fumarate induces a persistent change in the composition of the innate and adaptive immune system in multiple sclerosis patients

The effects of dimethyl fumarate (DMF) on the immune system in multiple sclerosis (MS) are not completely elucidated. In this study, an extensive immunophenotypic analysis of innate and adaptive immune cells of DMF-treated MS patients was performed. Peripheral blood immune cell phenotypes were determined using flow cytometry in a follow-up study of 12 MS patients before, after 3 and 12 months of DMF treatment and a cross-sectional study of 25 untreated and 64 DMF-treated MS patients. Direct effects of DMF on B cells were analyzed in vitro. After 12 months of DMF treatment, percentages of monocytes, natural killer cells, naive T and B cells and transitional B cells increased. Percentages of (effector) memory T cells, (non) class-switched memory B cells and double negative B cells decreased together with CD4+ T cells expressing interferon-γ (IFN-γ), granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-17 (IL-17). DMF treatment was fully effective as of 6 months and directly induced apoptosis and decreased expression of costimulatory CD40, antigen presentation molecule MHCII and B cell activating factor receptor (BAFFR) on B cells. DMF induced a persistent change of the immune system of MS patients, directly induced apoptosis and reduced expression of functional markers on B cells.

Effects of Probiotic Enterococci and Glatiramer Acetate on the Severity of Experimental Allergic Encephalomyelitis in Rats

The intestinal microbiota is currently regarded as a potential target for treatments in many pathologies underlying the genesis of inflammation, autoimmune reactions, and neurodegeneration. Multiple sclerosis (MS) is a disease whose pathogenesis combines all these processes. MS also involves impairment to the balance between the components of the intestinal microbiota, with development of dysbiosis. Various probiotics are widely used to correct dysbiotic conditions – bacteria with proven useful properties. We report here the use of a model of multiple sclerosis – experimental allergic encephalomyelitis (EAE) – to study the ability of the probiotic Enterococcus faecium strain L-3 to decrease disease severity in rats when used alone and in combination with glatiramer acetate (GA). Administration of E. faecium L-3 was found to decrease the severity of EAE in rats to essentially the same extent as GA. However, simultaneous use of probiotic enterococci with GA produced no protective action. It is suggested that these agents stimulate different components of the immune system, as their actions produce increases in different populations of immune cells circulating in the blood. The study results demonstrate the ability of E. faecium L-3 to produce significant direct and indirect (via correction of dysbacteriosis) influences on the immune system in MS, which allows these bacteria to be regarded as a potential agent for immunocorrection in autoimmune, inflammatory, and neurodegenerative disease.

Complexes assembled from myelin self-antigen and a toll-like receptor antagonist promote tolerance

Abstract Myelin, a matrix that insulates the axons of neurons, is attacked by the immune system in multiple sclerosis (MS), leading to neurodegeneration. MS treatments are currently limited because they are non-curative and broadly-acting immunosuppressants that can leave patients immunocompromised. Recent reports show co-delivery of myelin peptides (MOG) along with regulatory signals can promote tolerance to myelin rather than cause inflammation. New studies reveal inflammatory toll-like receptors (TLRs) play a significant role in driving disease in both humans and mice. Further, several reports demonstrate that regular treatment with TLR9 antagonist, GpG, attenuates disease in mouse models of MS. We hypothesized that GpG DNA and cationic MOG peptide would electrostatically self-assemble into complexes, allowing co-delivery, increased cargo protection, and enhanced uptake by immune cells. These complexes might redirect the response against myelin through suppression of inflammatory TLR9 signaling during myelin presentation. Importantly, polyplexes significantly reduced inflammatory TLR9 signaling in a reporter cell line. Primary dendritic cells (DCs) internalized MOG-GpG complexes, resulting in a reduction of activation and decreased proliferation of myelin-reactive T cells. In a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), complex injection reduced disease severity more than 2-fold and incidence by 30%. This data demonstrates the ability of GpG to condense self-antigens while remaining an active immunomodulator. This work also suggests a new carrier-free platform for co-delivery of antigens and immune signals that still provides the more attractive features of biomaterials.

GM-CSF upregulates IL-15 expression on specific human myeloid cells.

Abstract Although the salience of the immune system in multiple sclerosis (MS) pathology has been established, the mechanisms and mediators involved are incompletely characterized. We have identified IL-15, which aids in the development, activation, and survival of immune cells, as a relevant contributor to MS neuropathology. We previously showed that greater proportions of myeloid cells, including peripheral monocytes and brain macrophages/microglia, from MS patients express IL-15 versus controls. Thus, we aim to identify the factors that contribute to these elevated IL-15 levels in the context of MS. Primary human monocytes from MS patients and age/sex matched healthy donors are treated with M-CSF to trigger differentiation into macrophages (considered M0 macrophages) prior to being polarized into M1 or M2 macrophages. While a small proportion of M0 macrophages express IL-15, M2 polarization significantly enhances the percentage of IL-15+ macrophages. In contrast, M1 polarization does not affect IL-15 levels although it significantly increases MHCI and CD80 expression. GM-CSF is produced by pathogenic encephalitogenic T cells; monocytes and macrophages express the corresponding receptor (GM-CSF receptor). GM-CSF induces a major increase in the proportion of IL-15+ M0 and M2 macrophages from both donor groups. In contrast, GM-CSF does not modify IL-15 expression by monocytes although it induces STAT5 phosphorylation. In conclusion, GM-CSF is a potent trigger for IL-15 expression on M0/M2 macrophages but not monocytes. Moreover, M2 polarization of macrophages increases IL-15 expression. Identification of IL-15 triggers and further characterization of IL-15+ immune cells may provide novel targets for therapies for MS patients.

Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia

Background: The importance of the innate immune system in multiple sclerosis (MS) is increasingly recognized and the role of natural killer (NK) cells in controlling autoimmunity may be an important modulator of disease activity. Objective: To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity. Methods: We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to ‘No Evidence of Disease Activity’ (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression. Results: Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment (p < 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects (p < 0.05). Conclusion: The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.

Immunologic profiles of multiple sclerosis treatments reveal shared early B cell alterations

Objective:We undertook a systems immunology approach of the adaptive immune system in multiple sclerosis (MS), overcoming tradeoffs between scale and level of detail, in order to identify the immunologic signature of MS and the changes wrought by current immunomodulatory treatments.Methods:We developed a comprehensive flow cytometry platform measuring 38 immunologic cell types in the peripheral blood of 245 individuals in a routine clinical setting. These include patients with MS, untreated or receiving any of 4 current immunomodulatory treatments (interferon-β, glatiramer acetate, natalizumab, or fingolimod), patients with autoimmune thyroid disease, and healthy controls.Results:An increase in memory CD8+ T cells and B cells was observed in untreated patients with MS. Interferon-β and fingolimod induce significant changes upon multiple aspects of the peripheral immune system, with an unexpectedly prominent alteration of B cells. Overall, both treatments push the immune system in different directions, with only 2 significant effects shared across these treatments—an increase in transitional B cells and a decrease in class-switched B cells. We further identified heightened B cell-activating factor (BAFF) levels as regulating this shared B cell pathway.Conclusions:A systems immunology approach established different immunologic profiles induced by current immunomodulatory MS treatments, offering perspectives for personalized medicine. Pathways shared between the immunologic architecture of existing efficacious treatments identify targets for future treatment design.

Effect of Pentoxifylline on Recurrence in Patients With Multiple Sclerosis: A Non-Randomized Double-Blinded Placebo Controlled Clinical Trial

Background: The role of the immune system in multiple sclerosis (MS) has been proved. Pentoxifylline has an inhibitory effect on phosphodiesterase and the cytokine products. In some studies therapeutic effects of pentoxifylline have been documented in MS patients. Objectives: The aim of our study was to investigate the effects of pentoxifylline on the recurrence and the disease course in MS patients. Patients and Methods: In our double-blinded clinical trial study, 44 newly diagnosed relapsing-remitting MS patients were studied for 12 months. They were divided into 2 groups: in group 1, 22 patients received interferon and oral pentoxifylline (800 mg daily for 2 months) and in group 2 (control group), 22 patients received interferon with a placebo. The monthly attack rates and the clinical condition of the patients, using the expanded disability status scale (EDSS), were measured in 3 different times along the study (beginning of the treatment, 6 months after and at the end of the treatment). Analysis of the data was done using t-test and the nonparametric Mann-Whitney U test. Results: There was not any significant difference between the 2 groups in terms of age and sex. The recurrence in the first year was 0.4% and 0 in group 1 and 2, respectively. Also there was not any difference in the clinical course and the recurrence of the disease between two groups in one year of follow-up. Conclusions: Adding pentoxifylline to interferon does not have any synergistic therapeutic effects on the reduction of relapse frequency and EDSS in patients with relapsing-remitting multiple sclerosis in comparison with interferon.

Current and future therapies targeting the immune system in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The exact pathomechanism is unknown, but an aberrant immune response against CNS antigens, leading to inflammation in brain and spinal cord followed by demyelination, axonal damage and scar formation, seems to play a major role. Later in the disease course, inflammation decreases, while neurodegeneration proceeds. Approximately 80% of the patients initially show a relapsing-remitting disease course (RRMS), but the majority of them later develops a secondary progressive MS (SPMS). A minority suffers from primary progressive MS (PPMS). Primary goals of long-term MS therapy are to prevent relapses and disease progression. Assuming that MS is an autoimmune disease, most therapeutics aim to modulate or suppress the immune system. Until now many drugs have proven efficacy in RRMS, but none in PPMS. Interferon-β (IFN-β) and glatiramer acetate are known in RRMS therapy for years. Based on preclinical research and clinical trials, new treatment strategies have emerged and have been transferred from bench to bedside. The α4β-integrin-antagonist natalizumab was approved in 2005. Fingolimod, dimethyl fumarate and teriflunomide were the first oral drugs introduced in MS therapy. Recently alemtuzuab, another monoclonal antibody, was approved in Europe. Promising future perspectives are alemtuzumab, daclizumab, and laquinimod. Here, we review drug mechanisms in the therapy of MS. The mechanisms of action and the effect of the drugs on the immune system are summarized. We report recent results of clinical trials, highlight special features of different treatment strategies, and discuss future perspectives and ongoing clinical trials.

Vitamin D, the healthy and inflamed Immune System in multiple sclerosis

زمینه و هدف: بيماري مالتيپل اسکلروزيس، يک بيماري خود ایمن، چند عاملي پيشرونده است که غلاف ميلين در سيستم اعصاب مرکزي مورد هجوم سيستم ايمني قرار مي گيرد. مطالعات نشان داده اند عوامل ژنتیکی و محیطی و تعاملات آنها در بروز این بیماری موثرند. طی مطالعات چند دهه گذشته، دانشمندان موفق به شناسايي ژن CYP27B1 در مسیرمتابولیسم ویتامین D به عنوان یکی از عوامل موثر بر بروز MS شدند. CYP27B1 در بسیاری از سلول های بدن از جمله نورونها، سلولهای اپیتلیال و سلولهای سیستم ایمنی بیان می شود. این ژن با تولید آنزیم آلفا دهیدروکسیلاز ؛ ویتامین D را به فرم فعال تبدیل کرده که این فرم در تنظیم عملکرد سیستم ایمنی ذاتی و همورال نقش دارد. مواد و روش­ها: در این مطالعه مروری با بررسی مقالات مختلف و جدید در زمینه نقش ویتامین D در بیماری MS ، جدیدترین اطلاعات در این زمینه گردآوری و استفاده گردید. یافته ها: تحقیقات حاکی از نقش موثر و مهم ویتامین D در تعادل و تنظیم سیستم ایمنی بدن و همچنین سلامت سایر اعضا بدن از جمله سیستم اعصاب مرکزی می­باشد. از طرف دیگر کمبود ویتامین D مسبب بسیاری از بیماریهای خودایمن و برخی از سرطان­ها شناخته شده است. نتیجه گیری: با توجه به شیوع در حال افزایش MS در ایران و همچنین کمبود شدید ویتامین D در بین جامعه ایرانی بویژه زنان و ارتباط این دو عامل باهم، آگاهی جامعه و مطالعه ویتامین D به عنوان فاکتور درمانی امری ضروری است. واژگان کلیدی: ویتامین D ، CYP27B1 ، مالتیپل اسکلروزیس

The features of Sema4D/CD72 expression in the immune system in multiple sclerosis

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Decreased interferon-α production in response to CpG DNA dysregulates cytokine responses in patients with multiple sclerosis

Type I interferons (IFNs), represented by IFN-α and β, activate immune effector cells belonging to the innate and adaptive immune systems. Plasmacytoid dendritic cells (pDCs) produce IFN-α in response to CpG DNA. We aimed to examine the impact of pDC-produced IFN-α on the adaptive immune system in Multiple Sclerosis (MS). Our results demonstrated that CpG DNA-induced IFN-α production was significantly decreased in PBMCs from MS patients. Decreased levels of IL-12 p70, IFN-γ, and IL-17 and increased level of IL-10 were found in CpG DNA-treated PBMCs of healthy subjects unlike in those from MS patients. In samples pre-treated with IFN-α and IFN-β, decreased levels of IL-12 p70, IFN-γ, and IL-17 and increased level of IL-10 were detected in PBMCs from MS patients. These results suggest that CpG DNA-induced decreased IFN-α production causes pro-inflammatory cytokine secretion, and either IFN-α or IFN-β induces anti-inflammatory cytokine secretion in the adaptive immune system in MS.

Dissecting the Immune Component of Neurologic Disorders: A Grand Challenge for the 21st Century

Dissecting the Immune Component of Neurologic Disorders: A Grand Challenge for the 21st Century

Multiple Sclerosis: Are Protective Immune Mechanisms Compromised by a Complex Infectious Background?

The immunological background of multiple sclerosis (MS) manifests as an altered reactivity against a diverse range of infections, particularly with the Epstein-Barr virus. Although this could be only an epiphenomenon of a more generalised dysfunction of the immune system in MS, it is also possible that a complex infectious background forms the basis of a specific immune dysregulation finally causing the disease. It is thus suggested that the complex infectious background bears the key for an understanding of the immune pathogenesis of the disease. It appears probable that improved standards of hygiene cause regulatory defects in the immune system, allowing the abnormal expression of human endogenous retroviral (HERV) genes. On the basis of epidemiological observations we describe how a failure of expansion or an eclipse of a subfraction of self-antigen-specific CD8+ T cells mediating immune repair, and a deleterious mode of action of HERV gene products, could underlie the pathogenesis of MS.