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Quarterly Medical Review

The autoimmune concept of multiple sclerosis Bryan Nicol 1, Marion Salou 1, David-Axel Laplaud 1, Hartmut Wekerle 2

Available online:

1. CHU de Nantes, service de neurologie, Inserm CR1064, 44093 Nantes cedex, France 2. Max Planck institute of neurobiology, department of neuroimmunology, Planegg-Martinsried, 31, 81377 Munich, Germany

Correspondence: David-Axel Laplaud, Inserm CR1064, 30, boulevard J.-Monnet, 44093 Nantes cedex, France. [email protected]

Multiple sclerosis: from new concepts to updates on management David-Axel Laplaud, Nantes, France The autoimmune concept of multiple sclerosis Bryan Nicol et al., Nantes, France Environmental factors in multiple sclerosis Vasiliki Pantazou et al., Lausanne, Switzerland Update on clinically isolated syndrome Eric Thouvenot, Nimes, France Update on treatments in multiple sclerosis Laure Michel et al., Montréal, Canada Treatment of multiple sclerosis in children and its challenges Sona Narula et al., Philadelphia, United States Advanced imaging tools to investigate multiple sclerosis pathology Benedetta Bodini et al., Paris, France Update on rehabilitation in multiple sclerosis Cécile Donzé, Lille, France

Summary Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). With growing evidence for environmental and genetic factors, MS is now accepted as an autoimmune disease. This complex disease seems to implicate various cell types in both innate and adaptive compartments. Here, we discuss recent advances in the immunological field of MS research.

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edical literature commonly refers to multiple sclerosis (MS) as the most common autoimmune disease of the central nervous system. Certainly, the disease is common, at least in the temperate climate zones of the Northern hemisphere. But is it an autoimmune disease? It is safe to say that indeed there are several lines of evidence indicating that MS is the result of an autoimmune attack against the brain white matter. It should be noted however that all these arguments are indirect, but afford no formal proof. Evidence in support of an autoimmune pathogenesis includes the morphology of inflammatory lesions (perivascular infiltrates with parenchymal invasion, activation of potential APCs), the clonal expansion of infiltrating T cells (with silent mutations), the presence of oligoclonal Ig bands in CSF formed mostly by local B lymphocytes (of unknown specificity), the presence of circulating autoantibodies directed against autoantigens like the glial potassium channel autoantigen Kir4.1, which are seen in some, not all patients, and anti-MOG in subsets of (infantile) MS. Furthermore, genetic risk factors – as identified by recent Genome wide association studies (GWAS) – mostly implicate immune genes. Then animal autoimmune models with MS-like morphology provide additional support to the active role of the immune system. Finally, therapies targeting inflammatory and immune processes show a strong protective effect against the formation of new lesions. In the following paragraphs, we will summarize recent research detailing these individual issues.

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In this issue

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To cite this article: Nicol B, et al. The autoimmune concept of multiple sclerosis. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.02.009

B. Nicol, M. Salou, D-A Laplaud, H. Wekerle

Genome wide association studies MS is not a hereditary disease: while approximately 20% of all patients with European origin show a positive family history [1], it should be noted that a child born to an MS-affected parent has a risk of MS as low as 0.5%. However, there is a strong genetic component in its susceptibility as shown by the classical twin studies with concordance rates around 30% in monozygotic twins as compared to "only'' less than 5% in dizygotic twins. Classical tissue typing performed 40 years ago showed that gene locus HLA-D, in particular haplotype DR2, is the strongest genetic risk factor [2]. Important to note, HLA-D genes are absolutely essential in the development and function of the immune system. The govern of the development of the T cell receptor repertoire and their protein products act as templates presenting antigen to CD4+ T cells. More recently, Genome wide association studies (GWAS) have considerably revolutionized the genetic analysis of MS. Indeed, the analysis of alleles polymorphisms, called SNP (single nucleotide polymorphisms), have led to the discovery of more than 150 susceptibility variants, most of them being associated to immunological processes [3]. Variations in genes located within the HLA complex (chromosome 6p21.32) have been confirmed to be associated with the HLADRB1*15:01 allele which confers a 3-fold increased risk of developing MS. In addition, HLA class I genes have an impact on the disease. Indeed HLA-A*02:01 has an independent protective effect on MS [4]. Gene variants outside of the HLA complex, such as IL-7R and CD58, and recently ALCAM and CD6, were also noted [5]. The contribution of each of these genes is weak, but together their effect is considerable. One main caveat of the GWAS studies is that they rely on the detection of SNPs, DNA sequence variations, which may sit not only directly in the coding region of a gene, but also in regulatory sequences (e.g. promoter or enhancer region) or non-coding regions of unknown function. Thus, although the genes nearest to a particular SNP are justly considered candidate genes, there is a need to directly prove a functional association by additional experimentation. A clear case is IL-7 receptor alpha-chain polymorphism, which first was located in an exon [3] and subsequently has been verified functionally [6]. Another example comes from TNF receptor-1 polymorphism mapped by GWAS that was found to control the production of a soluble form of receptor that acts as a biological inhibitor of the inflammatory action of the cytokine [7].

Plaque infiltrates

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Inflammatory infiltrates in the CNS, associated to myelin destruction and axon damage, are hallmarks of the MS plaque [8]. The infiltrates are composed mainly of macrophages, but also T cells, mainly in perivascular areas but also disseminated in the surrounding parenchyma. Chronic active and acute lesions are characterized by myelin destruction in the presence of

preserved axons and by profuse macrophage infiltration. On the contrary, inactive plaques present fewer macrophages and a substantial loss of axons. Although the inflammatory reaction with macrophages and T cells seems to be a feature common to all active lesions, four patterns of demyelination have been distinguished. Pattern I is characterized by demyelination mediated mostly by macrophages toxins and T cell inflammation. Pattern II is mediated by antibody targeted to myelin structures, and is associated with activated complement. Pattern III is characterized by microvascular thrombosis with endothelial damage and especially by a distal oligodendropathy. Finally, pattern IV lesions feature primary oligodendrocyte degeneration [9]. Although MS lesions are classically described in white matter areas, more recently demyelination localized in gray matter have gained renewed interest [10]. Cortical plaques are found in early and late MS patients. They fall into three categories depending on their location. Type I lesions are located in leucocortical border areas and are contiguous with subcortical white matter lesions. In contrast, type II lesions are completely confined to the cortex. Finally, type III lesions extend from the pial surface into cortical grey matter. Cortical lesions have been shown to be important in demyelination, axonal and dendritic transection and the loss of neurons [11]. The cell infiltrates found in active lesion are composed of round cells. The prevailing cell types in MS plaques are activated resident microglia and invading macrophages [12]. Then come lymphocytes, with a CD8+ T cells more numerous than CD4+ T cells, plus some B cells and plasma cells. Evidence from experimental models of MS (vide infra) indicates that immune cell infiltrates are the motors that actively drive the neurodegenerative processes, rather than being just their passive consequence. In fact, molecular analyses of the TCR repertoire of invading T cells found in MS plaques strongly point to an active immune response going on, most probably an autoimmune response. Indeed, different plaques in the same patient can be infiltrated by the same T cell clone [13], and once infiltrated and expanded, the T cell clones persist over years in the patient [14]. Sequences of the TCR of the dominant CD8+ T cells indicate a powerful expansion of individual clones at last at the Vb level [15]. Many of the T cells use the same TCR, not a random set of multiple different sequences. Even more amazingly, there are T cells using the same TCR protein sequence, but encoded by a slightly different base sequence ("silent mutation''), which points toward a strong selection of the TCR from one or even independent clones. These T cells must have been either expanded locally, or recruited specifically to the plaque sites. Little is known of the target specificity of these invading T cells. T cell clones reactive to myelin autoantigens have been isolated from blood (in some cases also from CSF) by numerous groups. However, the pathogenic relevance of these cells has remained

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To cite this article: Nicol B, et al. The autoimmune concept of multiple sclerosis. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.02.009 The autoimmune concept of multiple sclerosis

Animal models of multiple sclerosis Immunization of rodents, monkeys and other animals against brain components (especially proteins of the myelin sheath surrounding neuronal axons) can result in a disease, which suggestively simulates some essential feature of human MS. Clinically, mostly of the affected animals suffer from a hind limb paralysis coincident with characteristic lesions mostly in spinal cord, but also in brain stem, cerebellum and optic nerves. Similar to active MS lesions, the hallmarks of EAE lesions are inflammatory infiltrates most pronounced around small blood vessels (post-capillary veinules) and the surrounding parenchyma, along with more or less pronounced degeneration of myelin and local axons. Infiltrates are dominated by activated macrophages, and activated CD4+ T cells, however with lesser contributions of CD8+ T cells, B cells and polymorphonuclear leukocytes. Classical EAE models are actively induced by immunization with myelin proteins in Freund's complete adjuvant, a strong immune adjuvant activating T lymphocytes. Then, there are passive transfer versions of EAE, which are induced by parenteral injection of freshly in vitro activated myelin autoimmune T cells. Finally, there exist spontaneous EAE models. These use transgenic mice that over-express the T cell receptor genes from a myelin-specific T cell clone in their immune repertoire. Actively induced and passively transferred EAE models have been of priceless value to identify and characterize brain pathogenic T cells, to prove the existence of their progenitors in the healthy immune repertoire and to detail the requirements of their pathogenic activation. These animal models have been especially instrumental for discovery and validation of new drugs. Finally, EAE studies of transgenic mice (or rats) allowed the functional characterization of immune regulatory genes in healthy and pathologic conditions. For example Th1/Th17/Treg contributions to CNS autoimmunity, inclusively signaling pathways had been defined using transgenic EAE systems. EAE transferred by genetically modified fluorescent T cells has been successfully used for studying T cell migration into the CNS. Using this approach, the itinerary of encephalitogenic effector T cells was explored in detail from initial activation sites via lung, to secondary lymphoid organs (the site of reprograming to "migratory phenotype''), then to the interaction with the

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vascular blood-brain barrier (adhesion, crawling, extravasation) and finally to the entry into the CNS and the interaction with local antigen presenting target cells. However, owing to their artificial mode of induction, classical active and passive EAE models were of little use to explore the earliest events leading to the spontaneous development of brain autoimmune disease, as in human MS. These investigations have become possible finally with the advent of spontaneous EAE models. One example are transgenic SJL/J mice which express a MOG specific TCR in > 70% of all CD4+ T cells. Within about 8 months of age, nearly all of these mice come down with a relapsing-remitting EAE, spontaneously, without the need of any experimental manipulation. The lesions observed in the CNS strikingly resemble early active MS lesions with round cell infiltrates, large confluent demyelinated areas and axonal degeneration. Studies of these mice led to the discovery of a new, unpredicted site of disease triggering, namely the gut. Indeed, spontaneous EAE development was only observed in mice maintained in conventional environment, but never in germ-free animals, pointing one the role of the gut microbiota as a regulator of the brain inflammation [20].

Immune regulation Both innate and adaptive immune systems play important roles in the initiation and progression of MS. Here we summarize what is currently known on the implication of several cell types in MS. However, numerous pieces of the puzzle are still lacking.

Innate immunity Macrophages Activated macrophages and microglia are always observed in active MS lesions [21]. EAE progression seems to be correlated with macrophage infiltration in the CNS [22] and the peripheral depletion of macrophages leads to decreased EAE clinical scores [23], stressing on the importance of this cell subset. Astrocytes/microglia Astrocytes and microglia act as accessory immune cells because they respond to stimuli and produce pro-inflammatory cytokines such as IL-1, IL-6 and TNF. Activated microglia are present and abundant in active MS plaques [9]. The triggering signals responsible for their activation can come from diverse pathological processes: either from the responses of autoimmune T cells, or, alternatively, from the degeneration of resident brain cells (myelin, axons). Stimulated astrocytes contribute to brain inflammation by generation of pro-inflammatory cytokines [24]. Furthermore, CCL20 (ligand to CCR6) is upregulated by IL-17 on astrocytes in vitro, supporting the formation of Th17 T cells infiltrates within the CNS tissue [25]. Natural killer (NK) cells The implication of NK cells in MS remains controversial. Indeed, blocking NK cell homing leads to disease exacerbation [26].

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obscure. Arguments in favor of an active role are as follows. When the genes encoding myelin-specific TCR were inserted in the genome of transgenic mice, the recipients spontaneously developed EAE [16]. One study identified a TCR-ab sequence in brain plaque material, which replicated the sequence of a MBPspecific CD4T cell clone isolated from another patient's peripheral blood [17]. However, very similar clones are isolated from perfectly healthy human donors [18,19]. Finally, to date, the antigen specificity of CD8 T cell clones invading MS lesions has remained unknown (vide infra).

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To cite this article: Nicol B, et al. The autoimmune concept of multiple sclerosis. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.02.009

B. Nicol, M. Salou, D-A Laplaud, H. Wekerle

However, a pathogenic role has also been suggested for NK cells, through their cytolytic and pro-inflammatory activities and through their interaction with T cells, B cells and antigen presenting cells [27,28]. In EAE induced in Knock-Out (KO) mice lacking the macrophage/microglia chemokine receptor CX3CR1, the selective depletion of CNS-resident NK cells was sufficient to exacerbate EAE [26]. In humans, several studies have monitored NK cell activity during immunomodulatory therapies (Glatiramer acetate or IFNb) of relapsing-remitting MS patients. GA has been shown to enhance the cytolysis of immature dendritic cells and to promote the inhibition of IFNg by NK cells [29]. Moreover, Kastrukoff et al. have shown that RRMS with elevated NK cell functional activity are prone to increased development of active lesions [30]. Neutrophils In MOG35–55-induced EAE in C57BL/6 mice, neutrophils were important for local immune cell recruitment, DC maturation and initiation of the EAE [31]. Recently, a study confirmed that neutrophils are involved in the initial events of EAE and are intimately linked to the inflamed status of the Blood-BrainBarrier [32]. However, neutrophils are generally absent from MS lesions although IL-8 (a leukocyte chemokine which extends neutrophils survival) is detected in the CSF of a particular type of MS patients (Opticospinal MS) [33]. Mast cells In MS, mast cells have been identified in meninges, choroid plexuses, parenchyma and at the edges of plaques, especially in chronic active lesions [34]. Real time PCR analyses of chronic MS lesions confirmed an upregulation of several genes linked to mast cells biology [35]. Moreover, tryptase (specific of human mast cells) has been found in the CSF, especially during relapse [36].

Adaptive immunity CD4 T cells MS was initially considered as mediated by CD4+ T cells. Among these cells, several subpopulations are distinguished according their genetic profile and their cytokine secretion. Here we focus on those, which were implicated in the pathology.

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Th1 Th1 cells are derived from naïve CD4+ T cells and are characterized by the expression of the transcription factor T-bet and by the secretion of pro-inflammatory cytokines such as IFNg, TNF and IL-2 [37]. The cytokine IL-12 is required for induction of the Th1 lineage. Th1 cells were first implicated as the main pathogenic T cell subset in EAE and MS [38]. Indeed, adoptive transfer of activated myelin-specific Th1 induces EAE in non-immunized mice [39] and IL-12p40 or T-bet KO mice are resistant to EAE [40,41]. However, paradoxically, transgenic mice lacking IFNg (the signature effector cytokine of Th1 cells) or its receptor show an exaggerated response to active EAE induction [42,43].

Importantly, in humans, attempts to treat MS with recombinant IFNg therapy clearly exacerbated the disease [44]. Also, IFNg levels in serum and IFNg production by MS PBMC correlated with MS disability scores [45,46]. Moreover, IL-12 is detectable in the CSF of MS patients and seems to parallel disease activity [47]. Th2 Th2 cells are also derived from naïve CD4 T cells after induction by IL-4, in the absence of IL-12. Their marker cytokine are IL-4, -5 and -13 [48]. Th2 cells are often considered as beneficial in MS. Indeed, MBP-primed Th2 cells were described to induce neurotrophins in microglial cells, which are important for the stimulation and control of neurogenesis and also the survival of neurons [49]. Moreover, a recent study showed that MBP-specific Th2 cells could inhibit the expression of IL-1b and NO (nitric oxide) resulting in the reduction of the pro-inflammatory climate in glial cells [50]. Also immune-modulatory therapies (copaxone) may act, at least partially, by diverting autoimmune T cells from Th1 to Th2 profiles. On the other hand, under particular conditions, myelin autoimmune Th2 cells can be detrimental, triggering allergy-like hypersensitivity [51]. Finally, Th2 T cells may contribute to the formation of anti-myelin autoantibodies (pattern II lesions). Th9 or IL-9 producing cells IL-9 was first described as a cytokine produced by Th2 cells that promotes the expansion of mast cells [52]. More recently, release of IL-9 was noted in a particular subset of CD4+ T cells, Th9 cells. In EAE models, IL-9 deficiency ameliorates the clinical score of the disease. Besides, the transfer of antigen-specific Th9 cells is able to induce EAE [53]. Moreover, IL-9-producing cells have been shown to induce the expression of CCL20 by astrocytes, which enhance the migration of Th17 cells into the CNS. Indeed, IL-9 and IL-9R are expressed in the CNS of EAE mice [54]. However, it remains currently unclear whether Th9 is a distinct subpopulation or whether IL-9 is produced by several populations including Th17 cells. Th17 Th17 cells have been proposed to act as the main effector cells in MS. This concept rested largely on EAE studies [55]. Th17 cells are characterized by the expression of the transcription factor RORgt and the secretion of IL-17, -21 and -22 [56]. Myelinspecific Th17 T cells are able to induce EAE [55] and that Th17 cells have been found in the CNS of acute phase EAE [57]. In EAE, RORgT KO mice are largely protected from EAE induction [58,59]. Also mice lacking IL-23, which is required for stabilizing Th17 lineage cells, or mice treated with anti-IL23 antibodies are resistant to EAE suggesting the involvement of this cell type in the pathophysiology of EAE [41]. In human MS, Th17 transcripts have been found in CNS lesions [60]. Moreover, IL-17A mRNA and protein levels were also increased in the blood and in the CSF of patients, particularly during relapses, as compared to healthy volunteers (HV) [61,62]. Th17 cell frequency was also higher in the blood of

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active RR patients compared to inactive patients and HV [63]. Interestingly, one study found about 80% IL-17+ cells in CD4+ T cells of active MS lesions [64]. More and more studies focus on IFNg and IL-17A double producers in MS lesions [65]. Moreover, also in EAE, the majority of Th17 cells seem to produce IFNg [66]. Regarding therapies, IFN-b treatment inhibits Th17 differentiation in vitro by promoting apoptosis, while fingolimod seems to decrease the Th17 response [67]. These observations identify IL17-producing cells as promising targets for future MS therapies. However, an early attempt to treat MS with a monoclonal antibody (Mab) blocking the receptors for IL-12 along with IL23 (two cytokines driving differentiation of Th1 and Th17 cells) was negative [68]. Trials studying the effect of a Mab blocking IL-17A, which has been of promise in organ specific autoimmune diseases like rheumatoid arthritis, and psoriasis [69], are currently underway. Th22 IL-22 was first described as a Th17 signature cytokine. However, IL-22 production may occur in a subset of CD4+ T cells independently of IL-17 production [70]. A recent study reported an increased frequency of Th22 cells in the blood of MS patients as compared to HV. Besides, these cells were expanded just before the active phase, as opposed to Th17, suggesting a possible preferential role in MS. The same work demonstrated that the peripheral Th22 cells were specific for MBP and express CCR6, a chemokine receptor potentially steering T cell homing through choroid plexus [71,72]. These cells were insensitive to IFN-b therapy, which could explain that about 50% of MS patients do not respond to the treatment [71,73]. Treg Autoimmune disease can develop following pathological activation of autoreactive effector cells, or, alternatively, after weakening of self-protective regulatory mechanisms, for example regulatory T cells. The search for regulatory factors in the pathogenesis of MS was spurred by early studies of autoimmune T cell clones in blood and CSF of patients with MS. These efforts were successful in demonstrating numerous myelin protein autoreactive T cell clones in peripheral blood, but the difference between healthy and patients' populations were subtle, if anything [74]. The role of regulatory T cells CD4+ CD25hi (Treg) in MS is controversial. On the one hand, in MOG-EAE model, depletion of Treg (using an anti-CD25 antibody) increased the susceptibility to EAE [75]. In addition, in a PLP model, Treg frequency inversely correlate with the inducibility of the disease [76]. These observations may reflect a potential beneficial role of Treg in MS disease. On the other hand, reports on the frequency of Treg in the blood of MS patients were discordant. Some studies found a reduced frequency of circulating Tregs [77], while in others the rates were unchanged, in the blood of MS patients [78], or even increased in the CSF [79]. Moreover, only very few Treg were detected in MS lesions. One hypothesis is that they are more

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susceptible to apoptosis [80]. The function of CD4+ CD25hi T cells seems to be impaired in MS [81,82]. In a recent study, Treg from MS patients showed a decreased response to IL-2, that can/may reflect a defect in tolerance in MS [83]. However, there remains the possibility that in studies of MS patients Treg populations have been diluted by non-suppressive T cells, thus mimicking reduced Treg functionality [84]. CD8+ T cells Although CD4+ T cells were the first to be widely incriminated, increasing evidence implicates CD8+ T cells in the physiopathology of MS. As mentioned, CD8+ T cells dominate the lymphocyte infiltrates of active MS lesions. Moreover, an allelic variant of HLA class I (encoding restrictions elements for CD8+ T cells) has been shown to confer an independent protective effect against MS development [85]. Finally, over the last decade, EAE CD8+ specific models (MBP or MOG) were developed, mainly based on transgenic mice [86,87]. CD8+ T cells possess cytotoxic properties that make them more suited than CD4+ T cells to produce direct damage into the CNS. Indeed, they are able to perform axonal transection [74,88]. Interestingly, a correlation between the number of CD8+ T cells in MS lesion and axonal damage was described [89]. Besides, in MS patients, astrocytes, oligodendrocytes, axons and neurons over-express MHC-I depending on the severity of the disease [90]. CD8+ T cells found in MS lesions express granzyme B (GZMB) and IFNg, suggesting a pro-inflamatory role in situ [91,92]. In addition, CSF from MS patients is enriched in CD8+ T cells that produce GZM-B strengthening their pathogenic role in MS [92,93]. Moreover, one report described increased cytotoxic activity against MBP in MS patients [94]. Recently, a subpopulation of IL-17-producing CD8+ T cells has been implicated in MS. Indeed, about 70–80% of CD8+ T cells generate IL-17 in active MS lesions [64]. Also in the blood, CD8+ T cells from MS patients secrete more IL-17 after activation than CD8+ T cells from HV [95]. The secretion of IL-17 is restricted to CD161 expressing CD8+ T cells [96] and the frequency of these CD8+ CD161hi was increased in the blood of MS patients [91]. The vast majority of CD8+ CD161high T cells belong to a peculiar subset of innate-like T cells called mucosal-associated invariant T (MAIT) cells. These cells express the chemokine receptor CCR6, which enables them to enter the CNS [72,91]. One particularly intriguing finding was the presence of TCR genes resembling the semi-invariant receptors of MAIT cells in inflammatory infiltrates of MS lesions [97] and gliomas [98]. Classical MAIT cells locate within the confines of mucous membranes, in particular in the gut, the liver and in the airways [99]. Human MAIT cells invariably use TCRs composed by a particular constant a chain (iVa7.2Ja33 rearrangement) often along with Vb2 and Vb13 [100]. The cells recognize microbial riboflavin precursor molecules in the context of MR1, a non-conventional MHC class I-related membrane protein [101]. They are involved in anti-microbial

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responses [102], contributing to the integral barrier function of mucous membranes. Their function in the MS brain remains obscure to date. It may be related to immunoregulation [103], but conversely with their cytotoxic potential, MAIT cells may contribute to the pathogenic process [104].

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B cells The implication of B cells in the pathogenesis of MS is well established. B cells are commonly detected in the parenchyma and in the leptomeninges, where they may form germinalcenter-like structures [105,106]. As mentioned, a particular pattern of MS plaques features inflammation characterized by a substantial B cell component together with activated complement decorating degenerating myelin sheaths. Intriguingly, the CNS milieu, which in general is not very supportive of immune reactions, provides a propitious milieu to B cells. In particular astrocytes produce B cell trophic factors, including BAFF that is further upregulated in MS lesions [107]. B cell aggregates are preferentially positioned in the leptomeninges and within the perivascular Virchow-Robin spaces [106]. In some cases aggregates seem to form structures resembling secondary B cell follicles in secondary lymph organs, or in ectopic inflamed tissues as seen in rheumatoid arthritis, Myasthenia Gravis or thyroiditis [108]. Leptomeningeal infiltrates with a strong B cell component are commonly seen in secondary progressive MS, but is also described in RR MS stages [109]. The involvement of B cells is indicated by the presence of oligoclonal IgG bands (OCB) in the CSF of more than 90% of MS patients. A molecular analysis aligning BCR sequences of CNS-resident B cells and OCB Ig sequences in single patients showed that most of these OCBs are the product of local B cells [110]. However, although a recent paper found that some IgM present in OCBs bind to glycolipids [111], to date, specificity and function of IgG OCBs remain still unknown. The presence of blood anti-brain autoantibodies is firmly established in neuromyelitis optica (NMO) and in certain EAE models but remains unclear in most MS Patients. In NMO, a demyelinating CNS disease distinct from MS, autoantibodies against the water channel protein aquaporin-4 (AQP4) are pathognomonic for a large proportion of cases, and they also seem to have a central role in the pathogenesis by the destruction of astrocytes. In MS, anti-MOG autoantibodies have been described in a small subset of cases, mostly in childhood MS [112]. Of note, similar anti-MOG antibodies seem to be present in also AQP4-negative NMO patients [113]. In EAE, anti-MOG autoantibodies enhance spontaneous disease either by stimulating APCs or by direct demyelination. Beyond classical myelin proteins, some patients with MS, produce antibodies to components of Ranvier's node, while in others autoantibodies against the potassium channel Kir4.1 (positioned on astro- and oligodendroglia membranes) has

been found [114]. This important observation remains to be reproduced in independent patient cohorts [115]. Nevertheless, the use of plasmapheresis has been proven to be useful in some patients resistant to corticosteroids, emphasizing on the role of antibodies on some patients in relapses. Moreover, B cell depletion therapies (mainly by anti-CD20 antibodies rituximab and ocrelizumab) were beneficial by reducing in relapse rates and lesional activity as recorded by MRI. The mechanisms of these therapies may be several fold: beyond reduction of autoantibody production, alternative B cell functions as antigen presentation [116] or cytokines release may contribute to reduce disease progression [117].

Therapeutic perspectives MS has been a therapeutic desert before advent of immunemodulatory therapies. Interferon-b, copaxone and more recently teriflunomide and dimethyl fumarate act on early relapsing-remitting MS by reducing relapse rates by about 30%, and by decreasing the lesion load as assessed by MRI [118]. These therapies are disease modifying but not curative. They function via numerous mechanisms: mostly by diverting effector T cells to non-pathogenic lineages, either directly or via antigen presenting cells (microglia, DCs, macrophages), or by preventing active proliferation following antigen stimulation (teriflunomide). Besides, two of the most efficient new therapies, natalizumab and fingolimod, target the migration behavior of immune cells. Although additional effects are by no means excluded, natalizumab, a humanized monoclonal antibody binding to the cell adhesion molecule VLA-4, blocks radically the passage of autoimmune effector T cells and B cells from blood circulation to the CNS parenchyma, as has been shown directly by in situ imaging in rat EAE [119], and most probably also prevents T cell immigration in humans too. The drug decreases peripheral lymphocyte circulation, with drastically reduced immune cell numbers (T-, B cells) in the CSF [120], and thus impairs physiological immune surveillance of the brain tissues. Unfortunately, the remarkable clinical improvements came in some patients with a deleterious consequence, namely the awakening of dormant viruses, due to blocked immune surveillance. Most important, the JC virus may exacerbate upon therapy and may lead to Progressive Multifocal Leukoencephalopathy like in cases of severe immunosuppression, e.g. AIDS [121]. Like natalizumab, fingolimod's main effect also seems to be on immune cells migration, but this drug retains the cells in secondary lymph organs, preventing them to enter blood circulation [122]. Especially Th17-like cells seem to be affected by the treatment [67]. As fingolimod acts as an antagonist of S1P receptors and is a small and lipophilic molecule, it may also acts directly on these receptors present on astrocytes or other resident CNS cells.

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Conclusion The pathophysiology of MS is complex, involving numerous factors and cell types that exert contradictory biological effects. Based on the arguments developed above, it appears that MS is a disease issuing from the immune system in which the CNS being "only'' the target. The study of the role of immunity is one of the major axis for the development of efficient treatments in order to reduce the progression of MS. Even if several treatments allow improving the clinical status

of patients, the study of the mechanisms implicated in demyelination and the role of microbiota seems to be very important for the future. Acknowledgements: the authors would like to thank the "Fondation ARSEP'' and "Association ANTARES'' for the continuous support of our group in the field of MS research. Disclosure of interest: the authors declare that they have no conflicts of interest concerning this article.

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