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      Editorial: Lymphocytes in MS and EAE: More Than Just a CD4 + World

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          Abstract

          Editorial on the Research Topic Lymphocytes in MS and EAE: More Than Just a CD4+ World Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects nearly two million people worldwide. Disease onset can occur at a young age, leaving sufferers with a significantly reduced quality of life. The fact that there is no cure for MS, plus the fact that its animal model experimental autoimmune encephalomyelitis (EAE) is considered a “classic” model of CD4+ T cell-triggered autoimmunity, has led MS pathogenesis to be an area of intense investigation in the past few decades. Numerous lines of evidence indicate that MS is driven by CD4+ T lymphocyte-mediated mechanisms (1–3). Polymorphisms in the HLA class II region are by far the strongest genetic link to MS (4). Moreover, the majority of currently available MS disease-modifying therapies are believed to act by modulating inflammatory CD4+ T cell responses, although in many cases the effects on other immune cell types are under-studied and may be at least as important. Furthermore, while current immunomodulatory drugs are able to reduce the frequency and severity of MS relapses, they are relatively ineffective in progressive forms of the disease (5). Attempted blockade of CD4+ T cells using anti-CD4-depleting antibody therapy did not produce clinical benefits to patients with MS (6). In contrast, more global immunosuppressive or immunomodulatory approaches reduce the number of relapses and disease progression of MS patients (7). Furthermore, numerous publications have presented data generated from autopsy material obtained from human patients supporting the notion that other cell types are involved (8–11). There is thus an urgent need to expand our view of immune-related pathogenesis in human disease. Despite evidence that lymphocytes such as B cells and CD8+ T cells play a role, their contributions are much less well studied experimentally compared to those of CD4+ T cells. In this Special Topic, we promote this expanded view of disease pathogenesis by presenting articles that examine the role played by lymphocytes other than CD4+ T cells in MS and its experimental models. The B cell-depleting reagents rituximab and ocrelizumab have shown success against relapsing/remitting (12) and even progressive MS (13). Thus, it is no surprise that this collection features several submissions considering different aspects of potential B cell contributions to CNS autoimmunity. Both Claes et al. and Michel et al. survey what is known about B cells in MS and discuss potential pathogenic mechanisms including antibody production, cytokine secretion, antigen presentation to T cells, and the promotion of disease from within the CNS. Claes et al. additionally present a detailed review of how B cell subpopulations and effector functions are altered both by broadly specific disease-modifying therapies such as interferon-beta and glatiramer acetate as well as by rituximab and ocrelizumab. B cell infiltration into the CNS in MS was a particular focus of the Michel et al. review, and this was further expanded upon by two additional reviews in this special topic. Blauth et al. describe the signals that may permit B cell entry to the CNS, such as CXCL13, VLA-4, and ICAM. Additionally, they discuss recent evidence suggesting that B cells can also exit the CNS so as to undergo additional affinity maturation in peripheral lymphoid tissues, as well as data indicating that the meninges can support differentiation of CNS-specific B cells independently of the periphery. Once in the CNS, B cells have been described to form aggregates in the meninges akin to tertiary lymphoid organ-like structures, and these are the subject of a review from Pikor et al. In particular, they discuss recent evidence suggesting that antigen-experienced T and B cells accumulate in these structures to promote CNS inflammation. A common theme of these reviews is the uncertainty regarding the neuropathogenic role of B cells in MS. Interestingly, evidence from the two primary research articles in this issue present a challenge to the hypothesis that autoreactive B cell responses are propagated within meningeal aggregates of lymphocytes. First, in an attempt to identify antigenic targets of B cell-mediated destruction in MS, Willis et al. cloned the IgV heavy and light chains of CNS-infiltrating B cell clones from six MS patients to generate putative CNS-reactive recombinant antibodies. Surprisingly, using various approaches (binding to candidate antigen, CNS cell lines, or antigen array) no CNS- or MS-specific antigen targets could be identified. Second, Dang et al. present data showing that the presence of B cells in spinal cord-associated meningeal clusters correlates with chronic symptoms in a B cell-dependent model of spontaneous EAE. Intriguingly, however, these “cluster B cells” have a naïve phenotype with little evidence of Ig class switching and the clusters themselves do not bear the features of structured lymphoid follicles, suggesting that the simple presence of B cells in the meninges is sufficient to promote disease progression. The remaining B cell-centric articles in this issue focus on other potential pathogenic mechanisms. B cells almost certainly shape the autoimmune response through the secretion of inflammatory cytokines such as TNFα, lymphotoxin, and GM-CSF, as described by Li et al. In addition, B cells can present antigen to T cells and modulate their properties. Márquez and Horwitz discuss the possibility that Epstein-Barr virus (EBV)-infected B cells preferentially elicit Th1 responses in the CNS. It is tempting to speculate that exposure to EBV, which is an environmental factor strongly associated with MS (14), influences disease outcomes by altering B cell activity. Furthermore, the effectiveness of B cell depletion therapy in MS may be due in part to reduced effector T cell function. While the “immune helper” functions of B cells in MS have been intensely investigated, the classic role of B cells as antibody-secreting cells cannot be neglected. Indeed, the presence of oligoclonal IgG bands in CSF has long been a clinical biomarker of MS and is still used as a differential diagnostic tool (15). Khorooshi et al. detail what is known about antibody-mediated pathogenic mechanisms in CNS autoimmunity. They pay particular attention to the role of anti-aquaporin 4 antibodies in neuromyelitis optica—a disease that has only recently been recognized as being independent of MS. They present a scheme in which these antibodies cross a disrupted blood–brain barrier and target astrocytes for complement-mediated destruction in a T cell-independent manner. CD8+ T cells are present in MS tissue at all stages of disease. They can greatly outnumber CD4+ T cells in lesions, perivascular cuffs, and normal-appearing white matter. Furthermore, unlike CD4+ T cells that mostly remain restricted to the perivascular space, CD8+ T cells infiltrate deep into the CNS parenchymal lesions (16). Salou et al. delineate some of the current lines of investigation into the role of CD8+ T cells in MS, such as ongoing efforts to characterize the antigenic repertoire of these cells, as well as recent advances in the study of CD8+ T cells using EAE and the importance of IL-17-producing CD8+ T cells in pathogenesis. Yang et al. describe the pathogenic function of CD8+ T cells in peripheral neuropathies such as Guillain–Barré syndrome, with a particular emphasis on a mouse model that features CD8+ T cell-driven inflammation in the peripheral sciatic, trigeminal, and facial nerves. By contrast, Sinha et al. argue that the role of regulatory CD8+ T cells (Treg) in CNS autoimmunity deserves further attention. Importantly, the frequency of CD8+ Treg is diminished during MS relapse, and the authors discuss findings suggesting that the drug glatiramer acetate may act, in part, by augmenting the CD8+ Treg response. Finally, Ignatius Arokia Doss et al. describe a transgenic mouse strain (1C6) in which both CD4+ and CD8+ T cells bear T cell receptor specificity to myelin antigen. The 1C6 transgene is on the NOD background, on which mice develop a relapsing-to-progressive pattern of EAE that models the form most commonly seen in human MS. The authors propose an approach in which 1C6 CD8+ T cells are stimulated ex vivo with distinct differentiation stimuli, prior to adoptive transfer. This would allow one to dissect the relative contributions of IFNγ-producing, IL-17-positive, and potentially even regulatory CD8+ T cells to CNS autoimmunity. While B cells and CD8+ T cells represent two-thirds of the lymphocytic “Holy Trinity,” there is an array of other lymphocyte subsets with innate immune-like properties that have been posited to play a role in MS. Edwards et al. and Malik et al. provide an overview of what is known about γδ T cells in MS and EAE, respectively. These cells, which are found principally in skin and mucosal tissues, readily produce IL-17-associated cytokines and thus may be important mediators of inflammation in the CNS. The role of natural killer cells in disease may be Janus-like, with inflammatory CD16+CD56dim cells being increased during MS relapse while the CD16dim/-CD56bright subset predominates during remission (Edwards et al.). Treiner and Liblau report what is known about recently identified mucosal-associated invariant T (MAIT) cells. These are lymphocytes with innate properties that, as their name suggests, are located in mucosal tissues such as in the gut. While studies in mouse EAE have suggested that MAIT cells are anti-inflammatory, the picture is less clear in humans as MS immunotherapy appears to affect the frequency of peripheral MAIT cells. However, as MAIT cells may proliferate in response to commensal microbial antigens (17), it is tempting to speculate that they may provide part of the answer to the question of how the microbiome can influence autoimmune inflammatory diseases such as MS. The past decades have seen remarkable progress in unraveling the complex and diversified immune mechanisms that contribute to MS pathobiology. Nevertheless, the precise etiology of MS remains elusive. Furthermore, despite an increasing number of immunomodulatory or immunosuppressive therapies altering relapsing-remitting MS, there is a pressing need for effective treatments for progressive disease. The more expanded view of disease pathology presented in this Special Topic may prove to be the key for the next generation of MS therapies. Author Contributions MR wrote the manuscript with the input of SK, NA, and JA. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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          Most cited references 12

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          The relation between inflammation and neurodegeneration in multiple sclerosis brains

          Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.
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            Clonal Expansions of Cd8+ T Cells Dominate the T Cell Infiltrate in Active Multiple Sclerosis Lesions as Shown by Micromanipulation and Single Cell Polymerase Chain Reaction

            Clonal composition and T cell receptor (TCR) repertoire of CD4+ and CD8+ T cells infiltrating actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented resolution at the level of single cells. Individual CD4+ or CD8+ T cells were isolated from frozen sections of lesional tissue by micromanipulation and subjected to single target amplification of TCR-β gene rearrangements. This strategy allows the assignment of a TCR variable region (V region) sequence to the particular T cell from which it was amplified. Sequence analysis revealed that in both cases investigated, the majority of CD8+ T cells belonged to few clones. One of these clones accounted for 35% of CD8+ T cells in case 1. V region sequence comparison revealed signs of selection for common peptide specificities for some of the CD8+ T cells in case 1. In both cases, the CD4+ T cell population was more heterogeneous. Most CD4+ and CD8+ clones were represented in perivascular infiltrates as well as among parenchymal T cells. In case 2, two of the CD8+ clones identified in brain tissue were also detected in peripheral blood. Investigation of the antigenic specificities of expanded clones may help to elucidate their functional properties.
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              Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand.

              Myelin-specific T lymphocytes are considered essential in the pathogenesis of multiple sclerosis. The myelin basic protein peptide (a.a. 83-99) represents one candidate antigen; therefore, it was chosen to design an altered peptide ligand, CGP77116, for specific immunotherapy of multiple sclerosis. A magnetic resonance imaging-controlled phase II clinical trial with this altered peptide ligand documented that it was poorly tolerated at the dose tested, and the trial had therefore to be halted. Improvement or worsening of clinical or magnetic resonance imaging parameters could not be demonstrated in this small group of individuals because of the short treatment duration. Three patients developed exacerbations of multiple sclerosis, and in two this could be linked to altered peptide ligand treatment by immunological studies demonstrating the encephalitogenic potential of the myelin basic protein peptide (a.a. 83-99) in a subgroup of patients. These data raise important considerations for the use of specific immunotherapies in general.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/182426
                URI : http://frontiersin.org/people/u/182571
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                13 February 2017
                2017
                : 8
                Affiliations
                1Department of Neurosciences, Centre de recherche du CHU de Québec – Université Laval , Quebec City, QC, Canada
                2Department of Molecular Medicine, Université Laval , Quebec City, QC, Canada
                3Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University , London, ON, Canada
                4Department of Neurosciences, Université de Montréal and CRCHUM , Montréal, QC, Canada
                5Department of Pathobiology, University of Pennsylvania , Philadelphia, PA, USA
                Author notes

                Edited by: Hans-Peter Hartung, University of Düsseldorf, Germany

                Reviewed by: Jorge Correale, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Argentina

                *Correspondence: Manu Rangachari, manu.rangachari@ 123456crchudequebec.ulaval.ca

                Specialty section: This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.00133
                5303706
                Copyright © 2017 Rangachari, Kerfoot, Arbour and Alvarez.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 17, Pages: 3, Words: 2447
                Categories
                Immunology
                Editorial

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