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Key Points Two decades of clinical experience with the immunomodulatory treatment of multiple sclerosis points to distinct immunological pathways that drive disease relapses and progression. Although the immunomodulatory drugs reduce the frequency of relapses, the trade-off of efficacy is a range of side effects, and the long-standing drugs approved for multiple sclerosis do not ultimately halt neurodegeneration. Dissecting the distinct roles of the immune system in multiple sclerosis is complicated by one, the multicellular pathophysiology that involves infiltrating adaptive and innate immune cells, as well as central nervous system (CNS)-resident innate cells with inflammatory capacity; and two, the chronic nature of the disease that unfolds over a period of many decades. Multiple sclerosis is associated with more than 100 different genetic variants that promote disease predisposition and with environmental influences that alter disease penetrance and stochastic occurrences, although the exact triggering events may vary from one patient to the next. Despite the progress in identifying the genetic determinants of the disease, their phenotypic consequences remain to be elucidated, and a substantial understanding of environmental contributors is lacking. Dysregulation of immune effector–suppressor cell interactions occurs in multiple sclerosis, ultimately resulting in autoreactive adaptive immune cells that are capable of infiltrating and promoting damage within the CNS. However, these cells may not be the main drivers of more chronic, progressive neurodegeneration. Chronic inflammation in multiple sclerosis may reflect a long-term stress response to homeostatic dysregulation in the CNS by tissue-resident innate cells that exceedingly burdens the system, leading to progressive and irreversible neurodegenerative decline. The most imminent goal for future treatment is the concomitant improved targeting of relapses and progression, potentially through combinatorial therapies that modulate both arms of the disease. Improved disease prognosis and potential patient stratification for more directed healthcare provision are also much-anticipated prospects and may become tangible as we move into the immune informatics era and as large-scale, organized health resources become increasingly accessible. This Review provides an insightful discussion on the current concepts in multiple sclerosis research, including genetic predisposition and environmental triggers, and explores the evolving link between inflammation and neurodegeneration. The authors highlight the clinical challenges and key questions that remain to be addressed. Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (T H 17) cells, which can also contribute to hypertension. Induction of T H 17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus . Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating T H 17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased T H 17 cells and increased blood pressure. Our results connect high salt intake to the gut–immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions. High salt intake changed the gut microbiome and increased T H 17 cell numbers in mice, and reduced intestinal survival of Lactobacillus species, increased the number of T H 17 cells and increased blood pressure in humans. Gut microbes worth their salt The role of the gut microbiota in human disease is becoming increasingly recognized. In this study, Dominik Müller and colleagues report that a diet high in salt alters the composition of the gut microbiota in mice, causing pronounced depletion of the commensal Lactobacillus murinus and reduced production of indole metabolites. Previous work has suggested that a high salt diet leads to the generation of pathogenic T helper 17 (T H 17) cells, which have been linked to hypertension and autoimmunity. The authors show that treatment of mice on a high salt diet with L. murinus prevents salt-induced aggravation of actively induced autoimmune encephalomyelitis and salt-sensitive hypertension, through the suppression of T H 17 cells. In a pilot study in a small number of humans, the authors also show that high-salt challenge induces an increase in blood pressure and T H 17 cells, associated with a reduction in Lactobacillus in the gut. However, future work is required to determine whether the findings for mice are translatable to humans.

Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood–brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials.Bruton tyrosine kinase inhibitors are an emerging treatment for multiple sclerosis. Krämer et al. consider the evidence that central nervous system-penetrant Bruton tyrosine kinase inhibitors might target both peripheral immune cells and compartmentalized inflammation and discuss promising preliminary results of clinical trials of these agents in multiple sclerosis.

There is growing recognition that B cell contributions to normal immune responses extend well beyond their potential to become antibody-producing cells, including roles at the innate–adaptive interface and their potential to modulate the responses of other immune cells such as T cells and myeloid cells. These B cell functions can have both pathogenic and protective effects in the context of central nervous system (CNS) inflammation. Here, we review recent advances in the field of multiple sclerosis (MS), which has traditionally been viewed as primarily a T cell–mediated disease, and we consider antibody-dependent and, particularly, emerging antibody-independent functions of B cells that may be relevant in both the peripheral and CNS disease compartments. In this Focus Review, Bar-Or and colleagues discuss the latest evidence that B cells play an important antibody-independent role in multiple sclerosis and the prospects this holds for therapeutic intervention.

Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, using single cell transcriptomics, we identify a specific location-associated composition and transcriptome of CSF leukocytes. Multiple sclerosis (MS) – an autoimmune disease of the CNS – increases transcriptional diversity in blood, but increases cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. An analytical approach, named cell set enrichment analysis (CSEA) identifies a cluster-independent increase of follicular (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promote B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction. Here the authors provide a single-cell characterization of cerebrospinal fluid and blood of newly diagnosed multiple sclerosis (MS) patients, revealing altered composition of lymphocyte and monocyte subsets, validated by other methods including the interrogation of the TFH subset in mouse models of MS.

Gil McVean and colleagues report a meta-analysis of Immunochip studies including over 17,000 multiple sclerosis cases and 30,000 controls, with imputation of classical HLA alleles. They find two interactions involving class II HLA alleles but no evidence for significant epistatic interactions or interactions between HLA and non-HLA risk variants. Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.

MRI red flags proposed over a decade ago by the European Magnetic Resonance Network in MS (MAGNIMS) have guided clinicians in the diagnosis of multiple sclerosis (MS). However, the past 10 years have seen increased recognition that vascular disease can coexist and possibly interact with MS, improvements in the reliability of ways to differentiate MS from novel antibody-mediated CNS disorders (such as anti-aquaporin-4 antibody and myelin-oligodendrocyte glycoprotein antibody-associated diseases) and advances in MRI techniques. In this Review, MAGNIMS updates the imaging features that differentiate the most common mimics of MS, particularly age-related cerebrovascular disease and neuromyelitis optica, from MS itself. We also provide a pragmatic summary of the clinically useful MRI features that distinguish MS from its mimics and discuss the future of nonconventional techniques that have identified promising disease-specific features.

The modern era of multiple sclerosis (MS) treatment began 25 years ago, with the approval of IFNβ and glatiramer acetate for the treatment of relapsing–remitting MS. Ten years later, the first monoclonal antibody, natalizumab, was approved, followed by a third important landmark with the introduction of oral medications, initially fingolimod and then teriflunomide, dimethyl fumarate and cladribine. Concomitantly, new monoclonal antibodies (alemtuzumab and ocrelizumab) have been developed and approved. The modern era of MS therapy reached primary progressive MS in 2018, with the approval of ocrelizumab. We have also learned the importance of starting treatment early and the importance of clinical and MRI monitoring to assess treatment response and safety. Treatment decisions should account for disease phenotype, prognostic factors, comorbidities, the desire for pregnancy and the patient’s preferences in terms of acceptable risk. The development of treatment for MS during the past 25 years is a fantastic success of translational medicine.

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated 1 . Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age 2 , along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment. Analysis of a large ancient genome dataset shows that genetic risk for multiple sclerosis rose in steppe pastoralists, providing insight into how genetic ancestry from the Neolithic and Bronze Age has shaped modern immune responses.

Key Points Integrin antagonists are highly successful drugs for targeting the ligand binding site of αIIbβ3, α4-containing or α4β7 integrins. Antagonists to αIIbβ3 integrin are still being used in patients receiving percutaneous angioplasty but are being replaced in many instances by new classes of anticoagulants and platelet inhibitors. Natalizumab, a monoclonal antibody against α4-containing integrins, is highly successful at treating multiple sclerosis, but can reactivate John Cunningham virus and cause lethal progressive multifocal leukoencephalopathy (PML). Vedolizumab, a monoclonal antibody against α4β7 integrin, and new antibodies against the β7 integrin subunit have not shown any signs of inducing PML. Vedolizumab is safe and effective in the treatment of inflammatory bowel disease and has effectively replaced natalizumab for the treatment of Crohn disease. Members of the integrin family of receptors, which are involved in cell–cell adhesion, have been successfully targeted for cardiovascular disease, multiple sclerosis and inflammatory bowel disease. Ley and colleagues review the biological basis for the development of the next generation of integrin-targeted drugs, highlighting lessons learned from successes and failures. Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.