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Key Points Neuronal and axonal degeneration in multiple sclerosis (MS) is a slow process initiated by acute lymphocytic inflammation, and subsequently driven by chronically smouldering, diffuse parenchymal myeloid and meningeal lymphocytic inflammation Oxidative stress, mitochondrial injury and subsequent ion channel dysfunction secondary to chronic inflammation seem to have a constant impact on neurons and axons, leading to their demise during progressive MS Several ion channels show compensatory changes in response to the inflammatory stimulus by altering their relative distribution in the neuron—a process that eventually becomes maladaptive and perpetuates neuroaxonal injury Several neuroprotective pathways have been identified in MS, but these pathways become overridden, resulting in neuronal degeneration that is probably mediated by the initiation of apoptosis and Wallerian degeneration The balance between continuous inflammatory stressors and intrinsic buffering mechanisms depends partly on age, sex and genetic factors, which eventually determine the clinical course of MS In an animal model of MS, few molecular targets with proven neuroprotective properties that are separable from their impact on inflammatory responses have been identified; these molecules include CyPD, ASIC1 and TRPM4 Great progress has been made in elucidating the acute inflammatory components of multiple sclerosis (MS), but the pathophysiological mechanisms of the concomitant neurodegeneration are poorly understood. Friese and colleagues review the current state of knowledge regarding the pathological mechanisms of neuroaxonal dysfunction and injury in MS, highlighting evidence that axonal and neuronal impairment are early and independent contributors to disease progression. Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the CNS, and imposes major burdens on young lives. Great progress has been made in understanding and moderating the acute inflammatory components of MS, but the pathophysiological mechanisms of the concomitant neurodegeneration—which causes irreversible disability—are still not understood. Chronic inflammatory processes that continuously disturb neuroaxonal homeostasis drive neurodegeneration, so the clinical outcome probably depends on the balance of stressor load (inflammation) and any remaining capacity for neuronal self-protection. Hence, suitable drugs that promote the latter state are sorely needed. With the aim of identifying potential novel therapeutic targets in MS, we review research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction. We focus on mechanisms inherent to neurons and their axons, which are separable from those acting on inflammatory responses and might, therefore, represent bona fide neuroprotective drug targets with the capability to halt MS progression.

Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measurable in blood, are largely lacking. We have investigated a broad set of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay. Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases. We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy similar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve [AUC] = 0.95). Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in comparison to healthy controls. Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively. In the discovery cohort, eotaxin-1 (CCL11) was associated with disease duration particularly in patients who had secondary progressive disease (P CSF < 4 × 10−5, P plasma < 4 × 10−5), and plasma CCL20 was associated with disease severity (P = 4 × 10−5), although both require further validation. Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy. We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity. Of particular importance is the set of markers discovered in blood, where validated biomarkers are lacking.

Genome-wide association studies in combination with functional analyses identify a genetic variant that explains why anti-tumour necrosis factor therapy, used in several autoimmune diseases, exacerbates multiple sclerosis. Genetic variation in multiple sclerosis Recent genome-wide association studies (GWAS) have indicated an association between multiple sclerosis and a single-nucleotide polymorphism in the TNFRSF1A gene that encodes tumour necrosis factor (TNF) receptor 1 (TNFR1). TNF has previously been implicated in autoimmunity and TNF antagonists are effective treatments in several autoimmune diseases, but not in multiple sclerosis. Interestingly, GWAS evidence shows no link between TNFRSF1A and multiple sclerosis. This study compares GWAS results across different autoimmune conditions, as well as findings from functional and biophysical investigations, to show that multiple sclerosis-associated genetic risk at the TNFR1 locus results in the generation of a novel, endogenous TNF antagonist. This genetic-risk effect parallels the effects of anti-TNF therapy, which has been reported — in rare cases — to induce clinical onset of multiple sclerosis. Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS) 1 , it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance 2 . Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS) 3 , 4 , but not with other autoimmune conditions such as rheumatoid arthritis 5 , psoriasis 6 and Crohn’s disease 7 . By analysing MS GWAS 3 , 4 data in conjunction with the 1000 Genomes Project data 8 we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS 9 , 10 , 11 , but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.

Expression of HLA-C varies widely across individuals in an allele-specific manner. This variation in expression can influence efficacy of the immune response, as shown for infectious and autoimmune diseases. MicroRNA binding partially influences differential HLA-C expression, but the additional contributing factors have remained undetermined. Here we use functional and structural analyses to demonstrate that HLA-C expression is modulated not just at the RNA level, but also at the protein level. Specifically, we show that variation in exons 2 and 3, which encode the α1/α2 domains, drives differential expression of HLA-C allomorphs at the cell surface by influencing the structure of the peptide-binding cleft and the diversity of peptides bound by the HLA-C molecules. Together with a phylogenetic analysis, these results highlight the diversity and long-term balancing selection of regulatory factors that modulate HLA-C expression. HLA-C expression levels correlate with immune responses to pathogens and autoimmunity, and vary in an allele-specific manner across individuals. Here the authors identify factors that drive differential expression of HLA-C allomorphs at the cell surface, and influence the structure of the peptide-binding cleft and diversity of peptides bound by HLA-C molecules.

Key Points The strength of the genetic association between specific MHC class II alleles and an individual's susceptibility to particular chronic inflammatory diseases renders these alleles the main known risk factor for many such diseases. The peptide-binding grooves of MHC class II molecules can be described in terms of pockets that must accommodate the side chains of residues at positions P1, P4, P6 and P9 of the peptide. Analyses of the characteristics of these pockets, as revealed by the crystal structures of MHC class II molecules, provide insights into how sequence polymorphisms determine the population of peptides a particular MHC class II molecule can bind, and indicate molecular mechanisms that could determine disease susceptibility. Structure-based analysis indicates that differential peptide binding between two closely related HLA-DQ6 molecules is central to their positive and negative association with the chronic neurological disorder narcolepsy, an observation that is consistent with narcolepsy being an autoimmune disease. Coeliac disease is an autoimmune-like disorder that is caused by an immune response to antigens present in wheat gluten. HLA-DQ2, and to a lesser extent HLA-DQ8, have peptide-binding-groove characteristics that strongly favour the binding of gluten-derived peptides, consistent with the association of these MHC class II molecules with coeliac disease. Crystal structures for the type-1-diabetes-associated MHC class II molecules HLA-DQ8, HLA-DQ2 and mouse H2-IA g7 reveal a distinctive P9 pocket, which might indicate similar pathophysiological pathways for developing type 1 diabetes in humans and non-obese diabetic mice. A comparison of the structures of disease-associated versus protective MHC class II molecules reveals a second characteristic; the P6 pocket shows a consistent trend in volume size that correlates from positive to negative association with type 1 diabetes. T cells are thought to play an important role in the development of rheumatoid arthritis and an immunodominant T-cell epitope from type II collagen is a candidate autoantigen. The structures of the disease-associated HLA-DR4.1 and HLA-DR1 molecules reveal P4 pockets that have in common an ability to bind acidic residues, plus shallow P6 and P9 pockets that are particularly well suited to binding the glycine-rich sequences typical of type-II-collagen-derived peptides. Distinctive structural characteristics of the multiple-sclerosis-associated MHC class II molecules HLA-DR2a and HLA-DR2b separately result in peptide residues P6–P9 assuming a raised position above the respective peptide-binding grooves. This differs considerably from the canonical mode of peptide presentation by other MHC class II molecules and might favour T-cell receptors that sample a reduced portion of the peptide, hence increasing the likelihood of a disease inducing crossreactivity. MHC class II molecules are important factors that contribute to the susceptibility of an individual to autoimmune disease. Jones and colleagues look for clues to their involvement in disease by analysing crystal structures of peptide–MHC-class II complexes. MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4 + T helper cells. Therefore, MHC class II molecules are central to effective adaptive immune responses, but conversely, genetic and epidemiological data have implicated these molecules in the pathogenesis of autoimmune diseases. Indeed, the strength of the associations between particular MHC class II alleles and disease render them the main genetic risk factors for autoimmune disorders such as type 1 diabetes. Here, we discuss the insights that the crystal structures of MHC class II molecules provide into the molecular mechanisms by which sequence polymorphisms might contribute to disease susceptibility.

Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration 1 , 2 . The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1) 3 , 4 is permeable to Na + and Ca 2+ , and excessive accumulation of these ions is associated with axonal degeneration 5 . We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1 −/− mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice. Consistently with acidosis-mediated injury, pH measurements in the spinal cord of EAE mice showed tissue acidosis sufficient to open ASIC1. The acidosis-related protective effect of Asic1 disruption was also observed in nerve explants in vitro . Amiloride, a licensed and clinically safe blocker of ASICs, was equally neuroprotective in nerve explants and in EAE. Although ASICs are also expressed by immune cells, this expression is unlikely to explain the neuroprotective effect of Asic1 inactivation, as CNS inflammation was similar in wild-type and Asic1 −/− mice. In addition, adoptive transfer of T cells from wild-type mice did not affect the protection mediated by Asic1 disruption. These results suggest that ASIC1 blockers could provide neuroprotection in multiple sclerosis.

Hypothalamic orexin/hypocretin neurons recently emerged as key orchestrators of brain states and adaptive behaviors. They are critical for normal stimulation of wakefulness and breathing: Orexin loss causes narcolepsy and compromises vital ventilatory adaptations. However, it is unclear how orexin neurons generate appropriate adjustments in their activity during changes in physiological circumstances. Extracellular levels of acid and CO 2 are fundamental physicochemical signals controlling wakefulness and breathing, but their effects on the firing of orexin neurons are unknown. Here we show that the spontaneous firing rate of identified orexin neurons is profoundly affected by physiological fluctuations in ambient levels of H + and CO 2 . These responses resemble those of known chemosensory neurons both qualitatively (acidification is excitatory, alkalinization is inhibitory) and quantitatively (≈100% change in firing rate per 0.1 unit change in pH e ). Evoked firing of orexin cells is similarly modified by physiologically relevant changes in pH e : Acidification increases intrinsic excitability, whereas alkalinization depresses it. The effects of pH e involve acid-induced closure of leak-like K + channels in the orexin cell membrane. These results suggest a new mechanism of how orexin/hypocretin networks generate homeostatically appropriate firing patterns. arousal hypocretin hypothalamus pH breathing

Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO 409–428 ), can induce anti-MPO autoimmunity. The peptide (6PGD 391–410 ) is part of a plasmid-encoded 6-phosphogluconate dehydrogenase found in some S. aureus strains. It induces anti-MPO T-cell autoimmunity and MPO-ANCA in mice, whereas related sequences do not. Mice immunized with 6PGD 391–410 , or with S. aureus containing a plasmid expressing 6PGD 391–410 , develop glomerulonephritis when MPO is deposited in glomeruli. The peptide induces anti-MPO autoreactivity in the context of three MHC class II allomorphs. Furthermore, we show that 6PGD 391–410 is immunogenic in humans, as healthy human and AAV patient sera contain anti-6PGD and anti-6PGD 391–410 antibodies. Therefore, our results support the idea that bacterial plasmids might have a function in autoimmune disease. Autoreactivity to myeloperoxidase (MPO) causes autoimmune vasculitis and severe glomerulonephritis. Here, Ooi et al. show that a Staphylococcus aureus plasmid encodes a peptide that is homologous to an immunodominant MPO epitope and induces anti-MPO autoimmunity and glomerulonephritis in mice.

Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment. Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction.

Microscopic polyangiitis is an autoimmune small-vessel vasculitis that often manifests as focal and necrotizing glomerulonephritis and renal failure. Antineutrophil cytoplasmic Abs (ANCAs) specific for myeloperoxidase (MPO) play a role in this disease, but the role of autoreactive MPO-specific CD4 ⁺ T cells is uncertain. By screening overlapping peptides of 20 amino acids spanning the MPO molecule, we identified an immunodominant MPO CD4 ⁺ T-cell epitope (MPO ₄₀₉–₄₂₈). Immunizing C57BL/6 mice with MPO ₄₀₉–₄₂₈ induced focal necrotizing glomerulonephritis similar to that seen after whole MPO immunization, when MPO was deposited in glomeruli. Transfer of an MPO ₄₀₉–₄₂₈-specific CD4 ⁺ T-cell clone to Rag 1 ⁻/⁻ mice induced focal necrotizing glomerulonephritis when glomerular MPO deposition was induced either by passive transfer of MPO-ANCA and LPS or by planting MPO ₄₀₉–₄₂₈ conjugated to a murine antiglomerular basement membrane mAb. MPO ₄₀₉–₄₂₈ also induced biologically active anti-MPO Abs in mice. The MPO ₄₀₉–₄₂₈ epitope has a minimum immunogenic core region of 11 amino acids, MPO ₄₁₅–₄₂₆, with several critical residues. ANCA-activated neutrophils not only induce injury but lodged the autoantigen MPO in glomeruli, allowing autoreactive anti-MPO CD4 ⁺ cells to induce delayed type hypersensitivity-like necrotizing glomerular lesions. These studies identify an immunodominant MPO T-cell epitope and redefine how effector responses can induce injury in MPO-ANCA–associated microscopic polyangiitis.