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Therapeutic monoclonal antibodies have shown considerable promise for the treatment of multiple sclerosis in animal models, but the translation of this approach to the clinic has been impeded by unexpected effects and adverse reactions. In this review, Reinhard Hohlfeld and Hartmut Wekerle discuss the current state of development of various monoclonal antibodies for the treatment of multiple sclerosis.

Cladribine, an oral immunomodulatory drug, has been denied FDA and European Medicines Agency approval for the treatment of relapsing–remitting multiple sclerosis. However, a new post-hoc analysis of CLARITY study data shows that cladribine treatment is associated with a significantly increased likelihood of sustained freedom from disease activity.

A genome-wide association study has identified the R92Q variant of the TNFRSF1A gene as a new susceptibility locus for multiple sclerosis. This locus is of special interest because the R92Q substitution was previously detected in a group of multiple sclerosis patients who had additional symptoms compatible with the autoinflammatory syndrome TRAPS.

In neuroinflammatory diseases such as multiple sclerosis, ion channels may fan the embers of neurodegeneration. A new study shows that the cation channel TRPM4 (transient receptor potential melastatin 4) crucially contributes to axonal loss in an animal model of multiple sclerosis (pages 1805–1811).

In monozygotic twins discordant for multiple sclerosis, the influence of genetic predisposition and environmental factors is determined using matched-pair analyses.

Increasing evidence supports a role for B cells and antibodies in the pathogenesis of multiple sclerosis (MS). Here, Meinl and colleagues discuss the proinflammatory contribution of B-cell signalling in MS, and consider potential targets of autoantibodies. The B-cell response to various MS therapies is also summarized.

MicroRNAs (miRNAs) seem to confer a novel layer of gene regulation, possibly fine-tuning the expression of ≈50% of genes in humans. Dysfunction of these short regulatory RNAs has been noted in various neurological disorders, including Alzheimer disease and Parkinson disease. Here, Junker and colleagues explore the possible involvement of miRNAs in multiple sclerosis, highlighting the therapeutic implications for this disease.

Fewer than half of patients with multiple sclerosis respond to interferon-b, one of the most widely prescribed therapies. The discovery that different subtypes of T cells may be involved in disease development in each affected individual suggests that it may be possible to predict therapeutic success by determining a patient's cytokine profile (pages 406–412).

In multiple sclerosis, the myelin sheath is heavily damaged. New evidence suggests that inhibitory signals mediated by the Notch pathway suppress remyelination (pages 1115–1121).

Monozygotic (MZ) twins are ideal to study the influence of non-genetic factors on complex phenotypes. Here, Souren et al. perform an EWAS in peripheral blood mononuclear cells from 45 MZ twins discordant for multiple sclerosis and identify disease and treatment-associated epigenetic markers.

Neuromyelitis optica (NMO) is a rare neuroinflammatory disorder that predominantly affects the optic nerves and spinal cord. NMO was originally considered to be a subtype of multiple sclerosis, but the recent discovery of NMO-specific serum autoantibodies has caused it to be reclassified as a distinct disease. In this article, Jariuset al. review clinical, serological and pathological findings in NMO, and discuss the evidence supporting an antibody-mediated mechanism in its pathogenesis.

B-cell maturation antigen (BCMA) regulates the survival of B cells and is essential for the maintenance of long-lived plasma cells. Here, the authors show that γ-secretase directly sheds BCMA from the cell surface and therefore regulates the number of plasma cells.

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer immunotherapy, but these agents carry a high risk of immune-related adverse events. Here, the authors introduce the mechanisms of action of ICIs and review their adverse effects on the CNS, which result in conditions such as paraneoplastic neurological syndromes and multiple sclerosis.

Finding new methods to define the target antigens recognized by MHC class I–restricted T cells is an unmet need. Katherina Siewert and her colleagues have developed a sensitive technique based on recombinatorial plasmid screening of T cell receptors (TCRs) isolated from individual T cells that overcomes many of the current limitations and enables the characterization of T cell antigens from most T cells, including those isolated from frozen biopsy samples by laser microdissection. The approach was validated using a well-characterized influenza virus–specific TCR, MHC and peptide combination.

In this article, members of the International Progressive MS Alliance discuss why experimental medicine trials are important for the development of treatments for progressive multiple sclerosis and set out their funding programme for such trials.

In this Review, the authors provide detailed insight into how the gut microbiota influences the immune system, with implications for neuroinflammation, and discuss the accumulating evidence that the gut microbiota is an important factor in multiple sclerosis pathogenesis and a potential therapeutic target.