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A variety of immune cell types contribute to disease in individuals with multiple sclerosis, an autoimmune condition of the central nervous system. Thomas Prod'homme and Scott Zamvil comment on the 'Bench to Bedside' approach, examining how recent basic research implicates the antigen-presenting cell in this disease. In our 'Bedside to Bench' column, Hans Link explores how recent clinical trials may bolster a mechanistic role for the B cell.

Findings from a mouse model of multiple sclerosis suggest that regulatory T cells alone cannot outduel pathogenic T cells in the central nervous system. The observations may have implications for experimental approaches designed to dampen autoimmune diseases by infusion of regulatory T cells (pages 423–431).

Statins are best known for their cholesterol-lowering effects, but they also have immunomodulatory properties that might be exploited to treat neuroinflammatory disorders, such as multiple sclerosis. This review describes the molecular and cellular mechanisms that are thought to underlie the immunomodulatory effects, and discusses the results of initial clinical trials of statins in patients with multiple sclerosis.

Autoimmune brain inflammation is associated with activation of macrophages and microglia. Here the authors show that fibrinogen induces encephalitogenic T-cell activation and macrophage recruitment to the central nervous system, and promotes demyelination in a mouse model of multiple sclerosis.

Immune checkpoint inhibitors provide beneficial anti-tumor immunity but risk immune-related adverse events occurring in normal tissues. Notably, selective deletion of PGLYRP1, a protein expressed by several immune cells, protects against tumor cell growth and autoimmunity.

An antibody screen of two distinct multiple sclerosis cohorts reveals an autoantibody signature that is detectable years before symptom onset and linked to a common microbial motif.

A better understanding of how multiple sclerosis (MS) can relapse and remit is needed for the identification of biomarkers and better therapeutics. Here the authors identify a CD8 + NK cell population in patients with relapsing remitting MS and validate its association with clinical outcome.

Statins are best known as cholesterol-lowering drugs but increasing evidence indicates that they might be an effective treatment for autoimmune disease. Their ability to inhibit post-translational protein prenylation could be key to their immunomodulatory effects.

Fibrin deposition occurs after the blood–brain barrier is breached. Akassoglou and colleagues generate a therapeutic monoclonal antibody that targets a cryptic fibrin epitope to suppress activation of innate immune responses in the CNS and diminish neuroinflammation.

Oxidative stress can promote neurodegeneration. Akassoglou and colleagues describe Tox-seq, a functional single-cell RNA sequencing method to identify oxidative stress transcriptional signatures in CNS-resident cells. Tox-seq identified coagulation and glutathione-redox pathway genes that are coupled to oxidative stress and that could be targeted by the glutathione-regulating small molecule acivicin.

A20 is a deubiquitinating enzyme that restrict inflammation by various mechanisms. Ma and colleagues show that A20 inhibits necroptosis by inhibiting the ubiquitination of RIPK3 and formation of the RIPK1-RIPK3 complex.

Macrophages in the tumour microenvironment (TME) acquire tumour-promoting functions upon M2 polarization. Here the authors show, in a mouse model of glioblastoma, that endothelial cells in the TME induce macrophage M2 polarization via IL-6 and that depletion of endothelial IL-6 improves survival.

Two clinical trials testing an altered peptide ligand (APL) in multiple sclerosis report seemingly contradictory results. Immunologic analysis shows that the biological effects of APLs extend far beyond what was initially envisioned, raising important issues for the development of this type of therapy (pages 1167–1175 & 1176–1182).

The precise role of follicular regulatory (T_FR) cells in the control of the germinal center (GC) reaction is unclear. Sage and colleagues develop a T_FR cell-deleter mouse that allows specific temporal deletion and show that T_FR cells primarily control early but not late GC responses.

Akassoglou and colleagues provide a single-cell RNA sequencing and phosphoprotein analysis of the responses of central nervous system microglia and macrophages to blood proteins including activated complement and fibrin. Their findings point to potential therapeutic targeting of microglia activation by immune and vascular signals.

In individuals with inflammation of the central nervous system, B cells enter and accumulate in the cerebrospinal fluid, brain parenchyma and perivascular spaces. Here, Joseph Sabatino and colleagues review the contributions of B cells — both in the periphery and sequestered within the central nervous system — to the pathogenesis of several autoimmune and neurodegenerative diseases.