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Using large cohorts from published clinical trials involving more than 8,000 patients with multiple sclerosis, a probabilistic machine learning model reconstructs the transition probabilities from data-derived diseases statuses, showing patterns that suggest how progression to severe stages occur and potential inversion of the process.

Autoimmune encephalitis (AIE) may involve neuron-specific cytotoxic T cells, but evidence is still lacking. Here the authors use induced pluripotent stem cells from patients with AIE and single cell RNA-sequencing of ex vivo CD8 T cells to find neuron-specific, KIR⁺CD8⁺ T cells with altered transcriptome that potentially contribute to AIE etiology.

Polyneuropathy causes are difficult to pinpoint. Here, authors used single-nucleus and spatial transcriptomics of 37 human peripheral nerves to identify focal perineurial hyperplasia and endoneurial lipid-associated macrophages in polyneuropathies.

Regulatory T (T_REG) cells are emerging as key players in the pathogenetic scenario of CNS autoimmune inflammation. In this article, Zozulya and Wiendl discuss how T_REG-cell dysfunction might influence the disease course in multiple sclerosis and experimental autoimmune encephalomyelitis, highlighting the importance of interactions between T_REGcells and dendritic cells. The authors also assess the potential for therapeutic use of these cell types in patients with multiple sclerosis.

Daclizumab is a humanized monoclonal antibody that targets the IL-2 receptor α chain, and has shown promise as a novel treatment for multiple sclerosis (MS). Here, Wiendl and Gross provide an overview of clinical experience with daclizumab in MS, including results from phase II trials. They also discuss the putative mechanisms of action of this drug in MS pathogenesis, which involve dampening of early T-cell activation and upregulation of immunomodulatory natural killer cells.

Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

Results from two phase III trials show the potency of alemtuzumab—a T-cell and B-cell depleting antibody—in reducing clinical and paraclinical measures of disease activity in relapsing–remitting multiple sclerosis. The effects of this immunotherapeutic agent highlight the relevance of T lymphocytes in the early pathogenesis of disease.

Rasmussen Encephalitis is a rare neurological disease accompanied by inflammation and T cell infiltration in the brain. Here the authors show that the severity of this disease correlates with clonal CD8 T cell expansion.

In this Review, Wiendl et al. consider how the study of rare but paradigmatic neuroimmunological diseases, including Susac syndrome, Rasmussen encephalitis and narcolepsy type 1, is providing fundamental insights into disease mechanisms that can be applied to more complex, heterogeneous neuroimmunological diseases such as multiple sclerosis.

This study identifies a unique multiple sclerosis lesion, the broad rim lesion, which is associated with rapid disease progression and marked by a distinct inflammatory profile involving innate inflammation, cellular stress, unfolded protein response and apoptosis.

Cell-mediated cytotoxicity observed in untreated SMA patients’ CSF and brain parenchyma. Spatial transcriptomic and multiplex immunohistochemistry linked cytotoxicity near affected motoneurons. Nusinersen treatment showed no impact on this profile.

The prognostic value of OCT in progressive vs relapsing multiple sclerosis (MS) is not clear. Analyzing 2651 OCTs of 407 MS patients, OCT predicted activity in all MS subtypes cross sectionally but longitudinal changes were not predictive in a multicenter setting.

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS).  Here the authors find that DNA methylation at HLA-DRB1 gene mediates the effect of DRB1*15:01 and of a protective HLA variant on HLA-DRB1 expression and the risk of MS.

How ischaemic stroke affects the brain borders is not fully understood. Here the authors show that a stroke-associated myeloid cell population occurs exclusively in brain parenchyma that shares features with neurodegenerative microglia and blockade of proteins on these cells can ameliorate stroke symptoms.

The skull dura contains B cells and B lineage precursors under homeostatic conditions. These cells are long-term tissue resident and mature upon neuroinflammation. This identifies the dura as a site of B cell residence and potentially development.

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.

Approximately half of the people currently with multiple sclerosis (MS) are ≥50 years of age, yet guidelines for management of MS in older age are lacking. This Consensus statement presents the outcomes of an International Advisory Committee on Clinical Trials (IACCT) in MS workshop on ageing and MS, including recommendations for advancing research, care and awareness.

Factor XII initiates the intrinsic blood coagulation cascade and the kinin system. Here the authors show that Factor XII is elevated in the blood of multiple sclerosis patients, activates dendritic cells via CD87 and cAMP, and its blockade inhibits immunopathology in a mouse model of the disease.

In this Review, the authors synthesize recommendations on the management of neuroimmunological disease in the context of the COVID-19 pandemic. They consider these recommendations alongside the first available data from patients, and provide an overview of management approaches in the COVID-19 era.

Blood brain integrity is compromised in autoimmune disorders of the central nervous system (CNS0. Here Stefan Bittner et al. report that expression of TWIK-related potassium channel-1 (TREK1) is decreased in individuals with multiple sclerosis and mice with autoimmune disease. The severity of EAE is increased in mice deficient in TREK1. Activation of TREK1 using riluzole or a diet enriched in linseed oil attenuates disease severity and reduces leukocyte infiltration into the CNS, suggesting that TREK1 may be targeted to reduce the migration of immune cells into the CNS.

This study demonstrates that the cytosolic helicases RIG-I and MDA5 act to negatively regulate the expansion of the encephalitogenic T_H1 and T_H17 T cells via a mechanism that induces type I interferon production specifically in dendritic cells. Activating this pathway leads to decreased pathology in response to CNS autoimmunity.

In this Perspectives article, Jan Lünemann and colleagues discuss the potential of immune reconstitution therapies to induce remission in individuals with multiple sclerosis. They highlight our limited understanding of the mechanisms underlying this remission and suggest future areas of research.

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.