Search

Neuromyelitis optica is an autoimmune disorder of the central nervous system characterized by episodes of optic neuritis and transverse myelitis. This Primer provides an overview of the epidemiology, pathophysiology, diagnosis and treatment of this disorder.

Oligodendrocyte death in the DTA mouse model leads to a fatal, secondary demyelinating disease associated with CNS T cell infiltration and myelin antigen-specific T cells in lymphoid organs, which can transfer a mild neurological disease to naive mice, indicating that oligodendrocyte death is sufficient to trigger an adaptive autoimmune response against myelin. These results suggest that the disease-initiating event in the autoimmune disorder multiple sclerosis may occur within the CNS.

In this study, Yu et al. found that a positive feedback loop between oxidized phosphatidylcholine and IL-1β promotes chronic neurodegeneration in the central nervous system and could be a contributing mechanism to progressive multiple sclerosis.

The mechanism by which NAD⁺ alters the systemic immune response is unclear. Here the authors show that NAD⁺ induces systemic homeostasis and protects against experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis, by regulating CD4⁺T cell differentiation and promoting myelin and axonal regeneration.

MHC II tetramers are used to study T cell expansion but they preferentially bind high affinity T cell receptors. Here the authors show that T cells with low affinity receptors expand in number along with the T-cell repertoire and might therefore contribute more to the primary immune response than was thought.

T cells that mediate neuroinflammation in EAE, a mouse model of multiple sclerosis, act through their production of cytokines. Here, the authors show that the transcription factor Bhlhe40 regulates the expression of GM-CSF and IL-10 by autoreactive T cells and is crucial for EAE induction.

Current multiple sclerosis treatments focus on prevention of immune attack on oligodendrocytes and myelin. Here the authors show a different strategy to ameliorate disease in several mouse models, protecting oligodendrocytes from inflammation-induced death with an FDA-approved drug, guanabenz.

Bali Pulendran and his colleagues explore ways that signaling through different pathogen receptors can program dendritic cells (DCs) to orchestrate inflammatory or tolerogenic immune responses. The yeast component zymosan triggers signaling through both Toll-like receptor 2 (TLR2) and the C-type lectin dectin-1. In the absence of TLR2, zymosan induces proinflammatory responses through dectin-1. But TLR2 triggering induces DCs to form the vitamin A–metabolizing enzyme Raldh2. The DCs can then form retinoic acid that acts in an autocrine manner on the DCs, programming them for the induction of regulatory T cell responses.

Paul and colleagues report the development and characterization of an antibody–drug conjugate targeting TRBC2 for the treatment of T cell malignancies.

Ghorbani and colleagues describe versican-V1 as an inhibitor of remyelination using transgenic mice that illuminate new GFP ⁺ oligodendrocytes. Mechanisms of versican-V1 include the direct inhibition of oligodendrocytes, and elevating Th17 cells.

Heterogeneous helper T (Th) cell responses contribute to differential susceptibility to immunological disorders. Here the authors perform haplotype-based computational screens of 16 inbred mouse strains to identify a transcription factor, p73, as an important negative regulator of Th1 differentiation, with p73 deficient mice manifesting alterations in two inflammatory disease models.

The mechanisms of pathological astrocyte responses during multiple sclerosis remain unclear. Kadowaki et al. found in MS mouse models that CLEC16A suppresses astrocyte pathogenic activities related to mitochondria by boosting mitophagy.

The affected cellular populations during Alzheimer’s disease progression remain understudied. Here the authors use a cohort of 84 donors, quantitative neuropathology and multimodal datasets from the BRAIN Initiative. Their pseudoprogression analysis revealed two disease phases.

Single-cell RNA sequencing was used to construct a map of gene expression in lesions from brains of patients with multiple sclerosis, revealing distinct lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation.

Oxidized phosphatidylcholines found in MS lesions are not just markers of oxidative stress but are also promoters of demyelination and axon injury. Microglia suppress oxidized-phosphatidylcholine-mediated neurodegeneration by phagocytosis through TREM2.

IL-2 has been used to expand regulatory T (Treg) cells for treating inflammatory disorders. Here the authors test an engineered IL-2 mutein, delivered subcutaneously as mRNA, to show its increased specificity for activating and expanding Treg cells in both rodents and non-human primates, and to demonstrate its ability to suppress autoimmunity in mouse models.

Multiple sclerosis is associated with a deficiency in generation of mature oligodendroctyes; an image-based screen for oligodendrocyte differentiation inducers identified the compound benztropine, which enhances remyelination acting through muscarinic receptors and decreases clinical severity in a multiple sclerosis model system.

A high-resolution gene expression atlas of prenatal and postnatal brain development of rhesus monkey charts global transcriptional dynamics in relation to brain maturation, while comparative analysis reveals human-specific gene trajectories; candidate risk genes associated with human neurodevelopmental disorders tend to be co-expressed in disease-specific patterns in the developing monkey neocortex.

FLVCR2 is expressed in the blood–brain barrier of mouse and human, and is the major mediator of choline uptake into the brain.

Steuernagel and Lam et al. present HypoMap, an integrated reference atlas of the murine hypothalamus based on 384,925 hypothalamic cells from publicly available single-cell sequencing datasets.

CD4⁺ T cell tolerance can be enforced by various mechanisms. Jenkins and colleagues use mice with entirely intact polyclonal T cell repertoires to comprehensively define the mechanisms of self-tolerance.

Quantification of the interaction of T-cell receptors with their peptide–MHC ligands in two–dimensional membranes is shown to yield larger dissociation rate constants than previous assays where one of the interacting partners was in solution.

Using single-cell and spatial transcriptomics, the authors identified several aging-associated and oxidized phosphatidylcholine-associated changes in microglia in the spinal cord, including an increase in osteopontin that contributed to neurodegeneration and neuroinflammation.

Clinical trials have led to the approval of new targeted therapies for neuromyelitis optica spectrum disorders. In this Review, Pittock et al. discuss the pathophysiological rationale for these drugs, the methodology and outcomes of the trials, and their implications for clinical practice.

Transcriptomic profiling using a newly-developed cre-inducible method to biotinylate wild-type and mutant MeCP2 protein highlights the cellular heterogeneity of transcriptional changes in rodent models of Rett Syndrome, including cell-type- and subcellular compartment-specific differences in male brains and X-linked mosaicism in female brains.

Biological sex affects all aspects of animal physiology. Using the model C. elegans, the authors show that metabolomes are highly sex-specific and include a vast space of yet unidentified metabolites that may control development and lifespan.

Anti-TRBC1 antibody–drug conjugates may offer a more potent T cell cancer therapy by bypassing the fratricide that may be limiting the efficacy of anti-TRBC1 CAR T cells in the clinical trial for patients with T cell cancers.

Nemazee and colleagues show that PLD3 and PLD4 are endolysosomal exonucleases that digest ingested nucleic acids and thereby prevent activation of endosomal TLRs. Mice that lack PLD3 and PLD4 develop autoinflammatory disease.

Bhardwaj et al. report that adding Flt3 ligand to the treatment strategy effectively increased DC populations and increased T-cell responses in a randomized phase II trial of a DC-targeted vaccine for the melanoma antigen NY-ESO-1.

Endocytic organelles are a dynamic continuum of vacuolar structures that impact various cell physiological processes. Here, the authors report a library of ultra-pH sensitive fluorescent nanoparticles for the controlled perturbation and quantification of catabolic organelle maturation at organelle resolution.

A selective, small-molecule inhibitor of NLRP3 suppresses activation of the inflammasome in vitro and in vivo and attenuates inflammatory disease.

DISCOVER-Seq+ is a high-sensitivity method for the detection of off-target effects of CRISPR genome editing.

The detection of antigen-specific CD4⁺ T cells is improved with engineered peptide:MHCII tetramers.

Chimeric antigen receptor T cells in the clinic currently target cell-type-specific extracellular antigens on malignant cells. Here, authors engineer tumor-specific chimeric antigen receptor T cells that target human leukocyte antigen-presented neoantigens derived from mutant intracellular proteins.

Single-cell RNA sequencing and T cell receptor sequencing are combined to identify transcriptional programs specific to mutation-associated neoantigen-specific T cells in non-small cell lung cancers treated with anti-PD-1, providing insights into resistance to PD-1 blockade.

Mutation associated neoantigens are a family of highly specific therapeutic targets for the treatment of cancer. Here, the authors describe the cryo-EM structure of an antibody bound to a neoantigen complex providing insights into the specificity of the antibody.

Mutations present at a low frequency in a sample are detected with high sensitivity and a low error rate.

Thymic regulatory T cells require IL-2 for their development. Robey and colleagues show that developing cells compete with pre-existing regulatory T cells for limiting amounts of IL-2 produced by antigen-bearing dendritic cells

The nitrogen-fixing anaerobic methanogen, Methanococcus maripaludis, can utilize tetrathiomolybdate and molybdenite, previously considered non-bioavailable, as sources of molybdenum for enzymes involved in nitrogen fixation and anaerobic metabolism.

Zhou and colleagues discuss the opportunities and challenges in targeting public neoantigens for cancer immunotherapy.