Abstract
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes demyelination, axonal degeneration and astrogliosis, resulting in progressive neurological disability. Fuelled by an evolving understanding of MS immunopathogenesis, the range of available immunotherapies for clinical use has expanded over the past two decades. However, MS remains an incurable disease and even targeted immunotherapies often fail to control insidious disease progression, indicating the need for new and exceptional therapeutic options beyond the established immunological landscape. In this Review, we highlight such non-canonical targets in preclinical MS research with a focus on five highly promising areas: oligodendrocytes; the blood–brain barrier; metabolites and cellular metabolism; the coagulation system; and tolerance induction. Recent findings in these areas may guide the field towards novel targets for future therapeutic approaches in MS.
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Supplementary information
Glossary
- Excitotoxicity
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Neuronal damage or death that is caused by excessive release of neurotransmitters such as glutamate or aspartate.
- Experimental autoimmune encephalomyelitis
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(EAE). An inflammatory, autoimmune demyelinating disease of the central nervous system in rodents that has high pathological and clinical similarities to human multiple sclerosis and is the most used experimental model for the disease.
- Glia limitans
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Also called the glia limiting membrane; defined as a barrier that surrounds the brain and spinal cord and is formed by astrocytic endfeet processes that limit the perivascular space.
- T helper 1 cells
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(TH1 cells). A subgroup of T helper cells (also known as CD4+ cells) that is mainly involved in the cell-mediated immune response against intracellular pathogens such as bacteria by maximizing the efficacy of macrophages and cytotoxic T cells. The main effector cytokines of TH1 cells are IFNγ and IL-2.
- TH2 cells
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A subgroup of T helper cells that is involved in the humoral immune system. TH2 cells secrete IL-4 and IL-10 (among others), are involved in the recognition of extracellular pathogens and activate the B cell-mediated antibody response.
- TH17 cells
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A subgroup of T helper cells that is developmentally distinct from TH1 and TH2 cells and is defined by production of IL-17. TH17 cells are involved in host defence against extracellular pathogens, but also contribute to the pathogenesis of immune-mediated diseases such as MS.
- Regulatory T (Treg) cells
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A subpopulation of CD4+ T cells, also known as suppressor T cells, characterized by the expression of CD4 and CD25. Treg cells have a critical role in preventing autoimmunity by controlling the immune response to self-antigens and can inhibit T cell proliferation and cytokine production.
- Epitope spreading
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The development/expansion of the immune response against the initial dominant epitope to include a secondary epitope over time.
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Bierhansl, L., Hartung, HP., Aktas, O. et al. Thinking outside the box: non-canonical targets in multiple sclerosis. Nat Rev Drug Discov 21, 578–600 (2022). https://doi.org/10.1038/s41573-022-00477-5
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DOI: https://doi.org/10.1038/s41573-022-00477-5
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