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Immunopathophysiologic basis of multiple sclerosis and implications for therapy-a narrative review


Abstract

Our current understanding of multiple sclerosis (MS) recognizes several immunopathological mechanisms leading to progressive axonal loss, brain atrophy, and neurological and cognitive disability. Autoreactive T cells eluding central tolerance in the thymus enter lymph nodes. There, antigen presenting cells expressing an antigen closely resembling a self-protein or autoantigen, activate CD4+ cells, which then differentiate into proinflammatory T helper cells (Th1 and Th17). These cells release TNF-alpha, causing myelin disruption and oligodendrocyte apoptosis, and INFγ which recruits CD8+ cells, B cells, and monocytes. These cells leave the lymph nodes and enter the CNS. CD8+ cells attack oligodendrocytes synthesizing myelin and exacerbate neuronal damage. Monocytes (macrophages) phagocytose the myelin sheath and release proinflammatory cytokines that enhance the local inflammatory response. MS progression is characterized by diffuse T and B cell infiltrates, astrogliosis and microgliosis. New evidence suggests that memory B cells may represent a principal component of MS etiology and T and B cell autoimmunity may be a secondary driver, of MS. Understanding the immunopathological underpinnings of MS has revolutionized the treatment of this neurological autoimmune disease with an array of disease-modifying drugs (DMDs) with mechanisms of action directed at various key points. Ideally, DMDs should be initiated early in the disease course with the goal to reduce disease activity, preserve brain tissue, and limit deterioration in cognitive and physical function. Currently approved DMDs can be broadly categorized into platform therapies (INFs and glatiramer acetate), S1P receptor modulators, fumarates, monoclonal antibodies, and other therapies. DMDs can also be categorized by overall treatment approach: chronic maintenance/escalation therapy and immune reconstruction therapy (IRT). It remains unclear, however, whether IRT agents reset the adaptive immune system or simply result in cell types with different repopulation dynamics. Other therapeutic approaches in clinical development include Bruton’s tyrosine kinase inhibitors, remyelination, neuroprotection, and modulation of microbiome triggers.

Keywords

immunology, multiple sclerosis, pathophysiology, disease modifying drugs, immunology, lesions, disability, magnetic resonance imaging

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