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English: f2-dddt-4-343: Possible mechanisms of injury and repair in MS. Genetic and environmental factors (including viral infection, bacterial lipopolysaccharides, superantigens, reactive metabolites, and metabolic stress) may facilitate the movement of autoreactive T cells and demyelinating antibodies from the systemic circulation into the CNS through disruption of the BBB. In the CNS, local factors (including viral infection and metabolic stress) may upregulate the expression of endothelial adhesion molecules, such as ICAM-1, VCAM-1, and E-selectin, further facilitating the entry of T cells into the CNS. Proteases, including matrix metalloproteinases, may further enhance the migration of autoreactive immune cells by degrading extracellular-matrix macromolecules. Proinflammatory cytokines released by activated T cells, such as IFN-γ and TNF-β, may upregulate the expression of cell-surface molecules on neighboring lymphocytes and antigen-presenting cells. Binding of putative MS antigens, such as myelin basic protein, myelin-associated glycoprotein, MOG, proteolipid protein, αβ-crystallin, phosphodiesterases, and S-100 protein, by the trimolecular complex – the TCR and class II MHC molecules on antigen-presenting cells – may trigger either an enhanced immune response against the bound antigen or anergy, depending on the type of signaling that results from interactions with surface costimulatory molecules (eg, CD28 and CTLA-4) and their ligands (eg, B7-1 and B7-2). Downregulation of the immune response (anergy) may result in the release of anti-inflammatory cytokines (IL-1, IL-4, and IL-10) from CD4+ T cells, leading to the proliferation of anti-inflammatory CD4+ Th2 cells. Th2 cells may send anti-inflammatory signals to the activated antigen-presenting cells and stimulate pathologic or repair-enhancing antibody-producing B cells. Alternatively, if antigen processing results in an enhanced immune response, proinflammatory cytokines (eg, IL-12 and IFN-γ) may trigger a cascade of events, resulting in the proliferation of proinflammatory CD4+ Th1 cells and ultimately in immune-mediated injury to myelin and oligodendrocytes. Multiple mechanisms of immune-mediated injury of myelin have been postulated: cytokine-mediated injury of oligodendrocytes and myelin; digestion of surface myelin antigens by macrophages, including binding of antibodies against myelin and oligodendrocytes (ie, antibody-dependent cytotoxicity); complement-mediated injury; and direct injury of oligodendrocytes by CD4+ and CD8+ T cells. This injury to the myelin membrane results in denuded axons that are no longer able to transmit action potentials efficiently within the CNS (loss of saltatory conduction). This slowing or blocking of the action potential results in the production of neurologic symptoms. The exposed axon segments may be susceptible to further injury from soluble mediators of injury (including cytokines, chemokines, complement, and proteases), resulting in irreversible axonal injury (such as axonal transection and terminal axon ovoids). There are several possible mechanisms of repair of the myelin membrane, including resolution of the inflammatory response followed by spontaneous remyelination, spread of sodium channels from the nodes of Ranvier to cover denuded axon segments and restore conduction, antibody-mediated remyelination, and remyelination resulting from the proliferation, migration, and differentiation of resident oligodendrocyte precursor cells.Copyright © 2000, Massachusetts Medical Society. All rights reserved. Adapted with permission from Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938–952.2Abbreviations: ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular-cell adhesion molecule 1; CNS, central nervous system; TNF-β, tumor necrosis factor-β; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; TCR, T-cell receptor; MHC, major-histocompatibility-complex; Th1, type 1 helper T; Th2, type 2 helper T; BBB, blood-brain barrier.