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Immunology of MS

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At present, much of the CNS damage in MS is believed to result from an immune-mediated process. This process includes components of the innate immune system (including macrophages, natural killer cells and others) as well as adaptive immune system activation of certain lymphocyte populations in peripheral lymphoid organs (Koch et al, 2013). CD4+ lymphocytes and CD8+ lymphocytes are activated in the peripheral lymph tissues. Antigen presentation to naïve CD4+ lymphocytes causes differentiation into various T lymphocyte cell populations, depending on the antigen presented, the cytokine environment and the presence of co-stimulatory molecules. The T lymphocyte cell populations include Th1 and Th17 lymphocytes (which are associated with a repertoire of inflammatory cytokines that activate macrophages and opsonizing antibodies) and Th2 lymphocytes and T regulatory cells (which drive humoral immunity or secrete anti-inflammatory cytokines) (Lubetzki & Stankoff, 2014; Koch et al, 2013; Durelli et al, 2009).

In people with MS, there is a bias towards a Th1 and Th17 environment with T regulatory dysfunction that allows inflammation to predominate (Viglietta et al, 2004). Secreted cytokines and matrix metalloproteinases disrupt the blood brain barrier (Obermeier et al, 2013). This disruption, along with up-regulation of adhesion molecules on blood vessel endothelium and activation of T cells, allows T cells to gain entry into the CNS, where additional activation takes place that initiates a damaging inflammatory cascade of events within the CNS. Multiple inflammatory cells become involved, including microglial cells and macrophages. In addition to CD4+ activation, CD8+ T lymphocytes have also been identified as important contributors to damaging CNS inflammation, and in fact have been identified by numerous researchers as the predominant T cell present in active MS lesions (Babbe et al, 2000).

Further contributions to CNS damage in MS are associated with B cell activation. B cells function as antigen presenting cells and also produce antibodies that have damaging effects on myelin, oligodendrocytes and other neuronal structures (Disanto et al, 2013). Recent studies have also revealed that mitochondrial damage, possibly as a result of free radical, reactive oxygen species and nitrous oxide (NO) activity associated with activated microglia, and iron deposition occur in MS and make a significant contribution to demyelination and oligodendrocyte damage (Witte et al, 2014; Haider et al, 2011; Trapp & Stys, 2009).

Immune-mediated responses leading to inflammation, with secretion of inflammatory cytokines, activation of microglia, T and B cell activity, mitochondrial damage and inadequate regulatory function, are believed to be at least partially responsible for demyelination, oligodendrocyte loss and axonal damage. Axonal loss, which correlates best with disability, begins early in the disease process as evidenced by identified pathological changes as well as imaging studies (Ellwardt & Zipp, 2014; Trapp et al, 1998).

Figure 1: Inflammatory cascade in multiple sclerosis

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