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Pathogenesis of Multiple Sclerosis

Multiple sclerosis (MS) is a complex genetically predisposed immune disease, wherein self-reactive T cells together with monocytes mediate inflammation of the central nervous system’s (CNS) white matter and demyelination of axons. MS is clinically categorized as either primary progressive MS (PPMS) or relapsing-remitting MS (RRMS) which can evolve into secondary progressive MS (SPMS).

MS is believed to initiate in genetically susceptible hosts, when common microbes that contain protein sequences cross-reactive with self-myelin antigens activate antigen presenting cells (APC) in the blood. These activated APCs activate myelin-reactive Th1 cells in the circulation. Immunoregulatory defects including reduced levels of regulatory T cells (Tr1, Th2, Th3) in MS patients allow myelin-reactive Th1-cells to extravasate, cross the blood brain barrier (BBB) and enter the CNS. Within the CNS, myelin-reactive Th1-cells interact with microglia (localized APCs) presented antigens and secret inflammatory cytokines (IL-2, IFNgamma, TNFalpha) which initiate inflammatory cascades.

Mononuclear phagocytes, T-cells and microglia containing the RANTES (CCL5) (regulated on activation, normal T-cell expressed and secreted) receptor CCR5 and T-cells containing the interferon-gamma-inducible protein of 10 kDa (IP-10) (CXCL10); monokine induced by interferon-gamma (Mig) (CXCL9) receptor CXCR3 are targeted to the inflammation, demyelination sites by the RANTES and IP-10/Mig chemokines, respectively.

References:

Balashov, K.E. et. al. (1999) CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. Proc. Natl. Acad. Sci. 96, 6873-6878.
Grigoriadis, N. et. al. (2006) Neuroinflammation in multiple sclerosis: evidence for autoimmune dysregulation, not simple autoimmune reaction. Clin. Neurol. Neurosurg. 108, 241-244.
Grigoriadis, N. et. al. (2004) Axonal damage in multiple sclerosis: a complex issue in a complex disease. Clin. Neurol. Neurolsurg. 106, 211-217.
Sorensen, T.L. et. al. (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J. Clin. Invest. 103, 807-815.

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