Immunological Aspects of Demyelinating Diseases

Abstract

Primary demyelination in the central nervous system results from damage to the myelin sheath or oligodendroglia and can be produced by a variety of mechanisms, including metabolic disturbances, toxicities, infection, and autoimmunity. The major human demyelinating disease affecting the central nervous system is multiple sclerosis (MS). Although the etiology of MS is not known, existing data indicate that both genetic and environmental factors contribute to pathogenesis. Experimental allergic encephalomyelitis (EAE) is induced by immunization of genetically susceptible animals with myelin proteins. This is mediated by autoimmune T cells. Characterization of MHC restriction, fine specificity of antigen recognition, and T cell receptor (TCR) usage by encephalitogenic T cells has resulted in highly specific immunotherapies. Both HLA and TCR genes have been linked to susceptibility for MS which is widely believed to be mediated by T cells that recognize an as yet unidentified autoantigen. Because of the advances in the understanding and treatment of EAE, recent research in MS has been focused on the characterization of cellular immune responses against myelin components. The results of these studies are reviewed and the potential implications of these findings for the pathogenesis and future therapy of MS are examined.

Myelin Basic Protein-primed T Cells Induce Nitric Oxide Synthase in Microglial Cells

“…However, the mechanism by which microglia are activated to induce the expression of iNOS for the production of NO in MS brain remains unclear. Although lipopolysaccharide is a potent inducer of iNOS in microglia, it has not been demonstrated to have a physiological relevance in MS (39). IFN-␥, alone or in combinations with other proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) and IL-1␤, can also induce iNOS in microglia (7,24,25,28); however, microglia isolated from adult human brain tend to be a poor source of iNOS-derived NO in response to these proinflammatory cytokines (40,41).…”

Transformation of human T-cell clones by Herpesvirus saimiri: intact antigen recognition by autonomously growing myelin basic protein-specific T cells.

“…Further, MBP is a prominent candidate autoantigen for multiple sclerosis, the most important human demyelinating disease of presumed autoimmune pathogenesis (35). Consequently, the human T-cell response against MBP and its physiological and pathological regulation are a major focus of current multiple sclerosis research (5,6,10). We anticipate that HVStransformed human T-cell clones specific for MBP or other human autoantigen will become a very useful tool for many applications.…”

Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis

“…It is characterized clinically by a relapsing͞remitting or chronic progressive course, frequently leading to severe disability. Current knowledge suggests that MS is associated with autoimmunity (1), that genetic background has an important influence (2), and that ''infectious'' agent(s) may be involved (3). Indeed, many viruses have been proposed as possible candidates, but, as yet, none of them has been shown to play an etiological role.…”