Multiple sclerosis: Genomic rewards

A large body of immunologic, epidemiologic, and genetic data indicate that tissue inury in multiple sclerosis (MS) results from an abnormal immune res ponse to one or more myelin antigens that develops in genetically susceptib le individuals after exposure to an as-yet undefined causal agent. The gene tic component of MS etiology is believed to result from the action of sever al genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, post transcriptio nal regulatory mechanisms, and significant nutritional and environmental in fluences. Equally significant, it is also likely that genetic heterogeneity exists, meaning that specific genes influence susceptibility and pathogene sis in some affects but not in others. Results in multiplex MS families con firm the genetic importance of the MHC region in conferring susceptibility of MS. Susceptibility may be mediated by the class II genes themselves (DR, De or both), related to the known function of these molecules in the norma l immune response, e.g. antigen binding and presentation and T cell reperto ire determination. The possibility that other genes in the MHC or the telom eric region of the MHC are responsible for the observed genetic effect cann ot be excluded. The data also indicate that although the MHC region plays a significant role in MS susceptibility, much of the genetic effect in MS re mains to be explained. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen real progress in the development of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and in defining the pathological basis of demyelination, setting the stage for the final characterization of the genes involved in MS susce ptibility and pathogenesis. Their identification and characterization is li kely to define the basic etiology of the disease, improve risk assessment a nd influence therapeutics. (C) 2001 Elsevier Science B.V. All rights reserv ed.