Genetics of multiple sclerosis--how could disease-associated HLA-types contribute to pathogenesis?

Multiple sclerosis is a chronic demyelinating disease of the central nervous system in young adults. It is considered a T cell-mediated autoimmune disease which is probably triggered by exogenous events, e.g. infectious agents, in susceptible individuals. Population, family and twin studies indicate that genetic factors and most likely several genes are associated with disease, but it is clear from the concordance rates of identical twins (25-30%) that genetic background as well as exogenous or somatic events are required to develop disease. Among many candidate genes which have been analyzed during recent years, the strongest association was shown for genes of the HLA-class II complex, in particular HLA-DR15 Dw2 and -DQw6. At present, it is not clear how the expression of a particular HLA-class II gene translates into susceptibility to develop an organ-specific autoimmune disease. Potential explanations how this could occur will be discussed.