Immunology of multiple sclerosis

Evidence linking the pathogenesis of MS to an immunologic process remains indirect and tentative. It is increasingly certain that the actual destruction of myelin is caused by activated macrophages. What is uncertain is the mechanism for activation of these macrophages. Although an immunologic mechanism seems most likely, it is still possible that activation could be a direct result of a viral infection. Extrapolation from observations made in various experiment models indicates that the most likely immunologic process is the induction of a DTH response with subsequent macrophage activation. Either a neural or viral antigen could trigger this response, and the genetic influence on susceptibility may reflect the genes coding for the HLA class II and T-cell receptor makeup necessary for recognition of the relevant antigen. Failure to demonstrate unique or enhanced T-cell reactivity is disturbing, but it could be due to the techniques used or to sequestration of this population within the CNS. Sequestration seems the least likely and has little support for experimental models. It is now clear that both astrocytes and endothelial cells can function as antigen-presenting cells. The nonspecific induction of HLA class II antigens on either population, but especially endothelial cells by lymphokines such as gamma interferon, provides an attractive mechanism for presenting antigen to circulating cells and triggering a local immune response that leads to demyelination. Periodic increases in HLA class II expression caused by nonspecific processes such as viral infections could provide a reasonable explanation for the fluctuating course of the disease. With continued disease progression the local production of lymphokines may become sufficient to maintain an ongoing immune response. Demyelination may be enhanced by local production of antibody capable of binding myelin. B cells with appropriate specificities migrating into the inflammatory site would find both antigen and lymphokines necessary for B-cell differentiation. The continued differentiation of B cells with production of antimyelin antibody could contribute to the conversion of the disease from a relapsing-remitting course to one of continued progression. The major unanswered questions concern the antigen and the role of the genetic influence on the response. The ability of T cells to recognize epitopes that consist of only several amino acids and that are not recognized by antibody may contribute to the difficulty in answering this question. Hopefully, techniques that allow manipulation of HLA genes and identification of characteristics of the T-cell receptor makeup, along with more specific immunologic methods, will contribute a greater understanding to these questions.