Multiple sclerosis is a chronic demyelinating disease of the human central nervous system. Genetic, viral and autoimmune factors are believed to play a role in the pathogenesis of this disorder. We now propose to investigate the immunoregulatory cells and mechanisms involved in multiple sclerosis by analyzing the proliferative and molecular characteristics of T cell clones specifically reactive against myelin components, in particular, the basic protein of myelin (MBP). Our hypothesis is that idiotypes expressed by autoantigen activated T lymphocytes regulate immune responses through interactions involving anti-idiotypic T cells and anti-idiotypic antibodies. A defect in this complex regulatory network may lead to autoimmune diseases such as multiple sclerosis. First, the response of the T cell clones to the autoantigen will be analyzed with respect to the MBP epitope sepcificity and MHC restriction. Next, we will study the autologous mixed lymphocyte response in nultiple sclerosis patients both at a polyclonal and monoclonal level. The idiotypic nature of anti-MBP T cell lines and clones will be investigated by determining their ability to induce the proliferation of resting autologous T cells (anti-idiotypic T cells). We will then determine the functional nature of the (anti- idiotypic T cells) generated in the reaction. Likewise, we will determine whether sera from patients with multiple sclerosis contain autoantibodies (anti-idiotypic antibodies) which bind anti- MBP clones. The immune abnormalities associated with multiple sclerosis that may be the result of defects in the function of anti- idiotypic autoimmunity will be revealed by these studies. Finally, molecular characterization of selected anti-MBP clones will be carried out by the analysis of the T cell receptor alpha and beta chain gene messages. It is conceivable that a restricted usage of variable region genes of this receptor exists in the T cell response to autoantigens. Identification of the varable region genes used would then provide useful markers for diagnostice and therapeutic purposes. Taken together, the functional, idiotypic and genetic characterization of autoreactive T cell clones should further our understandig of the immune cells and mechanisms involved in multiple sclerosis, and may provide novel means of specific immunological treatment.
