Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system white matter. The similarity of experimental autoimmune encephalomyelitis (EAE) and post viral encephalomyelitis with MS has implicated myelin basic protein (MBP) as a target autoantigen in the disease. The role of MBP has been further supported by the recent demonstration of in vivo activated MBP reactive T-cells in the blood of patients with MS. Other evidence of immune system involvement in the disease pathogenesis has been the association of MS with the MHC class II phenotype HLA-DR2/DQw1. As the ability of immunogenic peptides to bind to polymorphic regions of MHC is one requirement for T-cell receptor (TCR) recognition of antigen, it can be postulated that disease related MHC phenotype selectively present regions of autoantigens that are recognized by T-cells not clonally deleted in the thymus. Thus a major question in the investigation of MS is whether there are DR2 linked immunodominant regions of MBP as has been observed in rodents with EAE. A second major question is whether T-cell recognition of an immunodominant region of MBP is linked to a particular TCR sequence. The applicant's laboratory has demonstrated there is a higher frequency of T-cells reactive with a DR2 linked immunodominant region of MBP between residues 84 and 102 in patients with MS as compared to controls. The investigators have also examined TCR Vbeta gene usage among sixty-four T-cell lines from both MS patients and control subjects which were reactive with this region of human MBP. Vbeta 17 and Vbeta 12 were found to be the major recognition elements for this peptide among different individuals, with 34/64 lines using the Vbeta 17 and 9/64 lines using the Vbeta 12 TCR genes. These data are the first to demonstrate a restricted Vbeta gene usage for an immunodominant region of a human autoantigen. The present grant application has been substantially revised as suggested by the reviewers to reflect these recent observations. There is a series of new questions to be answered to complete these investigations: 1). Which TCR Valpha are used to recognize immunodominant MBP peptides in MS? 2). Are there common sequences among Vbeta chains or among Valpha chains used to recognize peptides of MBP among lines from the same patients or among different patients. 3. What are the MHC restriction elements for recognition of MBP peptides in relationship to TCR usage and are there common DR or DQ sequences used to bind MBP peptides? 4). Are there TCR polymorphisms associated with TCR peptide reactivity? 5). Is there sequestration of T-cells reactive to MBP in the CSF? These questions address the basic hypothesis that an immunodominant region of MBP, between residues 84 and 102, may be an encephalitogenic region in DR2+ individuals and can be one of the target antigens in MS.
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