HETEROGENEITY OF T-CELL RECEPTOR ALPHA-CHAIN COMPLEMENTARITY-DETERMINING REGION-3 IN MYELIN BASIC PROTEIN-SPECIFIC T-CELLS INCREASES WITH SEVERITY OF MULTIPLE-SCLEROSIS

The pathogenesis of multiple sclerosis (MS) is thought to involve a T- cell-mediated autoimmune process. Experimental allergic encephalomyeli tis (EAE), an animal model resembling MS, can be induced by immunizati on with myelin antigens such as myelin basic protein. The T cell antig en receptor (TCR) usage in EAE is highly restricted in some strains of animals and experimental treatments targeting the TCR have been succe ssful in EAE. Examination of the TCR beta chain variable-region (V-bet a) usage of MBP-specific T-cell lines in MS patients has produced conf licting results. Our previous studies of TCR alpha-chain variable-regi on usage in monozygotic twins demonstrated a general skewing of the TC R repertoire in individuals with MS. This skewing became apparent only after stimulation with antigens; in peripheral blood lymphocyte prepa rations from individuals with MS V(alpha)8-bearing T cells were prefer entially selected by stimulation with myelin basic protein. In the pre sent study we examined complementarity-determining region 3 of those V (alpha)8-positive TCRs. Marked sequence heterogeneity was found in all individuals with severe MS. In contrast, restricted areas of compleme ntarity-determining region 3 were found in healthy control individuals and in individuals with a mild form of MS. Sequences from tetanus tox oid-specific V(alpha)8-positive T cells generated from the same indivi duals were relatively homogeneous within individuals regardless of dis ease activity and were distinct from the sequences of complementarity determining region 3 in myelin basic protein-stimulated lines. These f indings suggest that disease severity may be associated with increased heterogeneity of myelin antigen-specific T cells and could reflect an impaired ability of the immune system to down-regulate these anti-sel f responses.