HLA RESTRICTION AND TCR USAGE OF T-LYMPHOCYTES SPECIFIC FOR A NOVEL CANDIDATE AUTOANTIGEN, X2 MBP, IN MULTIPLE-SCLEROSIS

Previous investigations of the major 18.5-kDa isoform of myelin basic protein (MBP) as a target autoantigen in multiple sclerosis (MS) have failed to identify an epitope uniformly recognized with higher frequen cy in MS patients compared with controls. Because remyelination has be en observed in MS plaques, we were prompted to investigate T cells spe cific for myelin protein isoforms with up-regulated expression during remyelination. We have recently described such T cells that recognize the exon 2-encoded region of MBP (X2 MBP), a sequence included in the 21.5- and 20.2-kDa isoforms of MBP. These cells were shown to be CD4(), HLA class II restricted, and cytolytic. In members of one multiplex MS family, X2 MBP-specific T lymphocytes were as prevalent as T cells specific for immunodominant regions within the major 18.5-kDa isoform of MBP. The present study characterizes X2 MBP-specific T cell respon ses in additional multiplex MS family members as well as in heterogene ous (nonfamilial) MS patients and in healthy controls. The frequencies of X2 MBP-specific T cells in each of the affected family members fro m two of three MS families:were significantly increased as compared wi th bath the heterogeneous MS group and the healthy control group. Also , X2 MBP-specific T cell lines from affected family members were prima rily restricted to molecules encoded by the DR2/DQw1 allele. Although TCR usage was generally heterogeneous, there was evidence of intraindi vidual sequence identity. These data suggest that: 1) Myelin proteins with up-regulated expression during the course of disease should be co nsidered as candidate autoantigens in MS. 2) The functional basis for the association of DR2/DQw1 inheritance with MS susceptibility may be related to presentation of autoantigens by this allele. 3) TCR therapy will need to be individually tailored to target the most prevalent au toantigen-specific response.