SKEWED T-CELL RECEPTOR REPERTOIRE IN GENETICALLY IDENTICAL-TWINS CORRELATES WITH MULTIPLE-SCLEROSIS

ALTHOUGH the cause of multiple sclerosis (MS) is unknown, it is though t to involve a T cell-mediated autoimmune mechanism. Susceptibility to the disease is influenced by genetic factors such as genes of the HLA and T-cell receptor (TCR) complex1-6. Other evidence for a genetic in fluence includes the low incidence in certain ethnic groups7, the incr eased risk if there are affected family members8 and the increased con cordance rate for disease in monozygotic twin pairs (26%)9, compared t o dizygotic twins. Epidemiological studies indicate that there may be an additional role for envirommental factors. Although the target anti gen(s) are not yet identified, several myelin or myelin-associated pro teins have been suspected10-12, among them myelin basic protein. A lac k of genetically comparable controls has impaired the analysis of the T-cell response in MS patients and caused disagreement on TCR usage in the disease13-15. Here we analyse the role of TCR genes in MS by comp aring TCR usage in discordant versus concordant monozygotic twins in r esponse to-self and foreign antigens. We find that after stimulation w ith myelin basic protein or tetanus toxoid, control twin sets as well as concordant twin sets select similar Valpha chains. Only the discord ant twin sets select different TCRs after stimulation with antigens. T hus exogenous factors or the disease shape the TCR repertoire in MS pa tients, as seen by comparison with unaffected genetically identical in dividuals. This skewing of the TCR repertoire could contribute to the pathogenesis of MS and other T-cell-mediated diseases.