OVEREXPRESSION OF SELECT T-CELL RECEPTOR V-BETA GENE FAMILIES WITHIN CD4(-CELL SUBSETS OF MYASTHENIA-GRAVIS PATIENTS - A ROLE FOR SUPERANTIGEN(S)() AND CD8(+) T)

Background: The principal symptoms of myasthenia gravis (MG), muscle w eakness and fatigue due to impaired neuromuscular transmission, are ca used by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). The mechanisms underlying the autoimmune response, however, ap pear to be initiated by activation of specific HLA class II-restricted CD4(+) T lymphocytes. Thus, central to elucidating the causation of M G is determining how T cells are recruited to contribute to misguided immunological assaults on the major autoantigenic target, AChR. Materi als and Methods: By combining a polymerase chain reaction (PCR)-based strategy and Southern blot technique, we have analyzed the frequency o f expression of 22 individual T cell receptor (TCR) V beta gene subfam ilies in CD4(+) and CD8(+) peripheral blood T cell subsets derived fro m eight MG patients and seven healthy controls. The quantification of relative usage of individual TCR J beta gene segments was performed by hybridization of PCR-amplified products (specifically V beta 1-C beta ) with a complete panel of P-32-5'-end-labeled J beta-specific oligonu cleotide probes, followed by scanning analysis of autoradiographs. Res ults: Comparisons of data obtained from VP analyses of T cells from MG patients with those from healthy individuals established that MG pati ents significantly overexpressed V beta 1, V beta 13.2, V beta 17, and V beta 20 gene family members within both CD4(+) and CD8(+) T cell su bpopulations. Moreover, analysis of the relative utilization of indivi dual TCR J beta gene segments in V beta 1(+)/CD4(+) and V beta 1(+)/CD 8(+) T lymphocytes revealed distribution patterns in patients indistin guishable from those recorded in the corresponding cell subsets derive d from controls. Conclusions: T lymphocytes from MG patients displayed a biased overexpression of four TCR V beta gene segments: V beta 1, V beta 13.2, V beta 17, and V beta 20. The relative frequencies of asso ciation of individual V beta 1(D beta)J beta combinations revealed tha t J beta gene usage in the V beta 1-over-represented T cell subsets ha d normal distribution patterns. It can thus be deduced that J beta gen e segment products appear not to have a selective effect on the proces s leading to overexpression of V beta 1 exons in MG patients. Hence, o ur observations suggest a possible role for superantigen(s) in the T c ell activation in MG patients.