TCR GENE USAGE IN EXPERIMENTAL AUTOIMMUNE MYASTHENIA-GRAVIS PATHOGENESIS - USAGE OF MULTIPLE TCRBV GENES IN THE H-2(B) STRAINS

Experimental autoimmune myasthenia gravis (EAMG) is an Ab-mediated aut oimmune disease. The pathogenic auto-antibody production depends on th e activation of CD4(+) cells after their TCR interact with dominant T cell epitopes within acetylcholine receptor (AChR) in the context of t he MHC class II molecule. In vitro analysis suggested that the TCRBV6 was the predominant TCR that recognized AChR and one of the dominant e pitopes, alpha 146-162, in C57BL6 (B6, H-2(b)) mice. However, in vivo depletion of TCRBV6 cells in H-2(b) mice by anti-TCRBV6 mAb neither su ppressed the in vitro immune response to AChR nor prevented developmen t of EAMG. Moreover, B10.TCR(c) (H-2(b)) strain with a genomic deletio n of TCRBV genes including TCRBV6, and B10.V beta 8.2 transgenic mice with a restricted TCRBV8S2 T cell repertoire, responded to AChR, alpha 146-162, and developed EAMG after immunizations with AChR/CFA. These data suggest that more than one TCRBV-bearing cell having the affinity for AChR-dominant peptides is involved in pathogenesis. Therefore, de pletion of a single TCRBV (e.g., TCRBV6) with mAb may not be sufficien t to completely suppress the response to AChR and development of EAMG. However, if a similar amino acid sequence in the TCR-VDJ (e.g., CDR3) region among different TCRBV gene(s) could be involved in recognizing the dominant AChR epitope(s), then motif-specific mAb reactive to the common motif within the VDJ region of different TCR could be used to eliminate the T cell clones involved in EAMG.