AUTOIMMUNE RESPONSES AGAINST ACETYLCHOLINE-RECEPTOR - T-CELL AND B-CELL COLLABORATION AND MANIPULATION BY SYNTHETIC PEPTIDES

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are induc ed by antibodies (Abs) against self acetylcholine receptor (AChR). We have mapped the T and B cell epitopes on AChR alpha subunit in human M G and in EAMG-susceptible (C57BL/6, B6) and nonsusceptible mouse strai ns. A T-cell epitope within residues alpha 146-162 (P14) of Torpedo ca lifornica (t)AChR plays an important role in EAMG pathogenesis of the auto Ab-induced disease. P14-specific T cell (P14Th) lines from tAChR- primed B6 mice activated, in vivo and in vitro, tAChR-primed B cells t hat secreted anti-AChR Abs directed against four other regions on the tAChR alpha-chain, but not against P14 itself. P14Th cells are pathoge nic because they help B cells that make Abs against a conserved tAChR region (t alpha 122-150) involved in ACh binding. These Abs cross-reac t with region alpha 122-150 of mouse (m)AChR, thereby disrupting its n ormal physiological function. Thus, a T cell epitope not recognized by Abs plays an active role in B cell responses against other epitopes o n the protein. We have found that in B6, the MHC region 62-76 of I-A b eta(b) is involved in the presentation of P14 to T cells. Anti-peptide Abs, prepared in BALB/c, were found to inhibit in vitro the prolifera tion of P14-specific T cells. Furthermore, this MHC peptide elicited A bs in B6 mice and we are investigating whether immunization of B6 with this peptide, before priming with tAChR, would suppress in vivo the T -cell response to the epitope in P14. Thus, these preliminary results would suggest that immunization with the MHC peptide might be employed for control of the autoimmune disease.