Autoimmune responses against acetylcholine receptor: T and B cell collaboration and manipulation by synthetic peptides.
Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are induced by antibodies (Abs) against self acetylcholine receptor (AChR). We have mapped the T and B cell epitopes on AChR alpha subunit in human MG and in EAMG-susceptible (C57BL/6, B6) and nonsusceptible mouse strains. A T-cell epitope within residues alpha 146-162 (P14) of Torpedo californica (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 that secreted anti-AChR Abs directed against four other regions on the tAChR alpha-chain, but not against P14 itself. P14Th cells are pathogenic because they help B cells that make Abs against a conserved tAChR region (t alpha 122-150) involved in ACh binding. These Abs cross-react with region alpha 122-150 of mouse (m)AChR, thereby disrupting its normal physiological function. Thus, a T cell epitope not recognized by Abs plays an active role in B cell responses against other epitopes on the protein. We have found that in B6, the MHC region 62-76 of I-A beta(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 proliferation of P14-specific T-cells. Furthermore, this MHC peptide elicited Abs 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.
Atassi
M Z
MZ
Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.
Oshima
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D011950:Receptors, Cholinergic