A gene conversion event between Ebb and Abb in the B6.C-H-2bm12 (bm12) strain, which alters three amino acids in the C-terminal half of the first domain of Abb (Ile-67-->Phe; Arg-70-->Gln; Thr-71-->Lys) resulted in resistance to experimental autoimmune myasthenia gravis (EAMG) pathogenesis. To study the effect of bm12 mutation on the T-cell responses to epitopes of acetylcholine receptor (AChR)-alpha subunit, C57BL6 (B6) and bm12 mice were primed with Torpedo californica AChR, and the profiles of T-lymphocyte proliferation were determined with 18 synthetic overlapping peptides encompassing the entire extracellular portion of the AChR-alpha subunit. The proliferative responses of AChR-primed bm12 lymphocytes were markedly reduced to two (alpha 146-162 and alpha 182-198) of the three AChR peptides (alpha 111-126, alpha 146-162, and alpha 182-198) that are immunodominant in B6 mice. Thus, the Ab residues encompassing the region 67-71 determine the immunogenicity of two of the AChR-alpha subunit T-cell epitopes. To test the involvement of AChR-alpha chain epitopes within peptide alpha 146-162 in EAMG pathogenesis, B6 mice were neonatally tolerized with soluble peptide alpha 146-162, and subsequently immunized with AChR in complete Freund's adjuvant. Neonatal tolerance to AChR or to peptide alpha 146-162 reduced the incidence of clinical myasthenia gravis and suppressed serum anti-AChR antibodies. This indicates the involvement of T-cell epitopes within AChR-alpha subunit region alpha 146-162 in EAMG pathogenesis. Neonatal tolerance to peptide alpha 146-162 could have caused specific clonal deletion, and/or clonal anergy, and/or recruited suppressor cells to prevent clinical EAMG. Presumably, epitope(s) with AChR alpha 146-162, in the context of Ab encompassing region 67-71, stimulate specific T helper cells which interact with specific B cells to produce pathogenic antibodies, the primary culprit causing the end plate lesion in patients with myasthenia gravis.