Autoantibodies directed against the acetylcholine receptor (AChR) lead to AChR loss and muscular weakness in myasthenia gravis and its experimental model, experimental autoimmune myasthenia gravis (EAMG). The role of different anti-AChR sequences and specificities in the pathogenesis of EAMG was investigated by sequencing a panel of 19 mouse mAbs, previously elicited against Torpedo and human AChR, that bound to at least four different epitope regions. The pathogenicity of eight mAbs that cross-reacted with mouse or rat AChR was tested. EAMG was induced by four mAbs against the main immunogenic region (MIR). Sequence analysis of different anti-AChR specificities showed a large diversity of H and L chain sequences. Highly homologous H chain sequences (> 90%) were found among some mAbs with similar specificities, whereas highly homologous L chain sequences were not restricted to Abs of a particular fine specificity. Sharing of a highly homologous VH gene or an identical DJH region was observed among three of four pathogenic anti-MIR mAbs, obtained by immunization with AChRs from different species. The VH genes of these three pathogenic mAbs were closely related to PC7183 germline genes indicating that some pathogenic Abs may already be present in the germline repertoire.