In myasthenia gravis (MG), antibodies to the muscle acetylcholine receptor (AChR) cause muscle weakness. Experimental autoimmune myasthenia gravis (EAMG) can be induced by immunisation against purified AChR; the main immunogenic region (MIR) is a conformation-dependent site that includes alpha 67-76. EAMG can also occur after immunisation against extracellular AChR sequences, but this probably involves intramolecular determinant spreading. In MG patients, thymic hyperplasia and germinal centres are found in about 50%, and thymoma in 10-15%. The heterogeneous, high affinity, IgG anti-AChR antibodies appear to be end-products of germinal centre responses, and react mainly with the MIR or a site on fetal AChR; the latter contains a gamma subunit and is mainly expressed on myoid cells in the thymic medulla. T cells cloned against recombinant AChR subunits recognise principally two naturally processed epitopes: epsilon 201-219 derived from adult AChR which is expressed in muscle, and sometimes in thymic epithelium, and alpha 146-160, common to fetal and adult AChR. Since AChR is not normally co-expressed with class II, it is unclear how CD4+ responses to AChR alpha and epsilon subunits are initiated, and how and where these spread to induce antibodies against fetal AChR. Various possibilities, including upregulation of class II on muscle/myoid cells and involvement of CD8+ responses to AChR and other muscle antigens, are discussed.