title: Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis.
abstract: 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.
authors.affiliation: Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK. angela.vincent@imm.ox.ac.uk
authors.forename: A
authors.initials: A
authors.lastname: Vincent
authors.forename: N
authors.initials: N
authors.lastname: Willcox
authors.forename: M
authors.initials: M
authors.lastname: Hill
authors.forename: J
authors.initials: J
authors.lastname: Curnow
authors.forename: C
authors.initials: C
authors.lastname: MacLennan
authors.forename: D
authors.initials: D
authors.lastname: Beeson
mesh_terms: D000818:Animals; D000939:Epitopes; D006801:Humans; D009157:Myasthenia Gravis / Q000209:etiology / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
chemical_list: D000939:Epitopes; D011950:Receptors, Cholinergic