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