Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis

Authors


  • Acknowledgements
    We are grateful to the Medical Research Council of Great Britain for support (Ay NW JC, MH), the Wellcome Trust (CM) and the Myasthenia Gravis Association/Muscular Dystrophy Group of Great Britain (DB).

Angela Vincent, Neurosciences Group, Department of Clinical Neurology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK, Fax: 44 1865 222402, e-mail: angela.vincent@imm.ox.ac.uk

Abstract

Summary: In myasthenia gravis (MG), antibodies to the muscle acetylcholine receptor (AChR) cause muscle weakness. Experimental autoimmune myaschenia gravis (EAMG) can be induced by immunisation against purified AChR; the main immunogenic region (MIR) is a conformation-dependent site that includes α67-76, 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 y 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: ɛ201 -219 derived from adult AChR which is expressed in muscle, and sometimes in thymic epithelium, and α 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 a and E 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.

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