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.

Autoimmune disorders of the neuromuscular junction

“…However, it is possible that a low-affinity or cross-reactive antibody may lead subsequently to a higher affinity reaction against the AChR. [26] We now believe that lower-affinity antibodies do exist in some patients. [27] …”

“…However, if AChR-sensitive T cells escape from the disordered thymic environment, they could get stimulated by the presence of AChRs on the myoid cells present in the adjacent "normal" thymus. Some of these possibilities are discussed by Vincent et al [26] Thymectomy generally does not lead to clinical improvement and most patients require immunosuppressive treatments.…”

Autoimmune diseases involving nicotinic receptors

“…What initiates and sustains the antibody-mediated autoimmune response that causes the muscular weakness and fatigability characteristic of MG is unknown (Vincent et al, 1998;Lindstrom, 2000aLindstrom, , 2002a.…”

“…Penicillamine is given as a chelating agent, but is capable of covalently reacting at thiol groups of proteins. It is suspected that penicillamineinduced MG results from haptenizing of AChR by penicillamine (Bever et al, 1982;Vincent et al, 1998), which might increase its immunogenicity, but this has not been critically demonstrated.…”

“…The weakness characteristic of MG results from impairment of neuromuscular transmission by an antibody-mediated autoimmune response to muscle AChRs (Drachman, 1994;Vincent et al, 1998;Lindstrom, 2000aLindstrom, , 2002a. Antibodies bound to muscle AChRs fix complement, resulting in focal lysis of the postsynaptic membrane.…”