Recombinant Human Acetylcholine Receptor Alpha-subunit 1-210 Induces Experimental Autoimmune Myasthenia Gravis

Background: Myasthenia gravis (MG) is a T cell - dependent antibody-mediated autoimmune neuromuscular disease. Antibodies to the nicotinic acetylcholine receptor (AChR) destroy the AChR, thus leading to defective neuromuscular transmission of electrical impulse and to muscle weakness. Experimental autoimmune myasthenia gravis (EAMG) in the mouse is the animal model for MG. AChR can be extracted from the electric organs of Torpedo californica or eel, and affinity purified to be used as an immunogen to induce autoimmunity to AChR, thus causing EAMG. AChR is located in the post synaptic membrane at neuromuscular junctions and a pentamer composed of four homologous subunits in a stoichiometry of α_βγδ . Eel electric organs have provided a valuble source of native AchR for readily inducing EAMG in rodents, but each of the individual subunits isolated from Torpedo AchR retains weak myasthenogenic activity when injected repeatedly in high doses with complete Freund's adjuvant (CFA) . Patients with acquired MG also exhibit minimal immune reactivity to electric organ AchR serologically and at the T cell level. Native AchR purified from human skeletal muscular is myasthenogenic in rats, but the very small yields of purified AchR recoverable from human skeletal muscle have limited its applicability in inducing EAMG. Although synthetic peptides of certain human a-subunit sequences are myasthenogenic, they must be injected repeatedly at high doses , and autoantibodies as well as signs of EAMG are transient. The a-subunit appears to be the prime target for pathogenic autoantibodies in the neuromuscular disease MG, and it has been a major...