Acetylcholine receptors and myasthenia

Much progress has been made in the 26 years since initial studies of the fi rst purified acetylcholine receptors (AChRs) led to the discovery that an a ntibody-mediated autoimmune response to AChRs causes the muscular weakness and fatigability characteristic of myasthenia gravis (MG) and its animal mo del, experimental autoimmune myasthenia gravis (EAMG). Now, the structure o f muscle AChRs is much better known. Monoclonal antibodies to muscle AChRs, developed as model autoantibodies for studies of EAMG, were used for initi al purifications of neuronal AChRs, and now many homologous subunits of neu ronal nicotinic AChRs have been cloned. There is a basic understanding of t he pathological mechanisms by which autoantibodies to AChRs impair neuromus cular transmission. Immunodiagnostic assays for MG are used routinely. Nons pecific approaches to immunosuppressive therapy have been refined. However, fundamental mysteries remain regarding what initiates and sustains the aut oimmune response to muscle AChRs and how to specifically suppress this auto immune response using a practical therapy. Many rare congenital myasthenic syndromes have been elegantly shown to result from mutations in muscle AChR s. These studies have provided insights into AChR structure and function as well as into the pathological mechanisms of these diseases. Evidence has b een found for autoimmune responses even to some central nervous system neur otransmitter receptors, but only one neuronal AChR has so far been implicat ed in an autoimmune disease. Thus far, only two neuronal AChR mutations hav e been found to be associated with a rare form of epilepsy, but many more n euronal AChR mutations will probably be found to be associated with disease in the years ahead. (C) 2000 John Wiley & Sons, Inc.