Sixty years have passed since the introduction of anticholinesterase (anti-ChE) drugs for the treatment of myasthenia gravis (MG) by Mary Walker.‘This discovery not only proved the first effective therapy for MG, but also provided important evidence for the neuromuscular junction as the site of the defect in this disease. Although treatment with anti-ChE agents produced some benefit in most myasthenic patients, the prognosis remained poor. In 1958, when anti-ChE drugs were widely used, the mortality rate for generalized MG was still 30%, and more than 60% of patients either failed to improve or actually deteriorated. 2 More recently, with the use of immunosuppressive therapy, the outlook for MG has improved dramati~ ally.~ With proper treatment, the great majority of patients can be restored to fully productive lives. Nevertheless, currently available immunotherapeutic agents themselves present considerable problems. Generalized immunosuppression compromises the immune system as a whole, with increased susceptibility to infection or neoplasia. The available agents may have adverse side effects unrelated to immune suppression, such as hypertension, osteoporosis, and renal or hepatic toxicity. Lifelong treatment is often required; the majority of patients undergo relapse after discontinuation of

As yet, the goal of a “cure” has remained elusive, despite our extensive knowledge of the pathophysiology, immunology, biochemistry, and molecular biology involved in MG. Ideally, treatment of MG should (a) specifically inhibit the autoimmune response to acetylcholine receptor (AChR), without otherwise interfering with the immune system;(b) be nontoxic; and (c) be long-lasting or permanent. Indeed, the goal of achieving discrete control of a specific immune response has been considered the “holy grail” of immunology. Given the detailed knowledge now available, it should be possible to design rational and specific therapy for MG; a strategy designed for MG could lead the way to treatment for a wide variety of other immune disorders as well.