MYASTHENIA GRAVIS is a disease that presents clinically ... The test for every action of every physician, of ... acetylcholine receptor antibody, are also cross-.
EDITORIALS
of involuntary service. The trend is clearly toward greater public control both of physicians and the medicine they practice. It is well to ask, then, does medicine have any real social, economic or political strength that it can bring to bear in these critical times-and if so where does it lie? It is certainly not at the ballot box. Physicians have only one vote in a thousand and legislators know this. It is not in the physicians' pocketbooks, although these have to be tapped to achieve a variety of professional goals. And it is clearly not in the profession's ability to cause suffering or hurt-or even unnecessary inconveniences-to the sick or injured. Rather the strength of medicine lies in the opposite of these. It lies in first earning and then mobilizing the vigorous support of patients and the general public for its goals. This can amount to an enormous power, far surpassing any power the profession can hope to generate within itself.
It needs to be cultivated continually, in times of stress as well as in times less stressful, so that it can be brought to bear when needed. These are times for the profession to keep its head-and for physicians to keep their cool. The role to be sought in society is that of wise and respected leadership, and the power to be mobilized is that of public understanding,and support. The test for every action of every physician, of every group of physicians and of the profession itself is whether or not that action is best for patients and, therefore, for the public generally. It will always be true that what is best for patients is in the long run best for the medical profession. If the withholding of physicians' services can be justified by this test, then well and good. But there can be no doubt that the withholding of physicians' services can be a double-edged sword, and one edge could turn out to be quite a lot sharper than the other. -MSMW
"Myasthenia Gravis" Or the Autoimmunity, Thymic Disease, Neuromuscular Block Poser MYASTHENIA GRAVIS is a disease that presents clinically with the symptoms of a postsynaptic neuromuscular block; the question arises-What causes this neuromuscular block? Two major clues loom large, thymic disease and autoimmunity; relating these to each other and to the neuromuscular deficit provides the poser of myasthenia gravis. Thymic disease is consistently present in myasthenia gravis. In 15 percent of cases there is thymoma and in the remaining cases infiltration of thymus with lymphocytes and plasma cells and lymphoid germinal centers (these histological changes are also found in the nontumorous thymus adjacent to thymoma in myasthenia gravis). The nontumorous thymus in myasthenia gravis is, by common usage, termed hyperplastic but since the weight falls within the normal range this term is probably incorrect; the histological changes are more consistent with thymitis. The other important point to note with respect to the thymus in myasthenia gravis is that thymectomy, on an empirical basis, has been shown to cure or produce a substantial remission in up to 80 percent of cases. Failure to respond to thymectomy can
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be attributed in most cases to ectopic thymic tissue, incomplete thymectomy or irreversible neuromuscular damage with long-standing disease. Autoimmunity was first suggested in myasthenia gravis in 1960 and since that time this concept has been amply substantiated. There is extensive serological evidence of antibodies to a variety of self antigens and other corroborative evidence, including clinical and serological overlap with other autoimmune diseases and a predominance of certain histocompatibility antigen types probably related to the presence of certain immune regulation genes. The real question seems to be not Is there an autoimmune reaction? but rather How does an autoimmune reaction cause neuromuscular block? Direct blockade of transmission by autoantibodies to the acetylcholine receptor sites is the concept that most people would regard as implicit when autoimmunity is broached in myasthenia gravis. This pathogenesis is supported by the finding that immunization of animals with purified acetylcholine receptors from electric eels results in autoantibodies to endogenous acetylcholine receptors which cause a postsynaptic lesion in the recipient and also produce an acute curare-like neuromuscular block when applied to a neuromuscular preparation in vitro.1'2 More recently, autoantibodies to acetylcholine receptor proteins have been detected in the serum of patients with
EDITORIALS
myasthenia gravis but these do not react with the acetylcholine binding site of the receptor2 and an acute curare-like activity has not been convincingly shown in the serum of patients with myasthenia gravis.3 Furthermore, a major deficiency of the concept of direct autoantibody blockade of neuromuscular transmission in myasthenia gravis is that it fails to account for thymic disease and the clear-cut ameliorative effects of thymectomy. Thymectomy does not produce a comparable amelioration of other autoimmune diseases such as systemic lupus erythematous or the autoimmune disease of New Zealand black (NZB) mice in which thymectomy not only fails to produce improvement but actually causes disease progression. The alternative interpretation of the triad of autoimmunity, thymic disease and neuromuscular block is that an autoimmune reaction is directed towards the thymus, and that as a consequence of autoimmune disease of the thymus a neuromuscular blocking substance is released; this theory places the thymus in the line of causality and explains the special relationship of thymic disease and thymectomy in myasthenia gravis. Thymopoietin is a polypeptide hormone of the thymus that causes a neuromuscular block similar to that of myasthenia gravis, and was in fact isolated by this neuromuscular effect. Thymopoietin also induces the differentiation of bone marrow precursor cells (prothymocytes) to thymocytes and this is considered its physiological function. The complete 49 amino acid sequence of thymopoietin (M.W. 5562) has been determined and a 13 amino acid fragment has been synthesized that is biologically active in producing both thymocyte differentiation4 and neuromuscular block.5 Thymopoietin is released in experimental autoimmune thymitis so that from these studies the autoimmune reaction in myasthenia gravis would appear to be directed primarily towards the thymus and result in autoimmune thymitis, release of thymopoietin and neuromuscular block. The muscle autoantibodies found in myasthenia gravis, including the acetylcholine receptor antibody, are also crossreactive with thymus2 and could thus be regarded as antithymus antibodies and indicative of autoimmunity to thymus. The mechanism by which thymopoietin causes neuromuscular block is of especial interest since thymopoietin does not simply compete for the acetylcholine receptor to produce a curare-like block. A single injection of as little as 4 ng thymopoietin per mouse causes a detectable neuro-
muscular deficit one to five days later. This suggests that thymopoietin is affecting a regulatory mechanism that inhibits the production of functional acetylcholine receptors, but does so with delayed kinetics that show a deficit after one to five days. It is envisaged that persistently elevated thymopoietin levels would result in chronic stimulation of this regulatory mechanism and cause the severe neuromuscular deficit that is found in myasthenia gravis. This delayed time-course for the appearance of thymopoietin-induced neuromuscular effects accounts for the seeming paradox in myasthenia gravis that whereas substantial evidence points to a circulating humoral substance produced by the thymus as a cause of the neuromuscular block, no acute curare-like activity can be detected in the thymus or in the serum of patients with myasthenia gravis; thymopoietin does produce a neuromuscular block but the kinetics of this are such that it would not be observed in the acute assays used to detect curare. Finally, the answers to two questions would seem particularly pertinent to resolving completely the interrelationship of autoimmunity, thymic disease and neuromuscular block. First, if autoantibodies to acetylcholine receptors cause the neuromuscular block of myasthenia gravis, Can immunoglobulin molecules from myasthenic serum be shown to cause an acute curare-like effect in vitro on a neuromuscular preparation?-since this can be done with neuromuscular blocking autoantibodies generated experimentally. Second, if thymopoietin causes the neuromuscular block of myasthenia gravis, Can elevated levels of thymopoietin be detected in the serum?-using a sensitive technique such as radioimmunoassay. The answers to these questions should soon be available so, it is hoped, we will soon have a solution that will satisfy all for the autoimmunity, thymic disease, neuromuscular block poser of myasthenia
gravis. GIDEON GOLDSTEIN,
MD, PH D
Memorial Sloan-Kettering Cancer Center New York City REFERENCES 1. Patrick J, Lindstrom JM, Culp B, et al: Studies on purified eel acetylcholine receptor and anti-acetylcholine receptor antibody. Proc Nat Acad Sci USA 70:3334-3338, Dec 1973 2. Lindstrom J, Lennon V, Seybold M, et al: Experimental autoimmune myasthenia gravis and myasthenia gravis: Biochemical and immunochemical aspects. Ann NY Acad Sci, in press 3. Goldstein G, Mackay IR: The Human Thymus. London, Heineman, 1969 4. Schlesinger DH, Goldstein G, Scheid MP, et al: Chemical synthesis of a peptide fragment of thymopoietin II that induces selective T-cell differentiation. Cell 5:367-370, Aug 1975 5. Goldstein G, Schlesinger DH: Thymopoietin and myasthenia gravis. Neostigmine-responsive neuromuscular block produced experimentally by a synthetic peptide fragment of thymopoietin. Lancet, in press
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