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Mechanisms of Acetylcholine Receptor Loss in Myasthenia Gravis

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Mechanisms of Acetylcholine Receptor Loss in Myasthenia Gravis J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.7.601 on 1 July 1980. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry, 1980, 43, 601-610 Mechanisms of acetylcholine receptor loss in myasthenia gravis DANIEL B DRACHMAN, ROBERT N ADAMS, ELIS F STANLEY, AND ALAN PESTRONK From the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA SUMMARY The fundamental abnormality affecting the neuromuscular junctions of myasthenic patients is a reduction of available AChRs, due to an autoimmune attack directed against the receptors. Antibodies to AChR are present in most patients, and there is evidence that they have a predominant pathogenic role in the disease, aided by complement. The mechanism of antibody action involves acceleration of the rate of degradation of AChRs, attributable to cross-linking of the receptors. In addition, antibodies may block AChRs, and may participate in producing destructive changes, perhaps in conjunction with complement. The possibility that cell-mediated mechanisms may play a role in the autoimmune responses of some myasthenic patients remains to be explored. Although the target of the autoimmune attack in myasthenic patients is probably always the acetyl- Protected by copyright. choline receptors, it is not yet clear which of these immune mechanisms are most important. It is likely that the relative role of each mechanism varies from patient to patient. One of the goals of future research will be to identify the relative importance of each of these mechanisms in the in- dividual patient, and to tailor specific immunotherapeutic measures to the abnormalities found. Reduction ofAChRs at neuromuscular junction in MG has subsequently been confirmed by a-BuTx In 1964, Elmqvist and his colleagues first made the binding,13 and by electrophysiological methods.14 important observation that the amplitude of min- We have continued to carry out motor point iature endplate potentials (mepps) was diminished in biopsies, and our findings suggest that in many muscles from patients with MG.3 They concluded cases measurement ofjunctional AChRs may be the that the mepp abnormality was due to a reduction most sensitive test for MG (Pestronk, Drachman, in the amount ofACh contained in a single quantum. Josifek, in preparation). However, there are other theoretically possible explanations of decreased mepp amplitudes, in- Role of AChR deficit in myasthenia http://jnnp.bmj.com/ cluding a reduced number of AChRs or a false Our observations raised the question of whether transmitter. In order to test the receptor hypothesis, the decrease of available AChRs per se could we obtained "motor point" biopsies from ten account for the physiological abnormalities in MG, patients with myasthenia gravis and a group of or whether it represented a secondary phenomenon. unaffected individuals and disease controls. The In order to explore this question further, we produced strips of muscle containing endplates were incubated pharmacological blockade of AChRs in rats by with 1251-a-BuTx, to saturate the AChRs, and the the use of the a-toxin from the cobra Naja naja excess a-BuTx was removed by washing. The atra,15 and compared the resultant changes in on September 28, 2021 by guest. bound 125I-a-BuTx was measured by scintillation neuromuscular transmission with the abnormalities counting, and autoradiography. Our findings showed occurring naturally in myasthenia.16 The most a marked reduction of AChRs at neuromuscular effective method of administration of cobra toxin junctions of patients with MG, averaging 80% proved to be a single intravenous injection (12 to less than controls.8 11 1 This finding of reduced 20 tg) followed by a long observation period of up AChRs at myasthenic neuromuscular junctions to 14 hours. Evoked potentials were recorded from the calf muscles during repetitive stimulation Address for reprint requests: Dr DB Drachman, Department of Neurology, Johns Hopkins School of Medicine, 1721 E. Madison St, of the sciatic nerve. Initially, the evoked action Baltimore, Maryland 21205, USA. potentials declined in amplitude as the AChR sites 601 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.7.601 on 1 July 1980. Downloaded from 602 Daniel B Drachman et al were blocked by the toxin. Following equilibration Passive Transfer of MG of the toxin in the musculature, the compound The question of whether the circulating antibodies action potentials returned to normal or near normal are pathogenic, or merely represent a secondary amplitudes. Partial blockade of AChRs developed, response to AChR damage caused by some other with a reduced margin of safety of neuromuscular agent, is of paramount importance in understanding transmission. During this phase, which remained the pathogenesis of MG. A well known "experi- stable for many hours, the "myasthenic" features ment in nature" suggested that a circulating factor- were readily seen. Repetitive nerve stimulation at possibly immunoglobulin-might be pathogenic: 3 Hz reproduced the characteristic decremental approximately one of every six infants born to pattern of MG. Furthermore, these responses were myasthenic mothers manifests transient signs of exaggerated by minute doses of d-tubocurarine MG during the first few postnatal weeks.26 In the (1/30th of the rat curarising dose), which is typical past, the results of numerous attempts 26 to transfer of the response in human MG. Treatment of the myasthenia from humans to experimental animals rats with neostigmine (2-5 to 7-5 tg intravenously) or nerve-muscle preparations weie generally nega- produced marked improvement or recovery of the tive or were criticised for inherent faults.27 However decremental responses. Finally, post-tetanic re- the possibility of a circulating factor assumed new ponses, thought to be particularly characteristic of importance in the light of the discovery of anti- MG17 were also reproduced by the cobra toxin bodies to AChR. In most previous studies, the model. Both the early improvement (post-tetanic exposure to myasthenic serum had been brief, potentiation) and later exaggeration of the decre- lasting minutes to hours. We wondered whether mental responses (postactivation exhaustion) oc- more prolonged exposure to levels of immunoglo- curred in the rats. Thus, from the point of view of bulin corresponding to those in the patient, might the electrophysiological features, the cobra toxin be required for the effect to take place. We therefore model faithfully reproduced the abnormalities designed an experiment in which physiologic levels Protected by copyright. found in human MG. Since the a-toxin of Naja of human myasthenic IgG could be maintained in a naja atra used in this study has been shown to block hardy strain (B6D2F1) of experimental mice for up AChRs specifically,15 our findings strongly support to 14 days.28 Immunoglobulin fractions, prepared the hypothesis that a reduction of available from the sera of myasthenic patients or controls by receptors per se can account for the defect of neuro- ammonium sulfate precipitation, were injected daily muscular transmission in MG. into recipient mice. In order to produce tolerance to the foreign serum, we treated the mice with a Autoimmur,e abnormality in MG single dose of cyclophosphamide (300 mg/Kg), 24 The possibility that MG might be an autoimmune hours after the first dose of immunoglobulin, disease was originally proposed on the basis of except in experiments lasting less than four days. indirect evidence, consisting of a high rate of Some of the experimental mice became clinically thymic abnormalities, the association between weak within a few days and showed decremental MG and other presumed autoimmune diseases,7 responses to repetitive nerve stimulation. The and reduced complement levels in some patients.18 most reliable tests were the measure of miniature A further clue that the autoimmune attack might endplate potentials and determination of the number http://jnnp.bmj.com/ be directed against AChRs came from the finding of AChRs per neuromuscular junction in the dia- that animals immunised with purified AChR in phragms of the recipient mice. Passive transfer of Freund's adjuvant developed a condition analogous immunoglobulins from 94% of patients resulted in to myasthenia.19 decreased mepp amplitudes, decreased AChRs at Based on the knowledge of a receptor deficit in neuromuscular junctions, or both.29 Purification MG, and the analogy with the experimental animal of immunoglobulin by column chromatography model, the search for antibodies directed against showed that the active fraction was IgG, while IgM AChRs in the human disease was soon begun. was without effect. Furthermore, absorption of IgG on September 28, 2021 by guest. Antireceptor antibody was identified by several by staphylococcal protein A completely eliminated different methods,20-24 all of which depend on the myasthenogenic effect of the immunoglobulin a-BuTx for their specificity. In the most sensitive preparation. Thus, the passive transfer experiment radioimmunoassay, which detects antibody that clearly demonstrated the pathogenicity of IgG from binds to AChR labelled with 125I-a-BuTx, elevated myasthenic patients. titers have been found in 80-90% of patients with MG.23 However, the antibody titre corresponds only Effect of myasthenic IgG on AChRs approximately to the clinical status of the patients. Theoretically, myasthenic patients' IgG might reduce the number of available AChRs by several
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