Antibodies in the sera of patients with myasthenia gravis are believed to play an important role in the pathogenesis of the disorder. They have recently been shown to accelerate the degradation of acetylcholine receptors in cultured mammalian skeletal muscle and at intact neuromuscular junctions. To elucidate the mechanism of the antibody-accelerated degradation process, we have prepared cultures in which one set of acetylcholine receptors was exposed to myasthenic immunoglobulin while a second set of acetylcholine receptors, newly incorporated after exposure to the immunoglobulins, was not. The set of acetylcholine receptors with bound myasthenic immunoglobulin was degraded at 2 to 3 times the normal rate, while the second set of acetylcholine receptors without bound immunoglobulin was degraded at the control rate. This suggest that the binding of antibody from myasthenic patients alters the acetylcholine receptors in some way that causes them to be selected for preferential degradation by the muscle cells. New synthesis and incorporation of the acetyl-choline receptors into the surface membrane of cultured skeletal muscle was unaffected by exposure to myasthenic immunoglobulin.

After rats had been fed a low-potassium diet for 4 to 8 weeks, skeletal muscle showed ultrastructural changes involving membranous organelles. Mitochondria were often swollen, condensed, or disintegrated. The transverse tubules were disoriented, focally dilated, and tortuous. The sarcoplasmic reticulum showed various degrees of dilatation. Vacuoles of different sizes occurred frequently. Whirls of membranes were closely associated with any of the membranous organelles, especially near an orifice of a transverse tubule. Supplementation of potassium reversed these changes. These findings are very similar to those in patients with hypokalemic periodic paralysis. The vacuolar myopathy in these patients may be secondary to the electrolyte alteration in skeletal muscles, and the chronic weakness of some patients may be due to excitation-contraction uncoupling as a result of the involvement of sarcotubular systems.

Degradation of acetylcholine receptors by cultured rat skeletal muscle cells was determined from the release of 125 I from bound 125 I-labeled α-bungarotoxin. Addition of immunoglobulin from patients with myasthenia gravis to the culture medium accelerated the degradation rate to a mean of 8.51 ± 0.44 percent per hour, compared with the mean control rate of 3.97 ± 0.14 percent per hour ( P < <.001). A similar mechanism may possibly be involved in the autoimmune pathogenesis of myasthenia gravis in man.

To study the role of humoral factors in the pathogenesis of myasthenia gravis, we employed passive transfer of human serum fractions to mice. Immunoglobulins from 16 patients with myasthenia gravis were injected into mice daily for one to 14 days. Typical myasthenic features of reduction in amplitude of miniature end-plate potentials (mean change more than 50 per cent, P less than 0.005) or reduction in acetylcholine receptors at neuromuscular junctions (mean change more than 50 per cent, P less than 0.005) (or both) were produced by immunoglobulin from 15 of the 16 patients. Some mice showed weakness or decremental responses to repetitive nerve stimulation as well. The active fraction was identified as IgG by three different purification methods. Its effect was enhanced by the third component (C3) of the complement system, but the fifth component (C5) had no effect. These data suggest that the pathogenesis of myasthenia gravis often involves and antibody-mediated autoimmune attack on the acetylcholine receptors of the neuromuscular junction.

Culture of dissociated thymus from rats and humans yielded cells identical to skeletal muscle with respect to morphology, contractility, electrophysiological properties, and the presence of acetylcholine receptors. These cells, strategically located in the thymus, may play a role in initiation of the autoimmune response against acetylcholine receptors, which is characteristic of myasthenia gravis.

The mechanism of action of botulinum toxin was analyzed by the use of calcium ionophores and black widow spider venom. Addition of calcium ionophores to nerve-muscle preparations blocked by botulinum toxin did not increase the frequency of miniature end plate potentials. However, the spider venom elicited a barrage of miniature end plate potentials after blockade by botulinum. Electron micrographs of preparations treated with botulinum toxin and then the spider venom revealed clumping of synaptic vesicles at release sites in the otherwise depleted nerve terminals. These findings indicate that the action of botulinum toxin is not due to deficient storage of acetylcholine in vesicles or blockade of calcium entry into nerve terminals. They suggest that the toxin interferes with the acetylcholine release process itself, possibly by blocking exocytosis at the release sites.

Annals of the New York Academy of SciencesVolume 274, Issue 1 p. 226-234 MYASTHENIA GRAVIS AS A RECEPTOR DISORDER Daniel B. Drachman, Daniel B. Drachman Department of Neurology Johns Hopkins Hospital Baltimore, Maryland 21205Search for more papers by this authorIng Kao, Ing Kao Department of Neurology Johns Hopkins Hospital Baltimore, Maryland 21205Search for more papers by this authorAlan Pestronk, Alan Pestronk Department of Neurology Johns Hopkins Hospital Baltimore, Maryland 21205Search for more papers by this authorKlaus V. Toyka, Klaus V. Toyka Department of Neurology Johns Hopkins Hospital Baltimore, Maryland 21205Search for more papers by this author Daniel B. Drachman, Daniel B. Drachman Department of Neurology Johns Hopkins Hospital Baltimore, Maryland 21205Search for more papers by this authorIng Kao, Ing Kao Department of Neurology Johns Hopkins Hospital Baltimore, Maryland 21205Search for more papers by this authorAlan Pestronk, Alan Pestronk Department of Neurology Johns Hopkins Hospital Baltimore, Maryland 21205Search for more papers by this authorKlaus V. Toyka, Klaus V. Toyka Department of Neurology Johns Hopkins Hospital Baltimore, Maryland 21205Search for more papers by this author First published: May 1976 https://doi.org/10.1111/j.1749-6632.1976.tb47688.xCitations: 39AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume274, Issue1Myasthenia GravisMay 1976Pages 226-234 RelatedInformation

Daily injections into mice of an ammonium sulfate-precipitated immunoglobulin fraction of serum from patients with myasthenia gravis were carried out for up to 14 days. The mice showed reduced amplitudes of miniature endplate potentials and reduced numbers of acetylcholine receptors at the neuromuscular junctions. Some mice showed typical decremental responses on repetitive nerve stimulation, with reversal by neostigmine. This represents the first evidence of a circulating factor in the serum of patients with myasthenia gravis which on passive transfer reproduces features of the disease in experimental animals.