The hypothesis advanced independently in 1960 by Nastuk et. al. ' and Simpson' that myasthenia gravis is a disorder with a possible autoimmune etiology, together with studies dealing with presumed immune associations of myasthenia gravis:'-12 have recently been reviewed in detai1,l3-I5 and need not be considered here.A t the New York Academy of Sciences Conference on Autoimmunity, held in February, 1964, Strauss et al.," reported findings which essentially confirmed and extended to a larger series the various observations of several previous investigations by Strauss et al.,3 Beutner et al.,5 Feltkamp et a1.' and van der Geld et al. ' with respect to a striated muscle (A-Band) binding serum globulin factor in myasthenia gravis, as well as to the more recent finding reported by van der Geld et a1." of associated serological reactivity with thymic epithelial cells. Serum 7-globulins of 99 (30 per cent) of 336 patients with myasthenia gravis were shown to react concurrently against alternate skeletal muscle striations and thymic epithelial cell cytoplasm. This was an in vitro demonstration, using the indirect fluorescent antibody technique, within specific test limits. Serums of 19 (95 per cent) of 20 patients with myasthenia gravis and associated thymomas were reactive against both skeletal muscle and thymus. In the same coded and random survey,I4 serological reactivity against both skeletal muscle and thymus was not seen in serums of 128 of 129 healthy individuals, nor in serums of 673 of 674 disease control individuals, including those with other so-called "auto-immune diseases," myopathies, dystrophies, heredo-familial neuromuscular diseases, lymphomas, tuberculosis, granulomatoses, dysproteinemias, thymomas unassociated with myasthenia gravis, etc., nor in individuals with histories of anticholinesterase consumption in the absence of myasthenia gravis. Reactivity, in the control 557 558 Annals New York Academy of Sciences FIGURE la. Pattern observed with serums of 930 individuals in earlier series:" 223 with myasthenia gravis, 128 normal controls, and 579 "disease controls." The same pattern was observed, in the present study, with serums of 32 patients with thymomas uraassociated with myasthenia gravis. No fluorescent striations nor thymic epithelial cells were seen. FIGURES l a through e. Patterns of immunofluorescence in skeletal muscle and thymus encountered in the coded, random study of serums from 1,139 individuals, previously reported.!' Patterns similar to those illustrated in FIGURES 1 a through d were observed, as detailed in text and below, with serums from 51 additional patients with thymomas unussociated with myasthenia gravis in the present study and with serums from thirteen additional patients with myasthenia gravis and thymomas not previously reported. Composite sections were (1) fixed with 95 per cent ethanol for 5 minutes, (2) washed in repeated changes of pH 7.2, 0.01M phosphate buffered 0.15M saline for 15 minutes, (3) incubated with serums, diluted 1:60, for 30 minutes, (4) washed with s...
Origins of the Study of Immunological Features of Myasthenia GravisIn 1954, prompted by certain clinical observations1" and the findings of other investigators,3.' Nastuk, Strauss, and Osserman undertook studies to determine what role, if any, humoral inhibitors of neuromuscular transmission might play in the pathogenesis of myasthenia gravis. Their findings have been reported in detail e l~e w h e r e .~'~ In early experiments, an isolated frog sartorius muscle was indirectly stimulated via its attached motor nerve and measurements were made of the muscle tension developed upon exposure of the muscle to serum diluted to isotonicity with frog plasma. I t was found that serums from a few of the myasthenic patients studied caused reduction in the muscle tension output and cytolytic destruction of fibers lying on the surface of the sartorius muscle. After a period of latency of 7 to 10 minutes with the most active samples, there appeared a wrinkling of the membranes of surface muscle fibers, a clouding of these cells, and shortly thereafter destruction of membranes and retraction of the contractile elements. Larger numbers of myasthenic and normal serums were studied for these effects. Of 36 patients with myasthenia gravis, 16 (44 per cent) had serums with cytolytic activity. Of 36 normal individuals, eight (22 per cent) had serums which showed cytolytic properties. No titrations were performed, however, to determine the cytolytic potency of individual serums in the myasthenic and control groups. On the other hand, the heat lability of the cytolytic function of myasthenic serum (inactivated by heating to 56°C. for 30 minutes), and its reconstitution by mixture with an equal volume of fresh noncytolytic normal serum suggested the participation of serum complement in these effects. This led Nastuk, Plescia, and O~s e r m a n~.~ to study the total serum complement (C') activity of myasthenia gravis patients and normal controls. Serum complement activity did not vary greatly in normal individuals. All determinations were within A 20 per cent of the mean value. In patients with myasthenia gravis, serum C' activity varied much more widely with values
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