Further Studies on the Specificity of Presumed Immune Associations of Myasthenia Gravis and Consideration of Possible Pathogenic Implications

Abstract

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...

Autoantibody Profiles and Neurological Correlations of Thymoma

“…The first autoantibodies recognized with thymoma were specific for sarcomeric ("striational") proteins of skeletal muscle (14). Striational antibody specificities identified to date include titin, myosin, actin, ␣-actinin, and ryanodine receptors (15)(16)(17)(18).…”

“…Striational antibody specificities identified to date include titin, myosin, actin, ␣-actinin, and ryanodine receptors (15)(16)(17)(18). Striational antibodies and muscle AChR antibody have both been reported in patients with thymoma without evident MG (14,19). Striational antibody (20) and a high level of muscle AChR-modulating antibody activity (21) are commonly associated with thymomatous MG.…”

Serological Detection of Thymoma in Myasthenia Gravis

“…28], Thus, several nonthymoma MG sera also react strongly in the IF test. Furthermore, the staining patterns observed with sera from thymoma and nonthymoma cases are indis tinguishable [25], It could be argued that a small thymoma might be present in such cases, but escape detection. Beutner et al [5] have, however, clearly confirmed in an au topsy case that such antibodies may be present in high titers without the presence of a thymoma.…”

Human monoclonal striational autoantibodies isolated from thymic B lymphocytes of patients with myasthenia gravis use VH and VL gene segments associated with the autoimmune repertoire

“…However, 80%-90% of patients with both MG and thymoma are seropositive for StrAb [4,5,121. While the pathogenic significance of StrAb is not known, the thymus is believed to play a critical role in their induction; these antibodies bind to epithelial and myoid cells of the thymus in addition to skeletal muscle [S-71.…”