Detection of Anti-Acetylcholine Receptor Factors in Serum and Thymus from Patients with Myasthenia Gravis

Mittag, Thomas W.; Kornfeld, Peter; Tormay, Anne; Woo, Charles

doi:10.1056/nejm197603252941303

Cited by 146 publications

(27 citation statements)

References 30 publications

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“…Thus, it is possible that the inhibitory effect of a-fetoprotein demonstrated in the present study is not just specific for the binding of AcChoR antibodies to AcChoR in myasthenia gravis but may play the same role in other autoimmune conditions during pregnancy. Moreover, a correlation between autoantibody level and the severity of several autoimmune conditions, including anti-AcChoR antibody level in myasthenia gravis (14,(55)(56)(57)(58)(59)(60), cannot always be demonstrated. Therefore, it is reasonable to speculate that a-fetoprotein or similar factors may play a role in the clinical course of myasthenia gravis and other autoimmune diseases, 'even without pregnancy, and may serve in the future as therapeutic agents.…”

Section: Resultsmentioning

confidence: 99%

Inhibitory effect of alpha-fetoprotein on the binding of myasthenia gravis antibody to acetylcholine receptor.

Brenner¹,

Beyth²,

Abramsky³

1980

Proc. Natl. Acad. Sci. U.S.A.

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The binding of myasthenia gravis antibody to acetylcholine receptor (AcChoR) as measured in vitro by radioimmunoassay with 125-labe ed a-bungarotoxin (a-BuTx), can be blocked by amniotic fluid, maternal serum, and umbilical cord serum. This inhibitory effect is due to a-fetoprotein present in high concentrations in amniotic fluid and serum, as shown by: (i) selective removal of several components from amniotic fluid and serum; (ih) selective addition of different components present in amniotic fluid and serum, including a-fetoprotein, to the radioimmunoassay; (iii) correlation between the inhibitory effect of both amniotic fluid and serum and between the amounts of a-fetoprotein they contain; (iv) blocking of the a-fetoprotein effect by pretreatment of the amniotic fluid with anti-a-fetoprotein anti'y. The inhibitory effect of a-fetoprotein in vitro suggests a similar effect in vivo in pregnant women with myasthenia gravis. This effect may explain in part the variability in the development of neonatal myasthenia gravis in the babies, due to transplacental transfer of maternal anti-AcChoR antibody, only after delivery and only in the minority of the cases. It also may explain the appearance of remissions in females with myasthenia gravis during the second and third trimesters of pregnancy. Similar phenomena observed during pregnancy in other autoimmune and immunopathogenic diseases also might be attributed to activity of a-fetoprotein.In studies from our laboratory (1, 2), we demonstrated that the in vitro binding of antibodies to acetylcholine receptor (AcChoR) from patients with myasthenia gravis to AcChoR antigen can be inhibited by: (i) human amniotic fluid obtained from healthy women during the second trimester; (Hi) serum obtained from healthy women during the second and third trimesters; and (iii) umbilical cord serum obtained after delivery from both healthy women and myasthenics. We suggested that a similar inhibitory effect in vivo on the binding of specific antibodies to AcChoR at the neuromuscular junction may occur during pregnancy in patients with myasthenia gravis. Because myasthenia gravis is an autoimmune disease caused by the immunopathologic effect of specific autoantibodies directed against AcChoR at the neuromuscular junction (3), such inhibitory effects may help to explain two phenomena observed in myasthenia gravis during pregnancy and after delivery: The occurrence of partial or complete remissions during the second and (especially) the third trimester, as well as exacerbations during the early postpartum period (4-8); and the appearance of transitory neonatal myasthenia gravis (NMG) in the newborn babies, due to placental transfer of maternal antibodies (9-11), only after birth and only in a minority of the cases (12, 13). This paper presents experimental data showing that the immunosuppressant a-fetoprotein, but not other components derived from both human amniotic fluid and human umbilical cord, is the factor inhibiting the binding of antibodies to AcChoR antigen present in the...

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Section: Resultsmentioning

confidence: 99%

Inhibitory effect of alpha-fetoprotein on the binding of myasthenia gravis antibody to acetylcholine receptor.

Brenner¹,

Beyth²,

Abramsky³

1980

Proc. Natl. Acad. Sci. U.S.A.

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“…Antibodies to the acetylcholine receptor have been found in the serum of patients with myasthenia gravis (25)(26)(27)(28)44) and in the serum of animals immunized with solubilized acetylcholine receptors (45,46). In contrast to the antibodies to the insulin and TSH receptors, these appear to alter acetylcholine receptor function without major alterations in the binding of a-bungarotoxin to the cholinergic binding site (26,28,44).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the antibodies to the insulin and TSH receptors, these appear to alter acetylcholine receptor function without major alterations in the binding of a-bungarotoxin to the cholinergic binding site (26,28,44). Antibodies to the prolactin receptor have been produced by immunization of guinea pigs with soluble prolactin receptor preparations (47).…”

Section: Discussionmentioning

confidence: 99%

Effects of Autoantibodies to the Insulin Receptor on Isolated Adipocytes

Kahn¹,

Baird²,

Flier³

et al. 1977

J. Clin. Invest.

243

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A B S T R A C T Autoantibodies to the insulin receptor have been detected in the sera of several patients with the Type B syndrome of insulin resistance and acanthosis nigricans. In this study we have used three of these sera (B-1, B-2, and B-3) as probes ofthe insulin receptor in isolated rat adipocytes. Preincubation of adipocytes with each of the three sera resulted in an inhibition of subsequent [1251]insulin binding. 50% inhibition of binding occurred with serum dilutions of 1:5 to 1:7,500. As in our previous studies with other tissues, Scatchard analysis of the insulin-binding data was curvilinear consistent with negative cooperativity. Computer analysis suggested that in each case the inhibition of binding was due to a decrease in receptor affinity rather than a change in available receptor number.In addition to the effects on insulin binding, adipocytes pretreated with antireceptor sera also showed alterations in biological responses. All three sera produced some stimulation of basal glucose oxidation. With serum B-3, maximal stimulation of glucose oxidation occurred at a serum concentration that inhibited binding by only 10-15%, whereas with serum B-2 the dilution curves for inhibition of binding and stimulation of glucose oxidation were superimposable. Serum B-1 behaved as a partial agonist; that is, it inhibited binding more effectively than it stimulated glucose oxidation. Cells pretreated with this serum in a concentration which inhibited binding by 80% also showed a five-fold shift to the right in the dose response of insulin-stimulated glucose oxidation, whereas sperminestimulated glucose oxidation was unaffected. Serum B-2, which contained the highest titer of antireceptor

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“…These symptoms are probably due to a reduced number of acetylcholine receptors (AcChoR) at the neuromuscular junction (3). Sera from patients with myasthenia contain antibodies to AcChoR (4)(5)(6)(7), and animals immunized with purified AcChoR (8)(9)(10)(11)(12)(13) develop symptoms similar to those of myasthenia gravis. Moreover, repeated injection of IgG from myasthenic patients produces symptoms of the disease in mice (14).…”

mentioning

confidence: 99%

Antibodies from patients with myasthenia gravis recognize determinants unique to extrajunctional acetylcholine receptors.

Weinberg¹,

Hall²

1979

Proc. Natl. Acad. Sci. U.S.A.

122

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We have examined the interaction between sera from patients with myasthenia gravis and acetylcholine receptor (AcChoR) purified from normal and denervated rat skeletal muscles [junctional receptor (UR) and extrajunctional receptor (EJR), respectively]. Eight of ten myasthenic sera had titers against EJR that were significantly higher (1.1-2.4 times) than their titers against JR. The antireceptor titers of these sera ranged from 2 to 102 nM. Although activities of three other sera were too low (<1 nM) to allow accurate titrations, provisional measurements with these sera gave titers against EJR that were at least as high (1.0-1.4 times) as those against JR. Competition

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Detection of Anti-Acetylcholine Receptor Factors in Serum and Thymus from Patients with Myasthenia Gravis

Cited by 146 publications

References 30 publications

Inhibitory effect of alpha-fetoprotein on the binding of myasthenia gravis antibody to acetylcholine receptor.

Inhibitory effect of alpha-fetoprotein on the binding of myasthenia gravis antibody to acetylcholine receptor.

Effects of Autoantibodies to the Insulin Receptor on Isolated Adipocytes

Antibodies from patients with myasthenia gravis recognize determinants unique to extrajunctional acetylcholine receptors.

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