Previous studies showed that circulating autoantibodies against M2 muscarinic receptors (anti-M2R Ab) are associated with decreased cardiac parasympathetic modulation in patients with chronic Chagas disease (CD). Here we investigated whether the exposure of M2R to such antibodies could impair agonist-induced receptor activation, leading to the inhibition of associated signaling pathways. Preincubation of M2R-expressing HEK 293T cells with serum IgG fractions from chagasic patients with cardiovascular dysautonomia, followed by the addition of carbachol, resulted in the attenuation of agonist-induced Gi protein activation and arrestin-2 recruitment. These effects were not mimicked by the corresponding Fab fractions, suggesting that they occur through receptor crosslinking. IgG autoantibodies did not enhance M2R/arrestin interaction or promote M2R internalization, suggesting that their inhibitory effects are not likely a result of short-term receptor regulation. Rather, these immunoglobulins could function as negative allosteric modulators of acetylcholine-mediated responses, thereby contributing to the development of parasympathetic dysfunction in patients with CD.

中文翻译：

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来自患有脉管自主功能减退的chagasic患者的自身抗体会导致激动剂诱导的M2毒蕈碱受体活化。

先前的研究表明，患有慢性Chagas病（CD）的患者中，针对M2毒蕈碱受体的循环自身抗体（抗M2R Ab）与心脏副交感调节降低有关。在这里，我们调查了M2R暴露于此类抗体是否会削弱激动剂诱导的受体活化，从而导致相关信号通路的抑制。将M2R表达的HEK 293T细胞与来自患有心血管自主功能低下的chagasic病人的血清IgG馏分进行预培养，然后再添加卡巴胆碱，从而减弱了激动剂诱导的Gi蛋白激活和restarin-2募集。这些作用没有被相应的Fab部分所模仿，表明它们是通过受体交联而发生的。IgG自身抗体不能增强M2R / arrestin相互作用或促进M2R内在化，这表明它们的抑制作用不可能是短期受体调节的结果。相反，这些免疫球蛋白可以充当乙酰胆碱介导的反应的负变构调节剂，从而促进CD患者副交感神经功能障碍的发展。