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Beltrame, Sabrina P.; Carrera Páez, Laura C.; Auger, Sergio R.; Sabra, Ahmad H.; Bilder, Claudio R.; Waldner, Claudia I.; Goin, Juan C.
Clinical immunology (Orlando, Fla.), March 2020, 2020-03-00, 20200301, Volume: 212Journal Article
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. Display omitted •The role of serum autoantibodies in Chagas disease-related dysautonomia was examined.•M2 muscarinic receptor antibodies inhibit agonist-induced Gi protein activation.•These antibodies also inhibit agonist-mediated arrestin-2 recruitment.•Anti-M2 receptor autoantibodies could function as negative allosteric modulators.•These autoantibodies could play a pathogenic role in chagasic dysautonomia.
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