Functional autoreactive anti-β2 adrenergic antibodies may contribute to insulin resistance profile in patients with chronic chagas disease

Potential activation of β2 adrenergic receptors (β2AR) by specific autoreactive antibodies (Abs) that arise during the host reaction to Trypanosoma cruzi, could contribute to the elevated prevalence of metabolic disturbances described in patients with chronic Chagas disease (CCD). This study aimed to determine the prevalence of anti-β2AR Abs in patients with CCD, as well as the correlation of these Abs with the presence of glucose and lipid metabolism disturbances, in order to explore their association with an insulin resistance profile. Additionally, we tested the functional effects of anti-β2AR Abs employing an in vitro bioassay with neuroendocrine cells expressing β2AR. A clinical and metabolic evaluation including an OGTT was performed in 80 CCD patients and 40 controls. Anti-β2AR Abs were measured by an in-house-developed ELISA, and the β2 adrenergic activity of affinity-purified IgG fractions from patient’ sera were assayed in CRE-Luc and POMCLuc transfected AtT-20 cells. A higher proportion of dysglycemia (72.5% vs. 37.5%; p = 0.001) was observed in the CCD group, accompanied by increased HOMA2-IR (p = 0.019), especially in subjects with Abs (+). Anti-β2AR Abs reactivity (7.01 (2.39–20.5); p = 0.0004) and age >50 years (3.83 (1.30–11.25); p = 0.014) resulted as relevant for IR prediction (AUC: 0.786). Concordantly, Abs (+) CCD patients showed elevated metabolic risk scores and an increased prevalence of atherogenic dyslipidemia (p = 0.040), as compared to Abs (−) patients and controls. On functional bioassays, Abs exerted specific and dose-dependent β2-agonist effects. Our findings suggest that anti-β2AR Abs may induce the activation of β2AR in other tissues besides the heart; furthermore, we show that in patients with CCD these Abs are associated with an insulin resistance profile and atherogenic dyslipidemia, providing biological plausibility to the hypothesis that adrenergic activation by anti-β2AR Abs could contribute to the pathogenesis of metabolic disturbances described in CCD patients, increasing their cardiovascular risk.Fil: Rodeles Antonelli, Luz María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral; ArgentinaFil: Vicco, Miguel Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral; ArgentinaFil: Siano, Alvaro Sebastían. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Química Organica. Laboratorio de Peptidos Bioactivos; ArgentinaFil: Fuchs, Leonardo Andrés. Universidad Nacional del Litoral; ArgentinaFil: Peverengo, Luz María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Tecnología Inmunológica; ArgentinaFil: Sanchez Puch, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Cymeryng, Cora Betriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Marcipar, Iván Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Tecnología Inmunológica; ArgentinaFil: Arias, Pablo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Cátedra de Fisiología Humana; Argentin