American Society for Cell Biology, Molecular Biology of the Cell, p. mbc.E20-06-0394, 2021
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Dysregulation of immune responses has been linked to the generation of IgG autoantibodies that target human β1ARs and contribute to deleterious cardiac outcomes. Given the benefits of β-blockers observed in patients harboring IgG3 sub-class of autoantibodies, we investigated the role of these autoantibodies in human β1AR function. Serum and purified IgG3(+) autoantibodies from patients with onset of cardiomyopathy were tested using HEK293 cells expressing human β1ARs. Unexpectedly, pre-treatment of cells with IgG3(+) serum or purified IgG3(+) autoantibodies impaired dobutamine-mediated adenylyl cyclase (AC) activity and cAMP generation while enhancing biased β-arrestin recruitment and ERK activation. Contrastingly, the β-blocker metoprolol increased AC activity and cAMP in the presence of IgG3(+) serum or IgG3(+) autoantibodies. Since IgG3(+) autoantibodies are specific to human β1ARs, non-failing human hearts were used as an endogenous system to determine their ability to bias β1AR signaling. Consistently, metoprolol increased AC activity reflecting the ability of the IgG3(+) autoantibodies to bias β-blocker towards G-protein coupling. Importantly, IgG3(+) autoantibodies are specific towards β1AR as they did not alter β2AR signaling. Thus, IgG3(+) autoantibody biases β-blocker towards G-protein coupling, while impairing agonist-mediated G-protein activation but promoting G-protein-independent ERK activation. This phenomenon may underlie the beneficial outcomes observed in patients harboring IgG3(+) β1AR autoantibodies.