The Ig3 Subclass Of Beta 1-Adrenergic Receptor Autoantibodies Is An Endogenous Biaser Of Beta 1ar Signaling

Dysregulation of immune responses has been linked to the generation of immunoglobulin G (IgG) autoantibodies that target human beta 1ARs and contribute to deleterious cardiac outcomes. Given the benefits of beta-blockers observed in patients harboring the IgG3 subclass of autoantibodies, we investigated the role of these autoantibodies in human beta 1AR function. Serum and purified IgG3(+) autoantibodies from patients with onset of cardiomyopathy were tested using human embryonic kidney (HEK) 293 cells expressing human beta 1ARs. Unexpectedly, pretreatment of cells with IgG3(+) serum or purified IgG3(+) autoantibodies impaired dobutamine-mediated adenylate cyclase (AC) activity and cyclic adenosine monophosphate (cAMP) generation while enhancing biased beta-arrestin recruitment and Extracellular Regulated Kinase (ERK) activation. In contrast, the beta-blocker metoprolol increased AC activity and cAMP in the presence of IgG3(+) serum or IgG3(+) autoantibodies. Because IgG3(+) autoantibodies are specific to human beta 1ARs, non-failing human hearts were used as an endogenous system to determine their ability to bias beta 1AR signaling. Consistently, metoprolol increased AC activity, reflecting the ability of the IgG3(+) autoantibodies to bias beta-blocker toward G-protein coupling. Importantly, IgG3(+) autoantibodies are specific toward AR as they did not alter beta 2AR signaling. Thus, IgG3(+) autoantibody biases beta-blocker toward 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(+) beta 1AR autoantibodies.