Abstract

Autoantibodies recognizing human {beta}1ARs generated due to dysregulation in autoimmune response are generally associated with deleterious cardiac outcomes. However, cellular studies show that isolates of {beta}1AR autoantibody from patients differentially modulate {beta}1AR function. {beta}1AR autoantibodies belong to the IgG class of immunoglobulins, however it is not known whether the IgG sub-classes mediate variability in {beta}1AR responses. To determine whether the IgG3 subclass of {beta}1AR autoantibodies uniquely modulate {beta}1AR function, HEK293 cells stably expressing human {beta}1ARs were utilized. Treatment of cells with IgG3(-) serum resulted in significant increase of cAMP compared to IgG3(+) serum. Pre-treatment of cells with IgG3(+) serum impaired dobutamine-mediated Adenylate Cyclase (AC) activity and cAMP generation whereas, it surprisingly increased AC activity and cAMP generation with {beta}-blocker metoprolol. Consistently, purified IgG3(+) {beta}1AR autoantibodies impaired dobutamine-mediated cAMP while elevating metoprolol-mediated AC activity and cAMP. Despite IgG3(+) autoantibodies reducing cAMP response to dobutamine, they mediate significant ERK activation upon dobutamine. IgG3(+) {beta}1AR autoantibodies did not alter {beta}2AR function, reflecting their specificity. The study shows that IgG3(+) {beta}1AR autoantibody impairs agonist-mediated G-protein coupling while preferentially mediating G-protein-independent ERK activation. Furthermore, it uniquely biases {beta}-blocker towards G-protein coupling. This unique biasing capabilities of IgG3(+) {beta}1AR autoantibodies may underlie the beneficial outcomes in patients.