Activation of T Lymphocytes as a Novel Mechanism in Beta1-Adrenergic Receptor Autoantibody-Induced Cardiac Remodeling.

BACKGROUND:Numerous studies have reported significantly elevated titers of serum autoantibody against the second extracellular loop of β₁-adrenoceptor (β₁-AA), a catecholamine-like substance with β₁-adrenergic activity, in patients with heart failure. Although evidence demonstrates that this autoantibody may alter T cell proliferation and secretion, the role of T lymphocytes in heart failure induced by β₁-AA remains unclear. The current study was designed to determine whether T cell disorder contributes to heart failure induced by β₁-AA. METHODS AND RESULTS:β₁-AA monoclonal antibodies (β₁-AAmAb) produced using the hybridoma technique were administered in wild-type mice or T lymphocyte deficiency nudes for 12 weeks. T lymphocytes from heart failure patients and neonatal cardiomyocytes were utilized in vitro. Mouse protein antibody array analysis was employed to detect the cytokines responsible for β₁-AAmAb-induced heart failure. Compared to wild-type mice, T lymphocyte deficiency mice prevented cardiac function from getting worse, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. As shown by protein array, the serum level of interleukin (IL)-6 was significantly lower in the nude group as compared to wild-type after β₁-AAmAb treatment. Mechanistic studies in vitro demonstrated that T lymphocyte culture supernatants stimulated by β₁-AAmAb caused direct damage in the cardiomyocytes, and β₁-AAmAb promoted proliferation of T lymphocytes isolated from patients with heart failure and increased IL-6 release. IL-6-specific siRNA virtually abolished cardiomyocyte apoptosis, suggesting that IL-6 may be a key cytokine released by T lymphocytes and responsible for β₁-AAmAb-induced cardiac remodeling. CONCLUSIONS:Collectively, we demonstrate that β₁-AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6.

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