Autoantibodies and Cardiomyopathy: Focus on Beta-1 Adrenergic Receptor Autoantibodies

Abstract

Antibody response to self-antigens leads to autoimmune response that plays a determinant role in cardiovascular disease outcomes including dilated cardiomyopathy (DCM). Although the origins of the self-reactive endogenous autoantibodies are not wellcharacterized, it is believed to be triggered by tissue injury or dysregulated humoral response. Autoantibodies that recognize G protein-coupled receptors are considered consequential because they act as modulators of downstream receptor signaling displaying a wide range of unique pharmacological properties. These wide range of pharmacological properties exhibited by autoantibodies has cellular consequences that is associated with progression of disease including DCM. Increase in autoantibodies recognizing beta-1 adrenergic receptor (b1AR), a G protein-coupled receptor critical for cardiac function, is observed in patients with DCM. Cellular and animal model studies have indicated pathological roles for the b1AR autoantibodies but less is understood about the molecular basis of their modulatory effects. Despite the recognition that b1AR autoantibodies could mediate deleterious outcomes, emerging evidence suggests that not all b1AR autoantibodies are deleterious. Recent clinical studies show that b1AR autoantibodies belonging to the IgG3 subclass is associated with beneficial cardiac outcomes in patients. This suggests that our understanding on the roles the b1AR autoantibodies play in mediating outcomes is not well-understood. Technological advances including structural determinants of antibody binding could provide insights on the modulatory capabilities of b1AR autoantibodies in turn, reflecting their diversity in mediating b1AR signaling response. In this study, we discuss the significance of the diversity in signaling and its implications in pathology.

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…Currently, a large number of autoantibodies to the ECLs of β 1 - and β 2 -AR are known, which are closely associated with cardiovascular diseases [ 432 , 433 , 434 ]. The most extensive and clinically important group are autoantibodies to β 1 -AR ECL2, which the presence of certain types is the root cause of dilated and ischemic cardiomyopathy [ 434 , 435 , 436 , 437 , 438 ].…”

“…Currently, a large number of autoantibodies to the ECLs of β 1 - and β 2 -AR are known, which are closely associated with cardiovascular diseases [ 432 , 433 , 434 ]. The most extensive and clinically important group are autoantibodies to β 1 -AR ECL2, which the presence of certain types is the root cause of dilated and ischemic cardiomyopathy [ 434 , 435 , 436 , 437 , 438 ]. Antibodies to ECL2, depending on the epitope for which they are produced, upon binding to β 1 -AR induce conformational changes that stabilize both the active and inactive conformation of the receptor.…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…Allosteric sites localized on the cytoplasmic side of the β-AR TMD are targets not only for low molecular weight compounds, but also for pepducins corresponding to the Currently, a large number of autoantibodies to ECLs of β1-and β2-AR are known, which are closely associated with cardiovascular diseases [431][432][433]. The most extensive and clinically important group are autoantibodies to β1-AR ECL2, the presence of certain types of which is the root cause of dilated and ischemic cardiomyopathy [433][434][435][436][437].…”

Relationship between β1-AA and AT1-AA and Cardiac Function in Patients with Hypertension Complicated with Left Ventricular Diastolic Function Limitation

“…Various autoantibodies, such as cardiac myosin, troponin-specific autoantibodies, or muscarinic M2 acetylcholine receptor (M2R), have been detected in the plasma of patients with various cardiac disorders. However, the exact pathophysiological mechanisms of autoimmune-mediated cardiac dysfunction have not been fully elucidated [ 13 ]. Studies have found that an autoimmune reaction is one important cause of hypertension [ 14 ], and the serum levels of β 1 adrenergic receptor autoantibodies ( β 1-AA) and angiotensin II type-1 receptor autoantibodies (AT1-AA) [ 15 , 16 ] in patients with dilated cardiomyopathy (DCM) are higher than those in normal control patients [ 17 ].…”