Drug-like actions of autoantibodies against receptors of the autonomous nervous system and their impact on human heart function

Abstract

Antibodies against cholinergic and adrenergic receptors (adrenoceptors) are frequent in serum of patients with chronic heart failure. Their prevalence is associated with Chagas' disease, idiopathic dilated cardiomyopathy (DCM), and ischaemic heart disease. Among the epitopes targeted are first and second extracellular loops of the β-adrenergic (β-adrenoceptor) and M2 muscarinic receptor. β(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. Corresponding rodent immunizations induce symptoms compatible with chronic heart failure that are reversible upon removal of the antibodies, transferable via the serum and abrogated by adrenergic antagonists. In DCM patients, prevalence and stimulatory efficacy of β(1)-adrenoceptor autoantibodies are correlated to the decline in cardiac function, ventricular arrhythmia and higher incidence of cardiac death. In conclusion, such autoantibodies seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion. However, the pharmacology of this interaction is poorly understood. It is unclear how the autoantibodies trigger changes in receptor activity and second messenger coupling and how that is related to the pathogenesis and severity of the associated diseases. Here, we summarize the available evidence regarding these issues and discuss these findings in the light of recent knowledge about the conformational activation of the human β(2)-adrenoceptor and the properties of bona fide cardiopathogenic autoantibodies derived from immune-adsorption therapy of DCM patients. These considerations might contribute to the conception of therapy regimen aimed at counteracting or neutralizing cardiopathogenic receptor autoantibodies.

Figure 1

Modes of modulation of receptor conformation and function by autoantibodies. G-protein coupled receptors idle between various conformations with different abilities to couple to specific signalling pathways; orthosteric agonists act by stabilizing receptor conformations linked to one specific signalling pathway (A). Autoantibodies can act as direct allosteric agonists by mimicing agonists (B) or act as direct allosteric antagonists by blocking the agonist's binding site (C). Autoantibodies can act as allosteric modulators by promoting inactive (D) or active (E) conformations of the unliganded receptor thereby enhancing or attenuating subsequent agonist actions. Autoantibodies can act as allosteric modulators by inducing alternative receptor conformations that predispose for coupling to other signalling pathways (F). Autoantibodies can also modify agonist action by promoting receptor polymerization, which may enhance, redirect (G) or attenuate agonist action (H) depending on which receptor is targeted. Autoantibodies can activate as yet unknown cardiodepressive signalling pathways by cross-linking G-protein coupled receptors with Fc-receptors (I).