Receptor-activating autoantibodies and disease: preeclampsia and beyond

Abstract

The research reviewed in this article provides examples of autoantibody-mediated receptor activation that likely contributes to disease. The classic example is Graves' hyperthyroidism, in which autoantibodies activate the thyroid-stimulating hormone receptor resulting in overproduction of thyroid hormones. Other compelling examples come from the cardiovascular literature and include agonistic autoantibodies targeting the cardiac β(1)-adrenergic receptor, which are associated with dilated cardiomyopathy. Autoantibodies capable of activating α(1)-adrenergic receptors are associated with refractory hypertension and cardiomyopathy. A prominent example is preeclampsia, a hypertensive disease of pregnancy, characterized by the presence of autoantibodies that activate the major angiotensin receptor, AT(1). AT(1) receptor-activating autoantibodies are also observed in kidney transplant recipients suffering from severe vascular rejection and malignant hypertension. AT(1) receptor-activating autoantibodies and antibodies that activate the endothelin-1 receptor, ET(A), are prevalent in individuals diagnosed with systemic sclerosis. Thus, the presence of agonistic autoantibodies directed to G protein-coupled receptors has been observed in numerous cardiovascular disease states. Rapidly emerging evidence indicates that receptor-activating autoantibodies contribute to disease, and that efforts to detect and remove these pathogenic autoantibodies or block their actions will provide promising therapeutic possibilities.

Figure 1. Thyroid-stimulating hormone receptor subunit structure with bound ligand

Thyroid-stimulating hormone receptor (TSHR) has an unusually large extracellular domain consisting of nine leucine-rich repeats that form a horseshoe-like structure that binds thyroid-stimulating hormone. Upon proteolytic cleavage resulting in the loss of approximately 50 amino acid residues (~316–366), TSHR forms a two-subunit structure (α and β) linked by disulfide bonds. Adapted with permission from [105].

Figure 2. Cardiovascular receptor-agonistic autoantibodies contribute to cardiovascular disease

AT₁, ET_A, α₁- and β₁-adrenergic receptors are important cardiovascular GPCRs that regulate cardiac function and blood pressure via activation by their respective ligands (Ang II, ET-1 and norepinephrine, respectively). In recent years, GPCR-AAs have been associated with multiple cardiovascular disorders and autoantibody titers correlated with disease severity. Additional evidence reviewed here supports a contributing role for these autoantibodies in disease pathogenesis. These findings highlight these pathogenic autoantibodies as potentially important presymptomatic biomarkers and therapeutic targets in the medical management of these diseases. AA: Activating autoantibody; GPCR: G protein-coupled receptor.

Figure 3. Angiotensin receptor agonistic autoantibodies induce multiple features of preeclampsia in pregnant mice via AT₁ receptor activation

Recent evidence indicates that AT₁-AA injection into pregnant rodents (mice or rats) results in multiple feature of preeclampsia, including IUGR. This experimental model of autoantibody-induced preeclampsia and IUGR in pregnant rodents provides important experimental opportunities to test the ability of various strategies to prevent or reverse autoantibody-induced clinical features associated with preeclampsia. AT₁-AA: Angiotensin receptor agonistic autoantibody; AT₁R: Angiotensin II receptor; IUGR: Intrauterine growth retardation.