When natural antibodies become pathogenic: autoantibodies targeted against G protein-coupled receptors in the pathogenesis of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a chronic, multisystem connective tissue, and autoimmune disease with the highest case-specific mortality and complications among rheumatic diseases. It is characterized by complex and variable features such as autoimmunity and inflammation, vasculopathy, and fibrosis, which pose challenges in understanding the pathogenesis of the disease. Among the large variety of autoantibodies (Abs) present in the sera of patients suffering from SSc, functionally active Abs against G protein-coupled receptors (GPCRs), the most abundant integral membrane proteins, have drawn much attention over the last decades. These Abs play an essential role in regulating the immune system, and their functions are dysregulated in diverse pathological conditions. Emerging evidence indicates that functional Abs targeting GPCRs, such as angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR), are altered in SSc. These Abs are part of a network with several GPCR Abs, such as those directed to the chemokine receptors or coagulative thrombin receptors. In this review, we summarize the effects of Abs against GPCRs in SSc pathologies. Extending the knowledge on pathophysiological roles of Abs against GPCRs could provide insights into a better understanding of GPCR contribution to SSc pathogenesis and therefore help in developing potential therapeutic strategies that intervene with pathological functions of these receptors.

Keywords: G protein-coupled receptor; autoantibodies; autoimmunity; inflammation; systemic sclerosis.

Figure 1

Pathogenesis of systemic sclerosis (SSc) and contribution of G-protein coupled receptors (GPCRs). The interplay between vasculopathy, autoimmunity, and fibrosis delineates the cardinal features of SSc pathogenesis. A microvascular injury is an early event in SSc that cause vascular pathologies such as vascular remodeling. Progressive vascular damage results in apoptosis, and dysregulation of the immune system (autoimmunity), where autoantibodies against various targets including GPCRs as well as proinflammatory cytokines are produced. Autoantibodies against GPCRs activate these receptors that amplify the inflammatory responses through their signaling pathway. Releasing mediators from smooth muscle cells and accumulating inflammatory cells cause severe vascular dysfunction (vasculopathy). Further endothelial damage and fibroblast conversion to the myofibroblast and extracellular matrix (ECM) deposition initiate the fibrotic process (fibrosis), which causes vessel stenosis and obliteration.

Figure 2

Functional autoantibodies against directed various GPCRs in systemic sclerosis (SSc). Autoantibodies against angiotensin II type 1 receptor (AT1R), endothelin-1 type A receptor (ETAR), C-X-C motif chemokine receptor 3 (CXCR3), CXCR4, protease-activated receptor-1 (PAR-1), and Muscarinic-3 Acetylcholine Receptor (M3R) have so far identified in SSc that can activate the respective receptors on endothelial cells and engage signaling pathway that regulates the transcription of several genes, such as increased gene expression of adhesion molecules, proinflammatory cytokines, and proteins of extracellular matrix (ECM). Interaction between the receptors (heterodimerization) such as AT1R and ETAR mediate receptor hypersensitization that may increase their sensitivity to the natural ligands.