Autoantibodies Targeting G-Protein-Coupled Receptors: Pathogenetic, Clinical and Therapeutic Implications in Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is a multifaceted connective tissue disease whose aetiology remains largely unknown. Autoimmunity is thought to play a pivotal role in the development of the disease, but the direct pathogenic role of SSc-specific autoantibodies remains to be established. The recent discovery of functional antibodies targeting G-protein-coupled receptors (GPCRs), whose presence has been demonstrated in different autoimmune conditions, has shed some light on SSc pathogenesis. These antibodies bind to GPCRs expressed on immune and non-immune cells as their endogenous ligands, exerting either a stimulatory or inhibitory effect on corresponding intracellular pathways. Growing evidence suggests that, in SSc, the presence of anti-GPCRs antibodies correlates with specific clinical manifestations. Autoantibodies targeting endothelin receptor type A (ETAR) and angiotensin type 1 receptor (AT1R) are associated with severe vasculopathic SSc-related manifestations, while anti-C-X-C motif chemokine receptors (CXCR) antibodies seem to be predictive of interstitial lung involvement; anti-muscarinic-3 acetylcholine receptor (M3R) antibodies have been found in patients with severe gastrointestinal involvement and anti-protease-activated receptor 1 (PAR1) antibodies have been detected in patients experiencing scleroderma renal crisis. This review aims to clarify the potential pathogenetic significance of GPCR-targeting autoantibodies in SSc, focusing on their associations with the different clinical manifestations of scleroderma. An extensive examination of functional autoimmunity targeting GPCRs might provide valuable insights into the underlying pathogenetic mechanisms of SSc, thus enabling the development of novel therapeutic strategies tailored to target GPCR-mediated pathways.

Keywords: G-protein-coupled receptors; functional autoantibodies; organ involvement; systemic sclerosis.

Figure 1

Main correlations between functional antibodies targeting G-protein-coupled receptors (GPCRs) and distinct clinical manifestations in SSc. Autoantibodies against AT1R, ETAR/ETBR, CXCR3/4, and PAR1 amplify constitutive inflammatory responses via their signalling pathways. The release of mediators from smooth muscle cells and the accumulation of pro-inflammatory cytokines further contribute to severe vascular dysfunction (vasculopathy). Autoantibodies against M3R disrupt the neurotransmission required for gastrointestinal motility. AT1R, angiotensin receptor type 1; CXCR3/4, C-X-C motif chemokine receptor type 3/4; ETAR, endothelin receptor type A; ETBR, endothelin receptor type B; M3R, muscarinic acetylcholine receptor 3; PAR1, protease-activated receptor 1. Created with BioRender.com.