Background Systemic sclerosis (SSc) features autoimmunity, vasculopathy and tissue fibrosis. The renin-angiotensin and endothelin systems have been implicated in vasculopathy and fibrosis. A role for autoantibody-mediated receptor stimulation is hypothesised, linking three major pathophysiological features consistent with SSc.
Methods Serum samples from 478 patients with SSc (298 in the study cohort and 180 from two further independent cohorts), 372 healthy subjects and 311 control-disease subjects were tested for antibodies against angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) by solid phase assay. Binding specificities were tested by immunoprecipitation. The biological effects of autoantibodies in microvascular endothelial cells in vitro were also determined, as well as the quantitative differences in autoantibody levels on specific organ involvements and their predictive value for SSc-related mortality.
Results Anti-AT1R and anti-ETAR autoantibodies were detected in most patients with SSc. Autoantibodies specifically bound to respective receptors on endothelial cells. Higher levels of both autoantibodies were associated with more severe disease manifestations and predicted SSc-related mortality. Both autoantibodies exert biological effects as they induced extracellular signal-regulated kinase 1/2 phosphorylation and increased transforming growth factor β gene expression in endothelial cells which could be blocked with specific receptor antagonists.
Conclusions Functional autoimmunity directed at AT1R and ETAR is common in patients with SSc. AT1R and ETAR autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.
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↵* EUSTAR investigators
Funding CellTrend provided support for the study by their unrestricted serum analyses. The study was also supported by the intramural grant of Charité Universitätsmedizin Berlin, by the Bundesministerium für Bildung und Forschung (BMBF)-funded German Systemic Sclerosis Network (DNSS, BMBF Fkz 01 GM 0310, C6, TP6) and German Scleroderma Foundation (DSS).
Competing interests HH is owner of the company CellTrend that has developed the assays together with GR, DNM and DD. Actelion, Pfizer and GSK have provided lecture fees for GR and DD. GR is member of the advisory board for Actelion, GSK and partially for Pfizer and she has received lecture fees from these companies. DD received travel grants from Actelion and lecture fees from Pfizer.
Ethical approval Written informed consent to use serum samples for research purposes was obtained from each patient. The institutional review boards of Charité University Hospital, Berlin and University Hospitals in Florence and Pecs approved the study.
Provenance and peer review Not commissioned; externally peer reviewed.