Involvement of functional autoantibodies against vascular receptors in systemic sclerosis

Gabriela Riemekasten, Aurélie Philippe, Melanie Näther, Torsten Slowinski, Dominik N. Müller, Harald Heidecke, Marco Matucci-Cerinic, László Czirják, Ivo Lukitsch, Mike Becker, Angela Kill, Jacob M. Van Laar, Rusan Catar, Friedrich C. Luft, Gerd R. Burmester, Björn Hegner, Duska Dragun*

*Korrespondierende/r Autor/-in für diese Arbeit
175 Zitate (Scopus)

Abstract

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-AT 1R 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. AT 1R and ETAR autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.

OriginalspracheEnglisch
ZeitschriftAnnals of the Rheumatic Diseases
Jahrgang70
Ausgabenummer3
Seiten (von - bis)530-536
Seitenumfang7
ISSN0003-4967
DOIs
PublikationsstatusVeröffentlicht - 03.2011

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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