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Involvement of functional autoantibodies against vascular receptors in systemic sclerosis

Lookup NU author(s): Professor Jaap Van Laar

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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 (AT(1)R) 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(1)R 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 beta gene expression in endothelial cells which could be blocked with specific receptor antagonists. Conclusions Functional autoimmunity directed at AT(1)R and ETAR is common in patients with SSc. AT(1)R and ETAR autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.


Publication metadata

Author(s): Riemekasten G, Philippe A, Nather M, Slowinski T, Muller DN, Heidecke H, Matucci-Cerinic M, Czirjak L, Lukitsch I, Becker M, Kill A, van Laar JM, Catar R, Luft FC, Burmester GR, Hegner B, Dragun D

Publication type: Article

Publication status: Published

Journal: Annals of the Rheumatic Diseases

Year: 2011

Volume: 70

Issue: 3

Pages: 530-536

Print publication date: 01/03/2011

ISSN (print): 0003-4967

ISSN (electronic): 1468-2060

Publisher: BMJ Group

URL: http://dx.doi.org/10.1136/ard.2010.135772

DOI: 10.1136/ard.2010.135772


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Funding

Funder referenceFunder name
Bundesministerium fur Bildung und Forschung
German Scleroderma Foundation (DSS)
German systemic sclerosis Network (DNSS)
Pfizer
Actelion
Charite Universitatsmedizin Berlin
Deutsche Forschungsgemeinschaft
BMBF Fkz 01 GM 0310Bundesministerium fur Bildung und Forschung (BMBF)
C6Bundesministerium fur Bildung und Forschung (BMBF)
DNSSBundesministerium fur Bildung und Forschung (BMBF)
TP6Bundesministerium fur Bildung und Forschung (BMBF)

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