RT Journal Article
SR Electronic
T1 Induced antibodies directed to the angiotensin receptor type 1 provoke skin and lung inflammation, dermal fibrosis and act species overarching
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1281
OP 1289
DO 10.1136/annrheumdis-2021-222088
VO 81
IS 9
A1 Xiaoyang Yue
A1 Junping Yin
A1 Xiaoqing Wang
A1 Harald Heidecke
A1 Alexander Maximilian Hackel
A1 Xiaoru Dong
A1 Brigitte Kasper
A1 Lifang Wen
A1 Liang Zhang
A1 Kai Schulze-Forster
A1 Juliane Junker
A1 Hanna Grasshoff
A1 Antje Müller
A1 Gerd Wallukat
A1 Ingolf Schimke
A1 Julian Zeiner
A1 Lisa Marie Deckstein
A1 Nicole Mertens
A1 Anja Kerstein-Staehle
A1 Jennifer Elisabeth Hundt
A1 Evi Kostenis
A1 Xinhua Yu
A1 Gabriela Riemekasten
A1 Frank Petersen
YR 2022
UL http://ard.bmj.com/content/81/9/1281.abstract
AB Objective To determine contributions and functions of autoantibodies (Abs) directed to the angiotensin receptor type 1 (AT1R), which are suggested to be involved in the pathogenesis of AT1R Abs-related diseases such as systemic sclerosis (SSc).Methods C57BL/6J mice were immunised with membrane-embedded human AT1R or empty membrane as control. Mice deficient for CD4+ or CD8+ T cells and B cells were immunised with membrane-embedded AT1R or an AT1R peptide proposed to be a dominant T cell epitope. A monoclonal (m)AT1R Ab was generated by hybridoma technique and transferred into C57BL/6J and AT1Ra/b knockout mice. The induced phenotype was examined by histology, immunohistochemistry, immunofluorescence, apoptosis assay and ELISA. In vitro, Abs responses towards AT1R were measured in cells of different origins and species.Results AT1R-immunised mice developed perivascular skin and lung inflammation, lymphocytic alveolitis, weak lung endothelial apoptosis and skin fibrosis accompanied by Smad2/3 signalling, not present in controls or mice deficient for CD4+ T and B cells. The AT1R peptide 149–172 provoked lung inflammation. Application of the mAT1R Ab induced skin and lung inflammation, not observed in AT1Ra/b knockout mice. In vitro, AT1R Abs activated rat cardiomyocytes and human monocytes, enhanced angiotensin II-mediated AT1R activation in AT1R-transfected HEK293 cells via AT1R binding and mAT1R Ab-activated monocytes mediated the induction of profibrotic markers in dermal fibroblasts.Conclusion Our immunisation strategy successfully induced AT1R Abs, contributing to inflammation and, possibly, to fibrosis via activation of AT1R. Therefore, AT1R Abs are valuable targets for future therapies of SSc and other AT1R Ab-related diseases.Data are available upon reasonable request.