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To examine concentrations of circulating antibodies targeting C3a and C5a complement receptors in ANCA-associated vasculitis (AAV) and analyze their association with disease activity.Concentrations of antibodies against C3a and C5a complement receptors and plasma complement fragments C3a and C5a were determined in patients with AAV (n = 110; granulomatosis with polyangiitis [GPA, n = 82], microscopic polyangiitis [MPA, n = 28]), systemic lupus erythematosus as disease control (SLE, n = 36) and healthy donors (HD, n = 220). C3aR and C5aR expression by circulating neutrophils, monocytes and T cells was analyzed using flow cytometry. Clinical data were assessed at time of serum sampling and during follow-up for 60 months.In AAV, anti-C3aR and anti-C5aR antibodies were decreased (P = 0.0026 and ≤ 0.0001, respectively). In remission, anti-C3aR antibody concentrations rose to values comparable to HD, whereas anti-C5aR antibody concentrations did not. In GPA, C5a and anti-C5aR antibody concentrations inversely correlated with each other (r = -0.6831, P = 0.0127). In newly diagnosed GPA, decreased concentrations of anti-C5aR antibodies but not anti-C3aR antibodies were associated with disease activity (P = 0.0009). Moreover, low anti-C5aR antibodies were associated with relapse in GPA (HR: 3.54, P = 0.0009) and MPA (HR: 4.41, P = 0.0041). The frequency of C5aR-expressing cells within T cell populations was increased in GPA (CD4+ T cells: P = 0.0021; CD8+ T cells: P = 0.0118), but not in MPA.Low concentrations of anti-C5aR antibodies reflect disease activity and are associated with an increased risk for relapse in AAV. This article is protected by copyright. All rights reserved.

ObjectiveTo 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).MethodsC57BL/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.ResultsAT1R-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.ConclusionOur 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.