Background:Activation of the alternative and final common pathways have been shown in ANCA-associated vasculitis (AAV) (1). Circulating titers of C5a are elevated and correlate with disease activity in AAV. Binding to the corresponding G protein-coupled receptor (GPCR) C5aR1 enhances the influx of neutrophils, leading to ROS generation and severe necrotizing of vascular walls (2). Moreover, subsequent interaction of C5a with C5aR1 may represent a proinflammatory amplification loop (3). Blocking of the receptor is protective in a murine model in AAV (4). In humans, avacopan, a C5aR1-inhibitor showed promising results as glucocorticoid-sparing agent in two randomized phase II and one ongoing phase III clinicals trials in AAV (NCT02994927). Notably, disease-specific anti-GPCR autoantibody (aab) signatures have been found in different autoimmune diseases (5).Objectives:The aim of the present study was to examine whether (patho)physiological anti-C3aR and anti-C5aR1 aabs correlate with clinical findings in AAV, and whether this is linked to the clinical outcome.Methods:Sera and plasma of AAV patients [granulomatosis with polyangiitis (GPA), n=64; microscopic polyangiitis (MPA), n=26; eosinophilic granulomatosis with polyangiitis (EGPA), n=11] were measured by Elisa for circulating autoantibodies against complement receptors C3a (anti-C3aR aab) and C5a (anti-C5aR1 aab) and plasma levels of C3a and C5a. Expression of C3aR and C5aR1 on T-cells was determined using flow cytometry. Clinical data were assessed at the time of serum sampling and during follow-up for 48 monthsResults:GPA displayed low titers of anti-C3aR aab (GPA:5.33±2.54vs. HD:6.47±2.61, P=0.0031). Anti-C5aR1 aab were decreased in AAV, especially in GPA (GPA:1.02±1.07vs. HD:6.63±2.91, P=<0.0001). Plasma levels of C5a and anti-C5aR aab yielded an inverse correlation in AAV (r=-0.6813, P=0.0127). C5aR1 expression was increased on T-cells in GPA (CD4+C5aR1+T-cells: GPA:10.76±2.55%vs. HD:3.44±0.68%, P=0.0021; CD8+C5aR1+T-cells GPA:9.74±2.10%vs.HD:4.11±0.92%, P=0.0198). Reduced titers of anti-C5aR1 aab <0.45U/ml displayed an increased relapse risk for major organ involvement in GPA (HR 12.85, P=0.0014).Conclusion:As potential diagnostic marker, anti-C5aR1 aab titer may additionally be useful to monitor disease activity in AAV.References:[1]Chen M et al.Complement deposition in renal histopathology of patients with ANCA-associated pauci-immune glomerulonephritis.Nephrol Dial Transpl. 2009;24:1247-1252[2]Schreiber A et al.C5a receptor mediates neutrophil activation an ANCA-induced glomerulonephritis.J Am Soc Nephrol. 2009; 20:289-298[3]Lamprecht P et al.: Pathogenetic and clinical aspects of Anti-Neutrophil Cytoplasmic Autoantibody-associated vasculitides.Front Immunol.2018 Apr 9;9-680[4]Xiao H et al.C5a receptor (CD88) blockade protects against MPO-ANCA GN.J Am Soc Nephrol. 2014;25(2):225-31[5]Klapa S et al. Decreased endothelin receptor A autoantibody levels are associated with early ischaemic events in patients with giant-cell arteritis.Ann Rheum Dis2019 Oct;78(19):1443-1444Disclosure of Interests:Sebastian Klapa Grant/research support from: Actelion, Consultant of: Pfizer, Abbvie, Antje Müller: None declared, Andreas Koch: None declared, Anja Kerstein-Staehle: None declared, Wataru Kaehler: None declared, Harald Heidecke Shareholder of: Cell Trend GmbH, Employee of: Cell Trend GmbH, Speakers bureau: Cell Trend GmbH, Susanne Schinke Speakers bureau: Pfizer, Markus Huber-Lang: None declared, Martin Nitschke: None declared, Silke Pitann: None declared, Christian Karsten: None declared, Gabriela Riemekasten Consultant of: Cell Trend GmbH, Janssen, Actelion, Boehringer Ingelheim, Speakers bureau: Actelion, Novartis, Janssen, Roche, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Peter Lamprecht: None declared
Regulation of elastase and plasminogen activator secretion in resident and inflammatory macrophages by receptors for the Fc domain of immunoglobulin G.
