Article
Decreased C5aR1 autoantibodies correlate with higher relapse rates in ANCA-associated vasculitis
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Published: | October 8, 2019 |
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Background: Activation of the alternative and final common pathway and in-situ deposition of components of the alternative pathway of complement have been shown in AAV. Circulating titers of the anaphylatoxin C5a are elevated and correlate with disease activity in AAV. Blocking of the receptor C5aR was protective in a murine model of NCGN in AAV. So far, autoantibodies targeting complement receptors C3a and C5a have not been analyzed in patients with AAV.
Methods: To determine circulating autoantibodies against complement receptors C3a (anti-C3aR aab) and C5a (anti-C5aR1 aab) and analyze their diagnostic and/or prognostic value, sera and plasma of patients with AAV [granulomatosis with polyangiitis (GPA), n=61; microscopic polyangiitis (MPA), n=26; eosinophilic granulomatosis with polyangiitis (EGPA), n=6] were measured by Elisa for antibody titers and plasma levels of C3a and C5a. Further, expression of C3aR and C5aR1 on T-cells and neutrophils was determined using flow cytometry. Clinical data including vasculitis scores BVAS V3.0 and VDI, inflammatory markers (ESR, C-reactive protein, creatinine), diagnostic autoantibodies (anti-MPO, anti-PR3) and treatment were assessed at the time of serum sampling and during follow-up for 48 months. The aim of this study was to determine if circulating autoantibodies directed against complement receptor C3a (anti-C3aR) and C5a (anti-C5aR1) are present and of diagnostic and/or prognostic value in AAV. Thus, sera and plasma of patients with AAV [n=93; granulomatosis with polyangiitis (GPA), n=61; microscopic polyangiitis (MPA), n=26; eosinophilic granulomatosis with polyangiitis (EGPA), n=6] were measured by Elisa for antibody levels and plasma levels of C3a and C5a. Further, expression of C3aR and C5aR on T-cells and neutrophiles were determined using flow cytometry. Clinical data (BVASv.3, VDI, therapy), inflammatory markers (ESR, C-reactive protein, creatinine) and diagnostic autoantibodies (anti-MPO, anti-PR3) were gathered at the time of serum sampling and follow up to 48 months.
Results: GPA patients displayed significantly lower titers of circulating anti-C3aR aab in comparison to MPA, EGPA and HC (GPA:5.33±0.34 vs. HC:6.47±0.18, p=0.0033). Further, concentrations of anti-C5aR1 aab were decreased in AAV with the lowest titres in GPA compared to HC (AAV:1.03±0.15 vs. HC:6.63±0.19, p=<0.0001). AAV patients without a history of cyclophosphamide and/or rituximab treatment showed a negative correlation between the concentration of anti-C5aR1 aab and disease activity (BVAS V.3.0; Spearman r=-0.39, p=0.0264). The expression of C5aR1 was increased on CD4+ T-cells in GPA and MPA compared to HC and on CD8+ T-cells in GPA (CD4+C5aR1+T-cells: GPA 10.76±2.55 vs. HC 3.44±0.68, p=0.0021; MPA 6.674±0.77, p=0.0404; CD8+C5aR1+T-cells GPA 9.74±2.10 vs. HC 4.11±0.92, p=0.0198). AAV patients with reduced titers of anti-C5aR1 aab <0.45U/ml displayed an increased relapse risk for major organ involvement (HR 8.428, p=0.0005).
Conclusion: The findings of our study suggest distinct roles for anti-C3aR and anti-C5aR1 aab in AAV. As a potential diagnostic marker, anti-C5aR1 aab titer may be additionally useful to monitor disease activity.