Functional Characterization of Autoantibodies against Complement Component C3 in Patients with Lupus Nephritis

Vasil V Vasilev,Remi Noe,Marie-Agnes Dragon-Durey,Sophie Chauvet,Valentin J Lazarov,Boriana P Deliyska,Veronique Fremeaux-Bacchi,Jordan D Dimitrov,Lubka T Roumenina

doi:10.1074/jbc.m115.647008

Abstract

Lupus nephritis (LN) is a complication of the autoimmune disease systemic lupus erythematosus. Because the complement system plays a critical role in orchestrating inflammatory and immune responses as well as in the clearance of immune complexes, autoreactivity to complement components may have considerable pathological consequences. Autoantibodies against the central complement component C3 have been reported in systemic lupus erythematosus, but their molecular mechanism and functional relevance are not well understood. The objective of this study was to evaluate the frequency and the functional properties of the anti-C3 autoantibodies. Anti-C3 autoantibodies were measured in plasma of 39 LN patients, and identification of their epitopes on the C3 molecule was performed. By using surface plasmon resonance, we analyzed the influence of patient-derived IgG antibodies on the interaction of C3b with Factor B, Factor H, and complement receptor 1. The capacity of these antibodies to dysregulate the C3 convertase on the surface of endothelial cell was measured by flow cytometry. Here we report that the frequency of anti-C3 autoantibodies in LN is ∼30%. They inhibited interactions of the negative complement regulators Factor H and complement receptor 1 with C3b. An enhanced C3 deposition was also observed on human endothelial cells in the presence of C3 autoantibodies. In addition, anti-C3 autoantibody levels correlated with disease activity. In conclusion, the anti-C3 autoantibodies in LN may contribute to the autoimmune pathology by their capacity to overactivate the complement system.

Highlights

Autoantibodies against complement C3 are found in patients with the autoimmune disease systemic lupus erythematosus
Prevalence of Anti-C3 Autoantibodies in Patients with Lupus nephritis (LN)— The screening revealed that 31% of the patients (12 of 39; Fig. 1A) and 33 of 84 samples were positive for anti-C3 antibodies
Correlation of the Anti-C3 Autoantibody Titers with Disease Activity—Anti-C3 autoantibodies were more frequent in the patients with severe disease, classified as category A according to the British Islet Lupus Assessment Group (BILAG) renal score, compared with patients with milder disease, classified as category B, C, or D (p ϭ 0.019; Fig. 2A)

Summary

Introduction

Autoantibodies against complement C3 are found in patients with the autoimmune disease systemic lupus erythematosus. Autoantibodies against the central complement component C3 have been reported in systemic lupus erythematosus, but their molecular mechanism and functional relevance are not well understood. By using surface plasmon resonance, we analyzed the influence of patient-derived IgG antibodies on the interaction of C3b with Factor B, Factor H, and complement receptor 1 The capacity of these antibodies to dysregulate the C3 convertase on the surface of endothelial cell was measured by flow cytometry. We report that the frequency of anti-C3 autoantibodies in LN is ϳ30% They inhibited interactions of the negative complement regulators Factor H and complement receptor 1 with C3b. The anti-C3 autoantibodies in LN may contribute to the autoimmune pathology by their capacity to overactivate the complement system

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Discussion

Conclusion