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Autoantibodies against Complement C1q Specifically Target C1q Bound on Early Apoptotic Cells¹

Cornelia Bigler^2,*, Monica Schaller^*, Iryna Perahud^*, Michael Osthoff^*, and Marten Trendelenburg^*,

^* Clinical Immunology Laboratory, University Hospital Basel, Basel, Switzerland; and Internal Medicine, University Hospital Basel, Basel, Switzerland

Autoantibodies against complement C1q (anti-C1q) are frequently found in patients with systemic lupus erythematosus (SLE). They strongly correlate with the occurrence of severe lupus nephritis, suggesting a pathogenic role in SLE. Because anti-C1q are known to recognize a neoepitope on bound C1q, but not on fluid-phase C1q, the aim of this study was to clarify the origin of anti-C1q by determining the mechanism that renders C1q antigenic. We investigated anti-C1q from serum and purified total IgG of patients with SLE and hypocomplementemic urticarial vasculitis as well as two monoclonal human anti-C1q Fab from a SLE patient generated by phage display. Binding characteristics, such as their ability to recognize C1q bound on different classes of Igs, on immune complexes, and on cells undergoing apoptosis, were analyzed. Interestingly, anti-C1q did not bind to C1q bound on Igs or immune complexes. Neither did we observe specific binding of anti-C1q to C1q bound on late apoptotic/necrotic cells when compared with binding in the absence of C1q. However, as shown by FACS analysis and confocal microscopy, anti-C1q specifically targeted C1q bound on early apoptotic cells. Anti-C1q were found to specifically target C1q bound on cells undergoing apoptosis. Our observations suggest that early apoptotic cells are a major target of the autoimmune response in SLE and provide a direct link between human SLE, apoptosis, and C1q.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ M.T. is a recipient of a SCORE fellowship from the Swiss National Foundation (3232B0-107248/1 and 3200B0-107249/1) and was supported by a grant from the Novartis Foundation for Medical and Biological Research.

² Address correspondence and reprint requests to Dr. Cornelia Bigler, Laboratory for Clinical Immunology, Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. E-mail address: cornelia.bigler{at}unibas.ch

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; 7-AAD, 7-aminoactinomycin D; DC, dendritic cell; HAGG, heat-aggregated IgG; HUVS, hypocomplementemic urticarial vasculitis syndrome; IC, immune complex; NHS, normal human serum.

⁴ The online version of this article contains supplemental material.