Human anti-C1q autoantibodies bind specifically to solid-phase C1q and enhance phagocytosis but not complement activation

Author:

Dijkstra Douwe J.1ORCID,van de Bovenkamp Fleur S.12,Abendstein Leoni3ORCID,Zuijderduijn Rob1,Pool Jos1,Kramer Cynthia S. M.1ORCID,Slot Linda M.4,Drijfhout Jan W.1ORCID,de Vor Lisanne5ORCID,Gelderman Kyra A.6ORCID,Rooijakkers Suzan H. M.5ORCID,Zaldumbide Arnaud3ORCID,Vidarsson Gestur7ORCID,Sharp Thomas H.3ORCID,Parren Paul W. H. I.18ORCID,Trouw Leendert A.1ORCID

Affiliation:

1. Department of Immunology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands

2. Lava Therapeutics, Utrecht 3584 CM, The Netherlands

3. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands

4. Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands

5. Department of Medical Microbiology, University Medical Center, Utrecht 3584 CX, The Netherlands

6. Sanquin Diagnostic Services, Amsterdam 1066 CX, The Netherlands

7. Department of Experimental Immunohematology, Sanquin Research, Amsterdam 1066 CX, The Netherlands

8. Gyes BV, Naarden 1411 DC, The Netherlands

Abstract

Autoantibodies directed against complement component C1q are commonly associated with autoimmune diseases, especially systemic lupus erythematosus. Importantly, these anti-C1q autoantibodies are specific for ligand-bound, solid-phase C1q and do not bind to fluid-phase C1q. In patients with anti-C1q, C1q levels are in the normal range, and the autoantibodies are thus not depleting. To study these human anti-C1q autoantibodies at the molecular level, we isolated C1q-reactive B cells and recombinantly produced nine monoclonal antibodies (mAbs) from four different healthy individuals. The isolated mAbs were of the IgG isotype, contained extensively mutated variable domains, and showed high affinity to the collagen-like region of C1q. The anti-C1q mAbs exclusively bound solid-phase C1q in complex with its natural ligands, including immobilized or antigen-bound IgG, IgM or CRP, and necrotic cells. Competition experiments reveal that at least 2 epitopes, also targeted by anti-C1q antibodies in sera from SLE patients, are recognized. Electron microscopy with hexameric IgG-C1q immune complexes demonstrated that multiple mAbs can interact with a single C1q molecule and identified the region of C1q targeted by these mAbs. The opsonization of immune complexes with anti-C1q greatly enhanced Fc-receptor-mediated phagocytosis but did not increase complement activation. We conclude that human anti-C1q autoantibodies specifically bind neo-epitopes on solid-phase C1q, which results in an increase in Fc-receptor-mediated effector functions that may potentially contribute to autoimmune disease immunopathology.

Funder

EC | ERC | HORIZON EUROPE European Research Council

Leids Universitair Medisch Centrum

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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