TY - JOUR
T1 - Human anti-C1q autoantibodies bind specifically to solid-phase C1q and enhance phagocytosis but not complement activation
AU - Dijkstra, Douwe J.
AU - van de Bovenkamp, Fleur S.
AU - Abendstein, Leoni
AU - Zuijderduijn, Rob
AU - Pool, Jos
AU - Kramer, Cynthia S. M.
AU - Slot, Linda M.
AU - Drijfhout, Jan W.
AU - de Vor, Lisanne
AU - Gelderman, Kyra A.
AU - Rooijakkers, Suzan H. M.
AU - Zaldumbide, Arnaud
AU - Vidarsson, Gestur
AU - Sharp, Thomas H.
AU - Parren, Paul W. H. I.
AU - Trouw, Leendert A.
N1 - Funding Information: ACKNOWLEDG?ENTS.Wethankthepatients,donors,doctors,andothertechnical staff in the Leiden University Medical Center (LUMC) for providing the samples.We are grateful to Nicole Thielens for supplying C1q CLR and GH domains. We thank Maartje Ruyken (University Medical Center Utrecht) for assistance in phagocytosis experiments. Furthermore, we thank the Flow Cytometry Core Facility of the LUMC for their help in cell sorting and flow cytometry experiments and Joost Bakker for aid in visualization. The project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 101001937, ERC-ACCENT) to S.H.M.R., and from the LUMC Research profile: Immunity, Infection and Tolerance to L.A.T. Publisher Copyright: © 2023 National Academy of Sciences. All rights reserved.
PY - 2023/12/12
Y1 - 2023/12/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85178592784&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.2310666120
DO - https://doi.org/10.1073/pnas.2310666120
M3 - Article
C2 - 38048459
SN - 0027-8424
VL - 120
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
IS - 50
M1 - e2310666120
ER -