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

Douwe J Dijkstra, Fleur S van de Bovenkamp, Leoni Abendstein, Rob Zuijderduijn, Jos Pool, Cynthia S M Kramer, Linda M Slot, Jan W Drijfhout, Lisanne de Vor, Kyra A Gelderman, Suzan H M Rooijakkers, Arnaud Zaldumbide, Gestur Vidarsson, Thomas H Sharp, Paul W H I Parren, Leendert A Trouw

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e2310666120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number50
Early online date4 Dec 2023
DOIs
Publication statusPublished - 12 Dec 2023

Keywords

  • Humans
  • Autoantibodies
  • Complement C1q
  • Antigen-Antibody Complex
  • Autoimmune Diseases
  • Lupus Erythematosus, Systemic
  • Complement Activation
  • Phagocytosis
  • Epitopes
  • Immunoglobulin G

Fingerprint

Dive into the research topics of 'Human anti-C1q autoantibodies bind specifically to solid-phase C1q and enhance phagocytosis but not complement activation'. Together they form a unique fingerprint.

Cite this