C1q binding to surface-bound IgG is stabilized by C1r 2 s 2 proteases

Proceedings of the National Academy of Sciences, vol. 118

Abstract

Significance Antibody-dependent complement activation plays a major role in various pathophysiological processes in our body, including infection, inflammation, autoimmunity, and transplant rejection. In order to activate complement, antibodies should bind to target cells and recruit complement component C1. C1 is a large, multimolecular complex that consists of the antibody recognition protein C1q and a heterotetramer of proteases (C1r 2 s 2 ). Although it is believed that interactions between C1 and IgGs are solely mediated by C1q, we here show that C1r 2 s 2 proteases affect the capacity of C1q to form an avid complex with surface-bound IgG molecules. Furthermore, we demonstrate that C1q–IgG stability is influenced by IgG oligomerization and that promoting IgG oligomerization improves phagocytosis of the pathogenic bacterium Staphylococcus aureus .

Authors 19

1. Seline A. Zwarthoff

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;

2. Kevin Widmer

   University of Basel

   Affiliation as printed

   Pharmaceutical Sciences, University of Basel, 4001 Basel, Switzerland;

3. Annemarie Kuipers

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;

4. Jürgen Strasser
   Affiliation as printed

   Nano Structuring and Bio-Analytics Group, TIMed Center, of Applied Sciences Upper Austria, 4020 Linz, Austria;

5. Maartje Ruyken

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;

6. Piet C. Aerts

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;

7. Carla J. C. de Haas

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;

8. Deniz Ugurlar

   Utrecht University

   Affiliation as printed

   Structural Biochemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands;

9. Maurits Arij den Boer

   Utrecht University · Netherlands Proteomics Centre

   Affiliation as printed

   Biomolecular Mass Spectrometry & Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, The Netherlands;

   Netherlands Proteomics Center, 3584 CH, Utrecht, The Netherlands;

10. Gestur Vidarsson

    Sanquin

    Affiliation as printed

    Experimental Immunohematology, Sanquin Research, 1066 CX Amsterdam, The Netherlands;

11. Jos A. G. van Strijp

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;

12. Piet Gros

    Utrecht University

    Affiliation as printed

    Structural Biochemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands;

13. Paul W.H.I. Parren Aachen Immunohematology and Blood Transfusion

    Leiden University Medical Center · Lava Therapeutics (Netherlands)

    Affiliation as printed

    Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;

    Lava Therapeutics, 3584 CM Utrecht, The Netherlands;

14. Kok P. M. van Kessel

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;

15. Johannes Preiner
    Affiliation as printed

    Nano Structuring and Bio-Analytics Group, TIMed Center, of Applied Sciences Upper Austria, 4020 Linz, Austria;

16. Frank J M Beurskens

    Genmab (Netherlands)

    Affiliation as printed

    Genmab, 3584 CT Utrecht, The Netherlands

17. Janine Schuurman

    Genmab (Netherlands)

    Affiliation as printed

    Genmab, 3584 CT Utrecht, The Netherlands

18. Daniel Ricklin

    University of Basel

    Affiliation as printed

    Pharmaceutical Sciences, University of Basel, 4001 Basel, Switzerland;

19. Suzan H. M. Rooijakkers corresponding

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;