Complement activation drives antibody-mediated transfusion-related acute lung injury via macrophage trafficking and formation of NETs

Blood, vol. 143, pp. 79–91

Abstract

ABSTRACT: Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion-related fatalities and, to date, is without available therapies. Here, we investigated the role of the complement system in TRALI. Murine anti-major histocompatibility complex class I antibodies were used in TRALI mouse models, in combination with analyses of plasma samples from patients with TRALI. We found that in vitro complement activation was related to in vivo antibody-mediated TRALI induction, which was correlated with increased macrophage trafficking from the lungs to the blood in a fragment crystallizable region (Fc)-dependent manner and that this was dependent on C5. Human immunoglobulin G 1 variants of the murine TRALI-inducing antibody 34-1-2S, either unable to activate complement and/or bind to Fcγ receptors (FcγRs), revealed an essential role for the complement system, but not for FcγRs, in the onset of 34-1-2S-mediated TRALI in mice. In addition, we found high levels of complement activation in the plasma of patients with TRALI (n = 53), which correlated with elevated neutrophil extracellular trap (NET) markers. In vitro we found that NETs could be formed in a murine, 2-hit model, mimicking TRALI with lipopolysaccharide and C5a stimulation. Collectively, this reveals a critical role of Fc-mediated complement activation in TRALI, with a direct relation to macrophage trafficking from the lungs to the blood and an association with NET formation, suggesting that targeting the complement system may be an attractive therapeutic approach for combating TRALI.

Authors 15

1. Saskia van der Velden

   Sanquin · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   1Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

2. Thijs L. J. van Osch

   Sanquin · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   1Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

3. Amina Seghier

   Sanquin · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   1Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

4. Arthur E. H. Bentlage

   Sanquin · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   1Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

5. Juk Yee Mok

   Sanquin

   Affiliation as printed

   2Sanquin Reagents, Amsterdam, The Netherlands

6. Dionne M. Geerdes

   Sanquin

   Affiliation as printed

   2Sanquin Reagents, Amsterdam, The Netherlands

7. Wim J.E. van Esch

   Sanquin

   Affiliation as printed

   2Sanquin Reagents, Amsterdam, The Netherlands

8. Richard B. Pouw

   Sanquin · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   3Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, The Netherlands

9. Mieke C. Brouwer

   Sanquin · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   3Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, The Netherlands

10. Ilse Jongerius

    Sanquin · Emma Kinderziekenhuis · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    3Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, The Netherlands

    4Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands

11. Masja de Haas Aachen 6Department of Immunohematology and Blood Transfusion

    Leiden University Medical Center · Sanquin · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    1Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    5Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands

    6Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, The Netherlands

12. Leendert Porcelijn

    Sanquin

    Affiliation as printed

    5Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands

13. C. Ellen van der Schoot

    Sanquin · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    1Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

14. Gestur Vidarsson

    Sanquin · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    1Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

15. Rick Kapur

    Sanquin · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    1Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands