PMID- 37801721 OWN - NLM STAT- MEDLINE DCOM- 20240105 LR - 20240324 IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 143 IP - 1 DP - 2024 Jan 4 TI - Complement activation drives antibody-mediated transfusion-related acute lung injury via macrophage trafficking and formation of NETs. PG - 79-91 LID - 10.1182/blood.2023020484 [doi] AB - 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 Fcgamma receptors (FcgammaRs), revealed an essential role for the complement system, but not for FcgammaRs, 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. CI - (c) 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies. FAU - van der Velden, Saskia AU - van der Velden S AUID- ORCID: 0000-0002-0809-1993 AD - Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. FAU - van Osch, Thijs L J AU - van Osch TLJ AUID- ORCID: 0000-0002-7566-2450 AD - Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. FAU - Seghier, Amina AU - Seghier A AD - Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. FAU - Bentlage, Arthur E H AU - Bentlage AEH AUID- ORCID: 0000-0002-7924-554X AD - Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. FAU - Mok, Juk Yee AU - Mok JY AD - Sanquin Reagents, Amsterdam, The Netherlands. FAU - Geerdes, Dionne M AU - Geerdes DM AD - Sanquin Reagents, Amsterdam, The Netherlands. FAU - van Esch, Wim J E AU - van Esch WJE AUID- ORCID: 0000-0002-7077-4349 AD - Sanquin Reagents, Amsterdam, The Netherlands. FAU - Pouw, Richard B AU - Pouw RB AUID- ORCID: 0000-0003-3469-8454 AD - Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, The Netherlands. FAU - Brouwer, Mieke C AU - Brouwer MC AD - Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, The Netherlands. FAU - Jongerius, Ilse AU - Jongerius I AD - Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, The Netherlands. AD - Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands. FAU - de Haas, Masja AU - de Haas M AD - Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. AD - Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands. AD - Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, The Netherlands. FAU - Porcelijn, Leendert AU - Porcelijn L AD - Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands. FAU - van der Schoot, C Ellen AU - van der Schoot CE AD - Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. FAU - Vidarsson, Gestur AU - Vidarsson G AUID- ORCID: 0000-0001-5621-003X AD - Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. FAU - Kapur, Rick AU - Kapur R AUID- ORCID: 0000-0002-1608-876X AD - Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antibodies) RN - 9007-36-7 (Complement System Proteins) SB - IM MH - Humans MH - Mice MH - Animals MH - *Transfusion-Related Acute Lung Injury MH - *Extracellular Traps MH - Lung MH - Antibodies MH - Macrophages MH - Complement Activation MH - Complement System Proteins EDAT- 2023/10/06 18:42 MHDA- 2024/01/05 06:42 CRDT- 2023/10/06 17:03 PHST- 2023/09/07 00:00 [accepted] PHST- 2023/03/15 00:00 [received] PHST- 2024/01/05 06:42 [medline] PHST- 2023/10/06 18:42 [pubmed] PHST- 2023/10/06 17:03 [entrez] AID - S0006-4971(23)02488-6 [pii] AID - 10.1182/blood.2023020484 [doi] PST - ppublish SO - Blood. 2024 Jan 4;143(1):79-91. doi: 10.1182/blood.2023020484.