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

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: Saskia van der Velden, Thijs L J van Osch, Amina Seghier, Arthur E H Bentlage, Juk Yee Mok, Dionne M Geerdes, Wim J E van Esch, Richard B Pouw, Mieke C Brouwer, Ilse Jongerius, Masja de Haas, Leendert Porcelijn, C Ellen van der Schoot, Gestur Vidarsson, Rick Kapur
• Journal: Blood (Blood) Vol. 143 Issue 1 Pg. 79-91 (01 04 2024) ISSN: 1528-0020 [Electronic] United States
• PMID: 37801721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 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.

Chemical References

• Antibodies
• Complement System Proteins

Topics

• Humans
• Mice
• Animals
• Transfusion-Related Acute Lung Injury
• Extracellular Traps
• Lung
• Antibodies
• Macrophages
• Complement Activation
• Complement System Proteins