Complement activation on endothelium initiates antibody-mediated acute lung injury.

Abstract

Antibodies targeting human leukocyte antigen (HLA)/major histocompatibility complex (MHC) proteins limit successful transplantation and transfusion, and their presence in blood products can cause lethal transfusion-related acute lung injury (TRALI). It is unclear which cell types are bound by these anti-leukocyte antibodies to initiate an immunologic cascade resulting in lung injury. We therefore conditionally removed MHC class I (MHC I) from likely cellular targets in antibody-mediated lung injury. Only the removal of endothelial MHC I reduced lung injury and mortality, related mechanistically to absent endothelial complement fixation and lung platelet retention. Restoration of endothelial MHC I rendered MHC I-deficient mice susceptible to lung injury. Neutrophil responses, including neutrophil extracellular trap (NET) release, were intact in endothelial MHC I-deficient mice, whereas complement depletion reduced both lung injury and NETs. Human pulmonary endothelial cells showed high HLA class I expression, and posttransfusion complement activation was increased in clinical TRALI. These results indicate that the critical source of antigen for anti-leukocyte antibodies is in fact the endothelium, which reframes our understanding of TRALI as a rapid-onset vasculitis. Inhibition of complement activation may have multiple beneficial effects of reducing endothelial injury, platelet retention, and NET release in conditions where antibodies trigger these pathogenic responses.

• Authors: Simon J Cleary, Nicholas Kwaan, Jennifer J Tian, Daniel R Calabrese, Beñat Mallavia, Mélia Magnen, John R Greenland, Anatoly Urisman, Jonathan P Singer, Steven R Hays, Jasleen Kukreja, Ariel M Hay, Heather L Howie, Pearl Toy, Clifford A Lowell, Craig N Morrell, James C Zimring, Mark R Looney
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 11 Pg. 5909-5923 (11 02 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 32730229 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Histocompatibility Antigens Class I
• Isoantibodies

Topics

• Animals
• Cell Line
• Complement Activation (immunology)
• Endothelium (immunology, pathology)
• Extracellular Traps (immunology)
• Histocompatibility Antigens Class I (immunology)
• Isoantibodies (immunology)
• Mice
• Mice, Inbred BALB C
• Neutrophils (immunology, pathology)
• Transfusion-Related Acute Lung Injury (immunology, pathology)