Complement activation on endothelium initiates antibody-mediated acute lung injury
Simon J. Cleary, … , James C. Zimring, Mark R. Looney
Simon J. Cleary, … , James C. Zimring, Mark R. Looney
Published October 12, 2020; First published July 30, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI138136.
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Research Article Immunology Pulmonology

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

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Figure 3

Spatially distinct retention of antibody, neutrophils, and platelets in the pulmonary vasculature during initiation of anti–MHC I–mediated lung injury.

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Spatially distinct retention of antibody, neutrophils, and platelets in ...
C57BL/6 (B6) or B6.H2d mice were given LPS i.p., 70 kDa FITC-dextran i.v. (green), and then i.v. injections of anti–H-2d–PE (magenta) during 2-photon lung intravital imaging. (A) Representative images of antibody deposition responses in B6.H2d pulmonary blood vessels and (B) quantification of anti–H-2d–PE signal in imaged regions of lungs over time (B6, n = 3; B6.H2d, n = 4). LysM-GFP × PF4-Cre × Ai14 mice (LysM+ cells, green; PF4+ platelets, red) were given LPS i.p., Evans blue i.v. (blue), and then i.v. injections of anti–H-2d or isotype control during 2-photon lung intravital imaging (n = 4). (C) Responses to anti–H-2d in a pulmonary blood vessel and quantification of (D) platelet and (E) LysM+ cell signal over time. (F) Surface renderings showing platelets associated with LysM+ cell surfaces (white) and those not (red). (G) Quantification of platelet signal from LysM+ cell–associated platelets and those not associated with LysM+ cells. Mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by 2-way ANOVA with P value for postbaseline effect of genotype (B), treatment (D and E), or LysM+ cell association (G).