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 July 30, 2020
Citation Information: J Clin Invest. 2020;130(11):5909-5923. https://doi.org/10.1172/JCI138136.
View: Text | PDF
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

×

Figure 7

High endothelial HLA class I expression in human lungs and complement activation after transfusion in clinical TRALI.

Options: View larger image (or click on image) Download as PowerPoint
High endothelial HLA class I expression in human lungs and complement ac...
Samples of human lungs were dissociated for measurement of cell surface HLA class I (HLA-ABC) expression using flow cytometry. (A) Gating strategy, (B) representative histograms of fully stained cells relative to FMO controls, and (C) quantification of HLA class I expression on different cells expressed as MFI (D–G) (n = 4). EC, endothelial cell. Plasma content of the classical/lectin pathway complement component C4 and its activation and degradation product C4d were measured using pre- and posttransfusion samples from patients diagnosed with TRALI or control patients who did not develop TRALI after transfusion. (D) Concentrations of C4d and (E) fold change in C4d after transfusion, and (F) C4d/C4 ratios and (G) fold change in C4d/C4 ratios after transfusion. Normalized data (E and G) provided for enhanced display of individual changes after transfusion. Mean (D and F, bars) or median (E and G, lines) and individual values (D and F). In D and F, a 2-way repeated-measures mixed-model approach was used with pretransfusion values set as covariates, followed by Holm’s multiplicity correction for comparisons of effect of TRALI development after transfusion and effect of transfusion within the control group and the TRALI group. Control group, n = 19; TRALI group, n = 9. P values < 0.05 are shown.