We also found distinct pathways leading to lung platelet retention and neutrophil extracellular trap (NET) formation, and an intervention that prevents immunologic injury to the lung. Combining insights from genetic and pharmacological studies with intravital lung microscopy, we were able to identify the site of antibody binding critical for lung injury. To support findings in mice with conditional MHC I removal, we also developed a new mouse strain enabling lineage-restricted restoration of B2m expression in order to study the effect of restoring MHC I exclusively on one cell type. In this manner, MHC I proteins were selectively removed from the surface of each of the cell types likely to be bound by antibody following intravenous infusion: endothelial cells, different myeloid leukocyte subsets, or the megakaryocyte-platelet lineage. The B2m gene encodes β-2-microglobulin (B2m), which is required for surface expression of MHC I proteins ( 10, 11). To accomplish this aim, we first used a genetic approach for lineage-restricted deletion of B2m ( 9). In this study, we aimed to identify the critical binding site of the antibody initiating lung injury in a mouse model of anti–MHC class I–mediated (anti–MHC I–mediated) TRALI, and then to determine the immediate downstream immunologic events leading to lung barrier disruption. In fact, a case report describing graft-localized TRALI in a unilateral lung transplant recipient transfused with blood containing lung donor–specific anti–HLA class I antibodies ( 7), and an irradiation and bone marrow reconstitution study in mice ( 8), point toward antibody binding to a nonhematopoietic cell as a probable initiating event in TRALI. However, nonleukocytic cells also express HLAs.
TRALI is classically associated with anti-granulocyte antibodies ( 5), and the binding of antibodies to monocytes has also been suggested to be critical for induction of anti–HLA class II–mediated TRALI ( 6). It also remains unclear how anti-HLA antibodies induce microvascular pathology and lung injury, and there is additional unmet need for improved pathological understanding to drive therapeutic innovation for anti-HLA–mediated rejection of solid organ transplants ( 4).Ī major unresolved issue in TRALI pathogenesis research has been determining the site of antibody binding required for initiation of lung injury. Research into the mechanistic basis of TRALI has directly led to successful mitigation strategies including exclusion from the donor pool of high plasma volume products from previously pregnant donors who have a high incidence of anti-HLA antibody positivity ( 2) however, substantial risk remains ( 3). One complication known to arise from anti-HLA antibodies is a leading cause of mortality from blood transfusions - transfusion-related acute lung injury (TRALI), a noncardiogenic form of pulmonary edema developing within 6 hours of transfusion ( 1). Human leukocyte antigens (HLAs), the major histocompatibility complex (MHC) proteins in humans, are frequently the targets of antibodies that are a major barrier to the success of blood transfusion and organ transplantation therapies. 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. 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. Human pulmonary endothelial cells showed high HLA class I expression, and posttransfusion complement activation was increased in clinical TRALI. 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. Restoration of endothelial MHC I rendered MHC I–deficient mice susceptible to 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.
We therefore conditionally removed MHC class I (MHC I) from likely cellular targets in antibody-mediated lung injury. It is unclear which cell types are bound by these anti-leukocyte antibodies to initiate an immunologic cascade resulting in lung injury. 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).
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