Complement activation on endothelium initiates antibody-mediated acute lung injury
Complement activation on endothelium initiates antibody-mediated acute lung injury
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DOI：
10.1172/jci138136
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发表时间：
2020-11-02
影响因子：
15.9
通讯作者：
Looney, Mark R.
中科院分区：
文献类型：
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作者：
Cleary, Simon J.;Kwaan, Nicholas;Looney, Mark R.
针对人白细胞抗原(HLA)/主要组织相容性复合体（MHC）蛋白的抗体限制了移植和输血的成功，它们在血液制品中的存在可导致致命的输血相关急性肺损伤（TRALI）。目前尚不清楚哪种细胞类型与这些抗白细胞抗体结合，从而引发免疫级联反应，导致肺损伤。因此，我们有条件地从抗体介导的肺损伤的可能细胞靶标中去除MHC I类（MHC I）。只有去除内皮细胞MHC I才能减少肺损伤和死亡率，这与缺乏内皮补体固定和肺血小板保留的机制有关。修复内皮细胞MHC我渲染MHC ！缺陷小鼠易受肺损伤。中性粒细胞反应，包括中性粒细胞胞外陷阱（NET）释放，在内皮型MHC i缺陷小鼠中是完整的，而补体消耗减少了肺损伤和NET。人肺内皮细胞表现出高HLA I类表达，临床TRALI患者输血后补体活化增加。这些结果表明，抗白细胞抗体的关键抗原来源实际上是内皮，这重新定义了我们对TRALI作为一种快速发作的血管炎的理解。在抗体触发这些致病反应的情况下，抑制补体活化可能具有多种有益作用，如减少内皮损伤、血小板滞留和NET释放。
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 antibodymediated 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 !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.