Pathogenesis of lung injury mediated by lung-restricted antibodies

原发性移植物功能障碍（PGD）在术后24-72小时内影响超过50%的受者

Primary graft dysfunction (PGD) affects over 50% of recipients within the first 24-72 hours after lung transplantation. PGD is the dominant risk for post-lung transplant mortality, transplant-associated multi-organ dysfunction, and chronic lung allograft rejection. Since lung transplantation is increasingly utilized as a life-saving treatment for both chronic lung diseases as well as acute respiratory distress syndrome, mitigation of PGD represents a critical component of a multi-pronged strategy to improve transplant outcomes. In a prospective clinical study, we found that over 30% of patients undergoing lung transplantation have lung- restricted autoantibodies (LRA) against self-antigens, collagen type V and k-alpha 1 tubulin, which was strongly associated with the development of PGD. Pre-existing LRA is associated with complement activation, neutrophil recruitment, a lower PaO2/FIO2 and worsened lung injury, all clinical hallmarks of PGD. In parallel work, we identified an important role for donor derived non-classical monocytes (NCM) that are retained in the lung grafts after perfusion in the development of PGD. Donor derived NCM sense damage associated molecular patterns (DAMPs) via redundant signaling through TLR2/4 to release CXCL2 and other cytokines that directly recruit neutrophils to the allograft and activate donor alveolar macrophages to recruit recipient classical monocytes stored in the spleen. Upon migration to the lung graft, the recipient classical monocytes (CM) permeabilize the pulmonary endothelium and amplify the extravasation of neutrophils to the alveolar space. Our published and preliminary data suggest important interactions between LRA, donor derived NCM and recipient derived CM in determining the severity of lung injury after lung transplantation. Specifically, we found that LRA bind Fc receptors on donor derived NCM to promote their retention in the allograft and activation. This enhances the recruitment of CM to the allograft which release IL-1. Permeabilization of the endothelium in response to IL-1 allows LRA access to the lung interstitium and promotes neutrophil migration into the alveolar space. In addition, CM release matrix metalloproteinase-8 (MMP8), which cleaves extracellular matrix proteins to release sequestered self-antigens and expose their immunogenic epitopes, enabling the extravasated LRA to form immune complexes. The resulting immune complexes activate complement to exacerbate lung injury in the first 24 hours after lung transplantation. Further preliminary data suggest LRA immune complexes activate donor derived NCM to release CXCL2 and promote neutrophil recruitment via a pathway that requires Src, PI3K and BTK but is independent of the TLR2/4/MyD88 pathway activated by DAMPs, resulting in delayed lung injury in the 48 to 72 hours after transplant. We will test the hypothesis that LRA interact with donor derived NCM and recipient CM to worsen PGD via complement dependent and independent pathways. Aim 1. To determine the mechanisms through which LRA activate NCM. Aim 2. To determine the role of IL-1 and MMP-8 released from recipient CM in the cleavage of sequestered self-antigens and their binding to LRA.