title: Endothelial molecules decipher the mechanisms and functional pathways in antibody-mediated rejection.
abstract: Microvascular endothelium is the main target of injury in antibody-mediated rejection of human organ transplants. Hence, antibody-mediated rejection histologically presents with microvascular inflammation (pulmonary or myocardial or peritubular capillaritis, glomerulitis), thrombosis, and endothelial remodeling (duplication and/or multilayering of glomerular and capillary basement membranes). We previously observed upregulation of several endothelial genes in kidney transplant biopsies from patients with donor specific antibodies, indicating active antibody-mediated rejection and poor graft survival. Furthermore, endothelial molecular signals discovered a previously unknown clinical phenotype: C4d negative antibody-mediated rejection. With the recognition of C4d negative antibody-mediated rejection, data from multiple transplant centers now show that antibody-mediated rejection is the most common cause of late kidney transplant failure. This paper reviews the current understanding of endothelial cell biology in antibody-mediated rejection, emphasizing recent advances and pending questions. Furthermore, the paper discusses functionally active pathways in human antibody-mediated rejection, which include aspects of endothelial activation with increased endothelial adhesive and pro-coagulant signals facilitating leukocyte trafficking and attachment, cell-to-basement membrane interactions, platelet activation, coagulation, and endothelial repair responses. To understand effector mechanisms of antibody-mediated rejection and quantify the degree of antibody-mediated tissue injury in clinical transplants, endothelial cells provide a useful read-out.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada T6G 2E1. bsis@ualberta.ca
authors.forename: Banu
authors.initials: B
authors.lastname: Sis
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D016377:Organ Transplantation; D011961:Receptors, Fc / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D011961:Receptors, Fc; D007371:Interferon-gamma