title: The molecular landscape of antibody-mediated kidney transplant rejection: evidence for NK involvement through CD16a Fc receptors.
abstract: The recent recognition that antibody-mediated rejection (ABMR) is the major cause of kidney transplant loss creates strong interest in its pathogenesis. We used microarray analysis of kidney transplant biopsies to identify the changes in pure ABMR. We found that the ABMR transcript changes in the initial Discovery Set were strongly conserved in a subsequent Validation Set. In the Combined Set of 703 biopsies, 2603 transcripts were significantly changed (FDR < 0.05) in ABMR versus all other biopsies. In cultured cells, the transcripts strongly associated with ABMR were expressed in endothelial cells, e.g. cadherins CDH5 and CDH13; IFNG-treated endothelial cells, e.g. phospholipase PLA1A and chemokine CXCL11; or NK cells, e.g. cytotoxicity molecules granulysin (GNLY) and FGFBP2. Other ABMR transcripts were expressed in normal kidney but not cell lines, either increased e.g. Duffy chemokine receptor (DARC) or decreased e.g. sclerostin (SOST). Pathway analysis of ABMR transcripts identified angiogenesis, with roles for angiopoietin and vascular endothelial growth factors; leukocyte-endothelial interactions; and NK signaling, including evidence for CD16a Fc receptor signaling elements shared with T cells. These data support a model of ABMR involving injury-repair in the microcirculation induced by cognate recognition involving antibody and CD16a, triggering IFNG release and antibody-dependent NK cell-mediated cytotoxicity.
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada; Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, Alberta, Canada.
authors: J M
authors: JM
authors: Venner
authors: L G
authors: LG
authors: Hidalgo
authors: K S
authors: KS
authors: Famulski
authors: J
authors: J
authors: Chang
authors: P F
authors: PF
authors: Halloran
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000906:Antibodies / Q000737:chemistry; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D015331:Cohort Studies; D016208:Databases, Factual; D005260:Female; D006084:Graft Rejection; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007674:Kidney Diseases / Q000473:pathology / Q000601:surgery; D016030:Kidney Transplantation; D007694:Killer Cells, Natural / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D017452:Receptors, IgG / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000906:Antibodies; C496124:FCGR3A protein, human; D017452:Receptors, IgG
keywords: basic (laboratory) research / science; biopsy; kidney transplantation / nephrology; natural killer (NK) cells / NK receptors; rejection: antibody-mediated (ABMR); signaling / signaling pathways