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; leukocyteendothelial 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.

Molecular assessment of disease states in kidney transplant biopsy samples

“…The top genes in any particular discovery set are highly conserved in a validation set that has the same algorithm and case mix [66][67][68] , but changes in the rules for the comparison or the definition of the positive and negative classes will produce gene lists that differ substantially. The purpose of a gene list must therefore be considered before it is generated, and the details of the class comparison algorithm must be recorded.…”

“…The injured endothelium resists antibody injury and tries to repair itself by inducing the expression of defensive molecules such as the com plement inhibitors CD55 and CD59 (REF. 67), but this mechanism is intrinsic to the injury response, and not a separate event. Some antibodies (particularly against A or B blood group antigens) are unable to injure the endothelium, but they do not induce a protective change indicative of accommodation.…”

Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy

“…Th The infl fl fla am a matory ry s signals s s t tha at re e esu su sult lt lt fr fr f om om th he stim mu ula at a i io i n of a a act t ctiv va ating F Fceceptors (Fc-R) f for C C-reactive protein (CR C P) P serum amyloid P P component (SA S P) and d IgG 21 . In addition, the FCGR3A polymorphisms have been reported to contribute to infection susceptibility [22][23][24] and coronary artery diseases 25,26 and predispose patients to severe complications after organ transplantation [27][28][29][30][31] . In the current study, we investigated whether CD16-dependent NK cell activation profiles and FCGR3A polymorphism may be associated with the development of CAV.…”

Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival

“…In addition, a suitable biomarker for immune-mediated graft damage would help in identifying appropriate treatments on a patient basis. Previous reports have implicated distinct gene expression patterns in acute cellular rejection (ACR) and antibody-mediated rejection (AMR) (5,6). In contrast, using a multicohort analysis (7-9) of 13 independent data sets consisting of 1,164 graft biopsies from 4 transplanted organs, we identified and validated a common rejection module (CRM) consisting of 11 genes, which (a) is able to diagnose AR, (b) correlates with the extent of graft injury, and (c) predicts subclinical graft injury (7).…”