A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation

• Published in: The Journal of pathology Vol. 237; no. 1; pp. 72 - 84
• Main Authors: Rascio, Federica, Pontrelli, Paola, Accetturo, Matteo, Oranger, Annarita, Gigante, Margherita, Castellano, Giuseppe, Gigante, Maddalena, Zito, Anna, Zaza, Gianluigi, Lupo, Antonio, Ranieri, Elena, Stallone, Giovanni, Gesualdo, Loreto, Grandaliano, Giuseppe
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.09.2015; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Biomarkers - metabolism; Biopsy; Case-Control Studies; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; chronic antibody-mediated rejection; Chronic Disease; Female; Gene Expression Profiling - methods; Gene Expression Regulation; Gene Regulatory Networks; Genetic Association Studies; Graft Rejection - blood; Graft Rejection - genetics; Graft Rejection - immunology; Humans; immunology; Interferon Type I - genetics; Interferon Type I - immunology; Interferon Type I - metabolism; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Kidney - surgery; kidney transplantation; Kidney Transplantation - adverse effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Male; messenger RNA and microRNA profiling; MicroRNAs - metabolism; Middle Aged; Oligonucleotide Array Sequence Analysis; peripheral blood mononuclear cells; RNA, Messenger - metabolism; Signal Transduction; T lymphocytes; Transcription, Genetic; Transcriptome; Treatment Outcome; type I interferon; T lymphocytes; peripheral blood mononuclear cells; type I interferon; chronic antibody-mediated rejection; kidney transplantation; messenger RNA and microRNA profiling; immunology
• ISSN: 0022-3417; 1096-9896; 1096-9896
• DOI: 10.1002/path.4553

Chronic antibody‐mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4+ T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy‐proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4+ T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up‐regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down‐regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon‐producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon‐induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control biopsies. We conclude that type I interferon signalling may represent the molecular signature of CAMR. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.