A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation.
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.
Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale L Pinto 1, Foggia, Italy.
Federica
F
Rascio
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G Cesare 11, Bari, Italy.
Paola
P
Pontrelli
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G Cesare 11, Bari, Italy.
Matteo
M
Accetturo
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G Cesare 11, Bari, Italy.
Annarita
A
Oranger
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G Cesare 11, Bari, Italy.
Margherita
M
Gigante
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G Cesare 11, Bari, Italy.
Giuseppe
G
Castellano
Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, Italy, Viale L Pinto 1, Foggia, Italy.
Maddalena
M
Gigante
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G Cesare 11, Bari, Italy.
Anna
A
Zito
Renal Unit, Department of Medicine, University of Verona, Piazzale A Stefani 1, Verona, Italy.
Gianluigi
G
Zaza
Renal Unit, Department of Medicine, University of Verona, Piazzale A Stefani 1, Verona, Italy.
Antonio
A
Lupo
Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, Italy, Viale L Pinto 1, Foggia, Italy.
Elena
E
Ranieri
Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale L Pinto 1, Foggia, Italy.
Giovanni
G
Stallone
Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G Cesare 11, Bari, Italy.
Loreto
L
Gesualdo
Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale L Pinto 1, Foggia, Italy.
Giuseppe
G
Grandaliano
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002908:Chronic Disease; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D006084:Graft Rejection / Q000097:blood / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D059467:Transcriptome; D016896:Treatment Outcome
D015415:Biomarkers; D007370:Interferon Type I; D035683:MicroRNAs; D012333:RNA, Messenger
T lymphocytes; chronic antibody-mediated rejection; immunology; kidney transplantation; messenger RNA and microRNA profiling; peripheral blood mononuclear cells; type I interferon