De novo-developed antibodies to donor MHC antigens lead to dysregulation of microRNAs and induction of MHC class II.
Immune responses to HLA and development of anti-donor HLA (DSA) were shown to play a role in chronic rejection following transplantation. We hypothesized that Abs to MHC change microRNAs (miRNAs), leading to chronic lung allograft rejection. Microarray analysis was performed in a murine model of anti-MHC-induced obliterative airway disease (OAD), a correlate of obliterative bronchiolitis. A unique profile of dysregulated miRNAs was detected in OAD mice on days 7 and 15 after Ab administration compared with control. Sixty-seven miRNAs were increased and 42 miRNAs were decreased in OAD mice on day 7. In addition, 15 miRNAs were overexpressed and 16 miRNAs were underexpressed in OAD mice on day 15. The expression of miR-16 and miR-195 was significantly decreased in lungs of OAD mice, as assessed by quantitative RT-PCR and in situ hybridization, with increases in H-2 Aa and H-2 Dma mRNA levels. Significant reductions in miR-16 and miR-195 levels were also noted in lung transplant (LTx) patients with DSA compared with LTx patients without DSA. Bioinformatic TargetScan and reporter assays identified the binding of miR-16 and miR-195 to the 3'-untranslated region of regulatory factor X 5. Quantitative PCR and immunohistochemistry indicated posttranscriptional increases in regulatory factor X 5 mRNA and protein expression in OAD mice, as well as in LTx recipients with DSA, which was associated with increased expression of HLA-DPA1, HLA-DQA1, and HLA-DRA mRNA. Therefore, our results demonstrated that miRNAs induced by alloimmunity may play important roles in chronic rejection after LTx.
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110;
Zhongping
Z
Xu
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110;
Deepak K
DK
Nayak
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110;
Nicholas
N
Benshoff
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and.
Ramsey
R
Hachem
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110;
Andrew E
AE
Gelman
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 kumart@wustl.edu.
Thalachallour
T
Mohanakumar
D000818:Animals; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006183:H-2 Antigens / Q000235:genetics* / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D023421:Models, Animal; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D015203:Reproducibility of Results; D014019:Tissue Donors; D014157:Transcription Factors / Q000235:genetics; D066027:Transplant Recipients
D004268:DNA-Binding Proteins; D006183:H-2 Antigens; D006649:Histocompatibility Antigens; D000949:Histocompatibility Antigens Class II; D007518:Isoantibodies; D035683:MicroRNAs; C509133:RFX5 protein, mouse; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors