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Aim Administration of anti-MHC class I (H-2Kb) leads to induction of transcription factor Zinc finger and BTB domain containing 7A (Zbtb7a) leading to inflammatory cascade and chronic rejection in a murine obliterative airway disease model. Development of DSA and Abs to lung-associated self-antigens (K-alpla-1 Tubulin (K α 1T) and Collagen V (Col-V) are significant risk factors in development of bronchiolitis obliterans syndrome (BOS) following human lung transplantation (LTx). The current study focused on the role of Zbtb7a in development of BOS following human LTx. Methods We analyzed 25 LTx patients that developed BOS years after LTx as well as 10 stable LTx performed at Barnes-Jewish Washington University. Kinetics of Zbtb7a expression was studied in bronchoalveolar lavage (BAL) cells. Quantitative PCR analysis was performed to evaluate mRNA levels and data was compared with the DSA, autoantibody and immunosuppression. Results Increases in the Zbtb7a expression was observed in BAL cells collected at visits immediately prior to clinical BOS diagnosis compared with earlier visits. Zbtb7a expression was significantly ( p < 0.01) increased (150%) in pre-BOS BAL cells. On the contrary, stable patients did not demonstrate any change in Zbtb7a levels. All of the BOS+ patients had developed DSA and Abs to K α 1T and Col-V. Zbtb7a expression in 13 patients who received Ab directed therapy following DSA demonstrated significant reduction along with decrease in DSA and Abs to lung self-antigens. Therefore, Zbtb7a activation is an important inducer of the DSA and autoantibody. Conclusions Up regulation of Zbtb7a was positively associated with de novo DSA and Abs to lung-associated self-antigens. Ab directed therapy significantly reduced Zbtb7a expression. We propose that Zbtb7a may be used as a prognostic marker in evaluating Ab-induced inflammation in the lung as well as efficacy of Ab directed therapy following development of DSA. [ABSTRACT FROM AUTHOR]

Aim Chronic rejection (bronchiolitis obliterans syndrome (BOS)) is the major limitation for long-term survival after lung transplantation (LTx). Its pathogenesis, however, is poorly understood and no effective predictive biomarkers have been identified. Several studies have shown that de novo development of antibodies to donor mismatched HLA (DSA) is a significant risk factor for the development of BOS. Methods Thirty LTx recipients from Barnes Jewish Hospital/Washington University School of Medicine (10 stable DSA− and BOS−, 10 DSA+ BOS− and 10 DSA+ and BOS+) were analyzed for circulating microRNAs (miRNAs). MiRNAs expression in the recipients’ serum was detected using RNA extraction and quantitative PCR analysis. Results We identified eight miRNAs which were selectively expressed on lung allograft recipients with de novo developed DSA and diagnosed with BOS in comparison to stable LTx without DSA and BOS: miR-369-5p, miR-144, miR-134, miR-10a, miR-195 miR-142-5p, miR-133b, and miR-155 ( p < 0.01). Among them, transforming growth factor beta (TGF- β ) associated miRNAs: miR-369-5p was down regulated (2.3-fold, p < 0.001), miR-144 was up-regulated (3.1-fold, p < 0.001) in the serum of LTx with DSA compared to stable, indicating their role in fibrogenesis mediated by TGF- β signalling. In addition, miR-134 involved in B cell receptor pathway was decreased ( p < 0.001) in the serum of LTx with DSA and BOS, demonstrating its role in B cell activation and DSA development following LTx. Furthermore, miR-10a, known to be associated with Treg development, was down-regulated ( p < 0.001) in LTx with DSA and BOS, demonstrating its involvement in down regulation of Treg function leading to development of DSA. Finally, results obtained from independent validation using an independent cohort of 9 stable, 7 DSA+ BOS−, and 10 DSA+ BOS+ LTx demonstrated that these miRNAs can discriminate LTx with development of DSA and BOS from those stable LTx without DSA and BOS ( p < 0.01). Conclusion Our results, for the first time, demonstrated differential expression of circulating miRNAs in lung allograft recipients with de novo development of DSA and BOS. These dysregulated miRNAs are involved in T and B cell regulation and fibrogenesis, indicating their role in the development of DSA leading to chronic lung allograft rejection. [ABSTRACT FROM AUTHOR]