Open AccessBach2 repression mediates Th17 cell induced inflammation and associates with clinical features of advanced disease in chronic pancreatitis
Author(s) -
Sasikala M,
Ravikanth VV,
Murali Manohar K,
Deshpande Neha,
Singh Sandhya,
Pavan Kumar P,
Talukdar R,
Ghosh Sudip,
Aslam Mohsin,
Rao GV,
Pradeep R,
Reddy D Nageshwar
Publication year - 2018
Publication title -
ueg journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.667
H-Index - 35
eISSN - 2050-6414
pISSN - 2050-6406
DOI - 10.1177/2050640617716596
Subject(s) - aryl hydrocarbon receptor , pancreatitis , transcription factor , immune system , rar related orphan receptor gamma , inflammation , flow cytometry , homeostasis , t cell , psychological repression , biology , microbiology and biotechnology , medicine , immunology , cancer research , endocrinology , gene , gene expression , foxp3 , genetics
Objectives Altered immune homeostasis and involvement of T cells has been reported in chronic pancreatitis (CP). We evaluated the role of Bach2 (BTB and CNC homology basic leucine zipper transcription factor 2), a key regulator of immune homeostasis in the chronicity of CP. Methods Expression of Bach2 and T‐cell transcription factors, enumeration of BACH2+/CD4+ T‐lymphocytes were performed by qRT‐PCR and flow cytometry respectively. Bach2 silenced human CD4+ T‐lymphocytes were exposed to CP tissue extract to assess T‐cell lineage commitment. Aryl hydrocarbon receptor ( Ahr ) and Deubiquitinase enzyme A (DUBA/ OTUD5gene ) were evaluated as markers of persistent Th17 cell differentiation. Bach2 gene (exons) was sequenced to identify risk variants and functionally validated. Results Decrease in Bach2 ( p < 0 . 0001) and increase ( p < 0 . 001) in TBX21 , RORC , Ahr , PRDM1, IL23R mRNA were noted in pancreatic tissues, while BACH2+/CD4+ T‐lymphocytes were decreased ( p < 0.01) in circulation and tissues. Exposure of Bach2 silenced CD4+ T‐lymphocytes to CP tissue extract showed increased Ahr , decreased OTUD5 , and enhanced Th17 cell differentiation. Sequencing of Bach2 gene revealed association of novel variant (rs9111 in 5′‐UTR) with advanced disease and luciferase assay confirmed its role in Bach2 repression. Conclusion Bach2 repression mediates Th17 cell induced inflammation and rs9111‐TT in individuals with primary genetic susceptibility to CP is associated with clinical features of advanced disease.