Journal
UNITED EUROPEAN GASTROENTEROLOGY JOURNAL
Volume 6, Issue 2, Pages 272-282Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/2050640617716596
Keywords
Chronic pancreatitis; inflammation; CD4+T-lymphocytes; Bach2; gene expression
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Funding
- Asian Healthcare Foundation
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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. Bach2silenced 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.
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