Bach2 repression mediates Th17 cell induced inflammation and associates with clinical features of advanced disease in chronic pancreatitis.

Objectives: Altered immune homeostasis and involvement of T cells has been reported in chronic pancreatitis (CP). We evaluated the role of (BTB and CNC homology basic leucine zipper transcription factor 2), a key regulator of immune homeostasis in the chronicity of CP.

Methods: Expression of and T-cell transcription factors, enumeration of BACH2+/CD4+ T-lymphocytes were performed by qRT-PCR and flow cytometry respectively. silenced human CD4+ T-lymphocytes were exposed to CP tissue extract to assess T-cell lineage commitment. Aryl hydrocarbon receptor () and Deubiquitinase enzyme A (DUBA/) were evaluated as markers of persistent Th17 cell differentiation. gene (exons) was sequenced to identify risk variants and functionally validated.

Results: Decrease in ( < 00001) and increase ( < 0001) in , , , mRNA were noted in pancreatic tissues, while BACH2+/CD4+ T-lymphocytes were decreased ( < 0.01) in circulation and tissues. Exposure of silenced CD4+ T-lymphocytes to CP tissue extract showed increased , decreased , and enhanced Th17 cell differentiation. Sequencing of gene revealed association of novel variant (rs9111 in 5'-UTR) with advanced disease and luciferase assay confirmed its role in repression.

Conclusion: 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.