Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis

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  • Potential conflict of interest: Nothing to report

Abstract

Immunoglobin G (IgG) 4-related sclerosing pancreatitis and cholangitis (autoimmune pancreato-cholangitis [AIPC]) are recently recognized disease entities characterized by high serum IgG4 concentrations and sclerosing inflammation with numerous IgG4-positive plasma cells, although the underlining immune mechanism remains only speculative. In this study, the immunopathogenesis of AIPC was examined with respect to the production of cytokines in situ and the possible involvement of regulatory T cells (Tregs) using fresh (5 cases) and formalin-fixed (28 cases) specimens of AIPC and related extra-pancreatobiliary lesions. Quantitative real-time polymerase chain reaction revealed that AIPC and extra-pancreatobiliary lesions had significantly higher ratios of interleukin (IL)-4/interferon-γ (IFN-γ) (45.8-fold), IL-5/IFN-γ (18.7-fold), IL-13/interferon (IFN)-γ (20.7-fold), IL-10/CD4 (45.3-fold), and tumor growth factor (TGF)-β/CD4 (39.4-fold) than did primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Lymphocytes with signals for IL-4 and IL-10 were frequently found in AIPC by in situ hybridization. The expression of Foxp3 messenger RNA, a transcription factor specific for naturally arising CD4+CD25+ Tregs, was significantly increased in AIPC and extra-pancreatobiliary lesions in comparison to PSC and PBC (36.4-fold). Immunohistochemically, CD4+CD25+Foxp3+ cells were frequently found in AIPC, while few were found in PSC and other disease controls. Taken together, AIPC could be characterized by the over-production of T helper (Th) 2 and regulatory cytokines. Tregs might be involved in the in situ production of IL-10 and TGF-β, which could be followed by IgG4 class switching and fibroplasia. Conclusion: AIPC is a unique inflammatory disorder characterized by an immune reaction predominantly mediated by Th2 cells and Tregs. (HEPATOLOGY 2007.)

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