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Naturally-occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis

Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan

Correspondence to:
Dr Yasuni Nakanuma, Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan; pbcpsc{at}kenroku.kanazawa-u.ac.jp

Background: Primary biliary cirrhosis (PBC) is an autoimmune liver disease targeting the intrahepatic small bile ducts showing chronic non-suppurative destructive cholangitis (CNSDC). Recent studies suggest that naturally-occurring CD4⁺CD25^high regulatory T cells (Tregs) expressing Forkhead box P3 (Foxp3) play an active role in immunological self-tolerance.

Aims: To investigate whether Foxp3+Tregs are involved in the pathogenesis of PBC.

Methods: Foxp3+Tregs was detected immunohistochemically in livers from patients with PBC (n = 27), chronic viral hepatitis (CVH) (n = 15), and normal subjects (n = 10). The distribution of Tregs in portal tracts was semi-quantitatively evaluated in each groups. Levels of Foxp3, IL-10, TGFß, IFN and TNF mRNA was evaluated in PBC (n = 15) and control livers (n = 21) using semi-quantitative reverse transcriptase-PCR.

Results: In PBC and CVH livers, the amounts of infiltrating Foxp3+Tregs in portal tracts were in parallel with the degree of portal inflammation irrespective of disease. The infiltration of Foxp3+Tregs into portal tracts with CNSDC in PBC was foremost in comparison with inflamed portal tracts in CVH or those without CNSDC in PBC (p<0.05). Focally, Tregs infiltrated into the biliary epithelial layer at the site of CNSDC. The level of Foxp3, IL-10 and TGFß mRNA expression was high in PBC compared with normal livers (p<0.05). IFN and TNF mRNA was high in early PBC and CVH livers.

Conclusion: Results of this evaluation of Foxp3+Tregs do not suggest that the reduced regulatory function accounts for the development of CNSDC in PBC.

Abbreviations: CNSDC, chronic non-suppurative destructive cholangitis; CVH, chronic viral hepatitis; Foxp3, Forkhead box P3; IL, interleukin; IFN, interferon; PBC, primary biliary cirrhosis; RT, reverse transcriptase; TGF, transforming growth factor; Th, T helper; TNF, tumour necrosis factor; Tregs, regulatory T cells

Keywords: primary biliary cirrhosis; regulatory T cells; Foxp3; IL-10; TGFß; autoimmunity