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

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, TGF beta, IFN gamma and TNF alpha 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 TGFb mRNA expression was high in PBC compared with normal livers (p < 0.05). IFN gamma and TNFa 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.