Abstract

IgG4 reactions consisting of marked infiltration by IgG4-positive plasma cells in affected organs is found in cancer patients as well as patients with IgG4-related diseases. Notably, extrahepatic cholangiocarcinomas accompanying marked IgG4 reactions clinicopathologically mimic IgG4-related sclerosing cholangitis. A regulatory cytokine, IL-10, is thought to induce the differentiation of IgG4-positive cells. In this study, to clarify the mechanism of the IgG4 reaction in extrahepatic cholangiocarcinoma, we investigated non-professional antigen-presenting cells (APCs) generating IL-10-producing regulatory T cells (anergy T cells) and Foxp3-positive regulatory cells producing IL-10. Immunohistochemistry targeting IgG4, HLA-DR, CD80, CD86, and Foxp3 was performed using 54 cholangiocarcinoma specimens from 24 patients with gallbladder cancer, 22 with common bile duct cancer, and 8 with cancer of the Papilla of Vater. Moreover, a molecular analysis of Foxp3 and IL-10 was performed using a cultured human cholangiocarcinoma cell line. Consequently, 43% of the cholangiocarcinomas were found to be abundant in IgG4. Those expressing HLA-DR, but lacking costimulatory molecules (CD80 and CD86), and those expressing Foxp3 detected by an antibody recognizing the N terminus, accounted for 54% and 39% of cases, respectively. Moreover, the number of IgG4-positive cells was larger in these cases than in other groups. In cultured cells, the presence of a splicing variant of Foxp3 mRNA and the expression of IL-10 were demonstrated. In conclusion, extrahepatic cholangiocarcinoma is often accompanied by the significant infiltration of IgG4-positive cells. Cholangiocarcinoma cells could play the role of non-professional APCs and Foxp3-positive regulatory cells, inducing IgG4 reactions via the production of IL-10 indirectly and directly, respectively. (HEPATOLOGY 2012.).

Copyright © 2012 American Association for the Study of Liver Diseases.