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Significance of immunoglobulin G4 (IgG4)‐positive cells in extrahepatic cholangiocarcinoma: Molecular mechanism of IgG4 reaction in cancer tissue
Author(s) -
Harada Kenichi,
Shimoda Shinji,
Kimura Yasushi,
Sato Yasunori,
Ikeda Hiroko,
Igarashi Saya,
Ren XiangShan,
Sato Hirohide,
Nakanuma Yasuni
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25627
Subject(s) - foxp3 , gallbladder cancer , cd86 , antibody , pancreatic cancer , bile duct , cd80 , cancer research , pathology , medicine , bile duct cancer , cancer , biology , immune system , immunology , t cell , cd40 , cytotoxic t cell , biochemistry , in vitro
IgG4 reactions consisting of marked infiltration by immunoglobulin G4 (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. The regulatory cytokine interleukin (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 nonprofessional 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 patients with common bile duct cancer, and eight patients 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 messenger RNA and the expression of IL‐10 were demonstrated. Conclusion : Extrahepatic cholangiocarcinoma is often accompanied by significant infiltration of IgG4‐positive cells. Cholangiocarcinoma cells could play the role of nonprofessional APCs and Foxp3‐positive regulatory cells, inducing IgG4 reactions via the production of IL‐10 indirectly and directly, respectively. (H EPATOLOGY 2012;56:157–164)