title: Significance of immunoglobulin G4 (IgG4)-positive cells in extrahepatic cholangiocarcinoma: molecular mechanism of IgG4 reaction in cancer tissue.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. kenichih@med.kanazawa-u.ac.jp
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kimura
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Saya
authors.initials: S
authors.lastname: Igarashi
authors.forename: Xiang-Shan
authors.initials: XS
authors.lastname: Ren
authors.forename: Hirohide
authors.initials: H
authors.lastname: Sato
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D000368:Aged; D014670:Ampulla of Vater / Q000473:pathology; D001650:Bile Duct Neoplasms / Q000276:immunology* / Q000473:pathology; D017734:Bile Ducts, Extrahepatic / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000276:immunology* / Q000473:pathology; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005706:Gallbladder Neoplasms / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008967:Molecular Biology; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D012042:Registries; D012680:Sensitivity and Specificity; D016610:Tissue Embedding
chemical_list: D015415:Biomarkers; D007074:Immunoglobulin G; D016753:Interleukin-10