Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Hepatology. 2012 Jul;56(1):157-64. doi: 10.1002/hep.25627. Epub 2012 Jun 5.
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.
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.
在癌症患者和 IgG4 相关疾病患者中，受影响器官中存在大量免疫球蛋白 G4（IgG4）阳性浆细胞浸润的 IgG4 反应。值得注意的是，伴有明显 IgG4 反应的肝外胆管癌在临床病理上类似于 IgG4 相关硬化性胆管炎。调节细胞因子白细胞介素（IL）-10 被认为可诱导 IgG4 阳性细胞的分化。在这项研究中，为了阐明肝外胆管癌中 IgG4 反应的机制，我们研究了非专业抗原呈递细胞（APC）产生产生白细胞介素（IL）-10 的调节性 T 细胞（无能 T 细胞）和 Foxp3 阳性调节细胞。使用来自 24 例胆囊癌、22 例胆总管癌和 8 例 Vater 乳头癌患者的 54 例胆管癌标本，对 IgG4、HLA-DR、CD80、CD86 和 Foxp3 进行了免疫组织化学靶向检测。此外，还使用培养的人胆管癌细胞系对 Foxp3 和 IL-10 进行了分子分析。结果，43%的胆管癌富含 IgG4。那些表达 HLA-DR 但缺乏共刺激分子（CD80 和 CD86）和那些通过识别 N 末端的抗体检测到 Foxp3 的表达占 54%和 39%，分别。此外，这些病例中的 IgG4 阳性细胞数量大于其他组。在培养的细胞中，存在 Foxp3 信使 RNA 的剪接变体和 IL-10 的表达。
肝外胆管癌常伴有大量 IgG4 阳性细胞浸润。胆管癌细胞可作为非专业 APC 和 Foxp3 阳性调节细胞，通过间接和直接产生白细胞介素（IL）-10 分别诱导 IgG4 反应。
