Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis
Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis
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DOI：
10.1002/hep.21697
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发表时间：
2007-06-01
期刊：
影响因子：
13.5
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
--
作者：
Zen, Yoh;Fujii, Takahiko;Nakanuma, Yasuni
免疫球蛋白G（IgG）4相关的硬化性胰腺炎和胆管炎（自身免疫性胰腺-胆管炎[AIPC]）是最近认识到的疾病实体，其特征是高血清IgG 4浓度和硬化性炎症伴大量IgG 4阳性浆细胞，尽管基本的免疫机制仍然只是推测性的。在这项研究中，AIPC的免疫发病机制进行了检查，在原位细胞因子的生产和调节性T细胞（Tcells）的可能参与使用新鲜（5例）和福尔马林固定（28例）标本的AIPC和相关的胰胆管外病变。实时定量聚合酶链反应显示，AIPC和胰胆管外病变的白细胞介素（IL）-4/干扰素-γ比值显著升高，（IFN-γ）（45.8倍），IL-5/IFN-γ（18.7倍），IL-13/干扰素（IFN）-γ（20.7倍），IL-10/CD 4（45.3倍）和肿瘤生长因子（TGF）-β/CD 4（39.4倍）。原位杂交结果显示AIPC中多见IL-4和IL-10阳性的淋巴细胞。与PSC和PBC相比，AIPC和胰胆管外病变中Foxp 3信使RNA的表达显著增加（36.4倍），Foxp 3信使RNA是一种特异于自然产生的CD 4（+）CD 25（+）T细胞的转录因子。免疫组化结果显示，AIPC中CD 4（+）CD 25（+）Foxp 3（+）细胞较多，而PSC和其他疾病对照中则较少。两者结合，AIPC的特征可以是T辅助细胞（Th）2和调节性细胞因子的过度产生。TGF-β可能参与IL-10和TGF-β的原位产生，随后可能发生IgG 4类转换和纤维增生。结论：AIPC是一种以Th 2细胞和T3细胞介导的免疫反应为主的独特的炎症性疾病。
Immunoglobin G (IgG) 4-related sclerosing pancreatitis and cholangitis (autoimmune pancreato-cholangitis [AIPC]) are recently recognized disease entities characterized by high serum IgG4 concentrations and sclerosing inflammation with numerous IgG4-positive plasma cells, although the underlining immune mechanism remains only speculative. In this study, the immunopathogenesis of AIPC was examined with respect to the production of cytokines in situ and the possible involvement of regulatory T cells (Tregs) using fresh (5 cases) and formalin-fixed (28 cases) specimens of AIPC and related extra-pancreatobiliary lesions. Quantitative real-time polymerase chain reaction revealed that AIPC and extra-pancreatobiliary lesions had significantly higher ratios of interleukin (IL)-4/interferon-gamma (IFN-gamma) (45.8-fold), IL-5/IFN-gamma (18.7-fold), IL-13/interferon (IFN)-gamma (20.7-fold), IL-10/ CD4 (45.3-fold), and tumor growth factor (TGF)-beta/CD4 (39.4-fold) than did primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Lymphocytes with signals for IL-4 and IL-10 were frequently found in AIPC by in situ hybridization. The expression of Foxp3 messenger RNA, a transcription factor specific for naturally arising CD4(+)CD25(+) Tregs, was significantly increased in AIPC and extra-pancreatobiliary lesions in comparison to PSC and PBC (36.4-fold). Immunohistochemically, CD4(+)CD25(+)Foxp3(+) cells were frequently found in AIPC, while few were found in PSC and other disease controls. Taken together, AIPC could be characterized by the over-production of T helper (Th)2 and regulatory cytokines. Tregs might be involved in the in situ production of IL-10 and TGF-beta, which could be followed by IgG4 class switching and fibroplasia. Conclusion: AIPC is a unique inflammatory disorder characterized by an immune reaction predominantly mediated by Th2 cells and Tregs.