The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid-Derived Suppressor Cell Activation in Immunoglobulin G4-Related Sclerosing Cholangitis
The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid-Derived Suppressor Cell Activation in Immunoglobulin G4-Related Sclerosing Cholangitis
复制标题
免疫球蛋白 G4 相关硬化性胆管炎中核因子 Kappa B 配体受体激活剂和骨髓源性抑制细胞激活的免疫生物学
DOI：
10.1002/hep.30095
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发表时间：
2018-11-01
期刊：
影响因子：
13.5
通讯作者：
Ma, Xiong
中科院分区：
文献类型：
--
作者：
Lian, Min;Wang, Qixia;Ma, Xiong
髓源性抑制细胞（MDSCs）的主要功能反映在它们在几种免疫介导疾病中的免疫调节作用。在免疫球蛋白G4 （IgG4）相关疾病（IgG4- rd）中，假设存在选择性调节缺陷导致T辅助2 （Th2）偏倚免疫反应。在此，我们利用igg4相关的硬化性胆管炎（IgG4-SC）患者（IgG4-RD最常见的胰腺外病变）以及由原发性硬化性胆管炎、自身免疫性肝炎和健康志愿者组成的对照组的一大队列来研究MDSCs。我们报道了IgG4-SC患者血清和肝脏中核因子κ B配体受体激活剂（RANKL）表达水平与肝脏疾病和健康对照相比显著升高。此外，在IgG4-SC肝脏中，RANKL分泌细胞特异性地与分化38阳性浆细胞簇和MDSCs，特别是单核细胞MDSCs共定位，并在肝脏中表达RANKL受体。同样，外周血MDSCs的频率和数量也显著增加。重要的是，RANKL的血清表达水平与血清γ -谷氨酰转移酶水平呈负相关，但与MDSCs的频率呈显著正相关。此外，我们证实RANKL通过RANKL/RANK/核因子κ B信号通路诱导MDSCs的增殖和活化。值得注意的是，rankl处理的MDSCs抑制t细胞增殖并诱导Th2分化。结论：我们的数据表明，浆细胞来源的RANKL诱导MDSCs的扩增和激活，从而抑制t细胞的增殖，并有助于IgG4-SC的th2型反应特征。
The primary function of myeloid-derived suppressor cells (MDSCs) is reflected in their immune modulatory role in several immune-mediated diseases. In immunoglobulin G4 (IgG4)-related disease (IgG4-RD), it has been hypothesized that there are selective regulatory defects that lead to a T helper 2 (Th2) bias immune response. Herein we have taken advantage of a large cohort of patients with IgG4-related sclerosing cholangitis (IgG4-SC), the most common extrapancreatic involvement of IgG4-RD, as well as controls consisting of primary sclerosing cholangitis, autoimmune hepatitis, and healthy volunteers, to study MDSCs. We report dramatically increased levels of receptor activator for nuclear factor kappa B ligand (RANKL) expression in serum and liver from patients with IgG4-SC compared to both liver-disease and healthy controls. Moreover, in IgG4-SC liver, RANKL-secreting cells specifically colocalized with cluster of differentiation 38-positive plasma cells and MDSCs, particularly monocytic MDSCs, and express the RANKL receptor in liver. Similarly, the frequency and number of peripheral blood MDSCs were significantly increased. Importantly, serum expression levels of RANKL were inversely correlated with the serum level of gamma-glutamyltransferase but significantly positively correlated with the frequency of MDSCs. Moreover, we confirmed that RANKL induced the expansion and activation of MDSCs through the RANKL/RANK/nuclear factor kappa B signal pathway. Of note, RANKL-treated MDSCs suppressed T-cell proliferation and induced Th2 differentiation. Conclusion: Our data suggest that plasma cell-derived RANKL induces the expansion and activation of MDSCs, which suppress T-cell proliferation and contribute to the Th2-type response characteristic of IgG4-SC.