OBJECTIVE IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD. METHODS SGs from 15 patients with IgG4-RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR-1 through TLR-10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)-transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist. RESULTS In patients with IgG4-RD, TLR-4, TLR-7, TLR-8, and TLR-9 were overexpressed. Polymerase chain reaction validated the up-regulation of TLR-7 in IgG4-RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR-7-positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7-transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL-33 in huTLR-7-transgenic mice was distinctly increased upon stimulation with a TLR-7 agonist (P < 0.05). CONCLUSION TLR-7-expressing M2 macrophages may promote the activation of Th2 immune responses via IL-33 secretion in IgG4-RD.

中文翻译：

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激活的M2巨噬细胞通过Toll样受体7 / Interleukin-33信号转导与IgG4相关疾病的发病机理。

目的IgG4相关疾病（IgG4-RD）是一种独特的炎症性疾病，其中Th2细胞因子促进IgG4的产生。此外，最近的研究已经暗示了Toll样受体（TLR）途径。这项研究旨在检查IgG4-RD患者唾液腺（SGs）中TLR的表达。方法对15例IgG4-RD患者，15例干燥综合征（SS），10例慢性涎腺炎患者和10例健康对照者的SGs进行组织学检查。通过DNA微阵列分析下颌下腺（SMG）中的TLR家族基因表达（TLR-1至TLR-10）。IgG4-RD患者的SG中证实了TLRs的上调。最后，在用TLR激动剂刺激之前和之后评估人TLR-7（huTLR-7）-转基因C57BL / 6小鼠的表型。结果在IgG4-RD患者中，TLR-4，TLR-7，TLR-8和TLR-9过表达。与其他组相比，聚合酶链反应证实了IgG4-RD中TLR-7的上调。免疫组织化学分析证实，IgG4-RD患者的SG中TLR-7阳性细胞强烈浸润。双重免疫组织化学染色显示TLR-7表达与CD163 + M2巨噬细胞共定位。用TLR-7激动剂进行体外刺激后，CD163 + M2巨噬细胞产生更高水平的白细胞介素33（IL-33），这是激活Th2的细胞因子。在huTLR-7转基因小鼠中，SMG，胰腺和肺中的焦点和纤维化得分明显高于野生型小鼠（P <0.05）。此外，经TLR-7激动剂刺激后，huTLR-7转基因小鼠的血清IgG，IgG1和IL-33浓度明显增加（P <0.05）。