Table_1_TLR7 Signaling Drives the Development of Sjögren’s Syndrome.docx

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that affects predominately salivary and lacrimal glands. SS can occur alone or in combination with another autoimmune disease like systemic lupus erythematosus (SLE). Here we report that TLR7 signaling drives the development of SS since TLR8-deficient (TLR8ko) mice that develop lupus due to increased TLR7 signaling by dendritic cells, also develop an age-dependent secondary pathology similar to associated SS. The SS phenotype in TLR8ko mice is manifested by sialadenitis, increased anti-SSA and anti-SSB autoantibody production, immune complex deposition and increased cytokine production in salivary glands, as well as lung inflammation. Moreover, ectopic lymphoid structures characterized by B/T aggregates, formation of high endothelial venules and the presence of dendritic cells are formed in the salivary glands of TLR8ko mice. Interestingly, all these phenotypes are abrogated in double TLR7/8-deficient mice, suggesting that the SS phenotype in TLR8-deficient mice is TLR7-dependent. In addition, evaluation of TLR7 and inflammatory markers in the salivary glands of primary SS patients revealed significantly increased TLR7 expression levels compared to healthy individuals, that were positively correlated to TNF, LT-α, CXCL13 and CXCR5 expression. These findings establish an important role of TLR7 signaling for local and systemic SS disease manifestations, and inhibition of such will likely have therapeutic value.

干燥综合征（Sjögren’s syndrome, SS）是一种主要累及唾液腺与泪腺的慢性全身性自身免疫性疾病，可单独发病，也可与系统性红斑狼疮（systemic lupus erythematosus, SLE）等其他自身免疫性疾病合并发生。本研究发现，Toll样受体7（TLR7）信号通路驱动干燥综合征的发生发展：因树突状细胞TLR7信号增强而罹患狼疮的Toll样受体8缺陷（TLR8敲除, TLR8ko）小鼠，同样会出现随年龄进展的类似继发性干燥综合征的病理表现。TLR8ko小鼠的干燥综合征表型表现为涎腺炎、抗SSA与抗SSB自身抗体生成增多、免疫复合物沉积、唾液腺内细胞因子生成增加，同时伴随肺部炎症。此外，TLR8ko小鼠的唾液腺中会形成以B/T细胞聚集为特征的异位淋巴结构、高内皮微静脉，并存在树突状细胞浸润。值得注意的是，上述所有表型在TLR7/8双缺陷小鼠中均被消除，这表明TLR8ko小鼠的干燥综合征表型依赖于TLR7信号通路。此外，对原发性干燥综合征患者唾液腺中TLR7及炎症标志物的评估发现，相较于健康个体，患者体内TLR7的表达水平显著升高，且其表达水平与肿瘤坏死因子（TNF）、淋巴毒素α（LT-α）、C-X-C基序趋化因子配体13（CXCL13）以及C-X-C基序趋化因子受体5（CXCR5）的表达呈正相关。本研究证实了TLR7信号通路在局部与全身性干燥综合征疾病表现中的关键作用，针对该通路的抑制有望具备治疗价值。