Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population
Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population
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DOI：
10.1136/ard.2006.065961
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发表时间：
2007-07-01
影响因子：
27.4
通讯作者：
Yasutomo, Koji
中科院分区：
文献类型：
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作者：
Tao, Kayoko;Fujii, Mutsuko;Yasutomo, Koji
背景：系统性红斑狼疮 (SLE) 的特点是自身反应性淋巴细胞和抗原呈递细胞失调。 Toll 样受体 9 (TLR9) 是先天免疫反应的介质，通过 Toll 样受体 9 (TLR9) 发出的信号在树突状细胞和自身反应性 B 细胞的激活中发挥作用。 目的：研究 TLR9 多态性是否与 SLE 风险增加相关。方法：从 220 名日本 SLE 患者（符合 4 美国风湿病学会 SLE 标准）和 203 名对照者中获取 DNA 样本。通过PCR检测TLR9的遗传变异，随后进行DNA测序。通过荧光素酶报告基因测定测定TLR9的启动子和增强子活性。通过 ELISA 分析对照或 TLR9 缺陷小鼠血清中抗 dsDNA 抗体的滴度。结果：位置 + 1174 的 G 等位基因（位于 TLR9 的内含子 1）与 SLE 风险增加密切相关（p = 0.029）。此外，SLE 患者往往在位置 21486 处具有 C 等位基因 (p = 0.11)。通过报告基因检测，两个等位基因均下调 TLR9 表达。 C57BL/6 背景下的 TLR9 缺陷小鼠比对照 C57BL/6 小鼠具有更高滴度的抗 dsDNA 血清抗体。结论：这些结果表明 TLR9 + 1174 位置处 G 等位基因的存在使人类患 SLE 的风险增加。据推测，TLR9 通常可以阻止人类 SLE 的发展。
Background: Systemic lupus erythematosus ( SLE) is characterised by dysregulation of autoreactive lymphocytes and antigen- presenting cells. Signalling through Toll- like receptor 9 ( TLR9), a mediator of innate immune responses, has a role in activation of dendritic cells and autoreactive B cells.Objective: To investigate whether TLR9 polymorphisms are associated with an increased risk of SLE.Methods: DNA samples were obtained from 220 Japanese patients with SLE ( with.4 American College of Rheumatology criteria for SLE) and 203 controls. The genetic variations of TLR9 were detected by PCR, followed by DNA sequencing. The promoter and enhancer activities of TLR9 were measured by luciferase reporter gene assay. The titres of anti- dsDNA antibodies in sera from control or TLR9- deficient mice were analysed by ELISA.Results: The G allele at position + 1174 ( located in intron 1 of TLR9) is closely associated with an increased risk of SLE ( p = 0.029). Furthermore, patients with SLE tend to have C allele at position 21486 ( p = 0.11). Both alleles down regulate TLR9 expression by reporter gene assay. TLR9- deficient mice under a C57BL/ 6 background possess higher titres of anti- dsDNA serum antibodies than control C57BL/ 6 mice.Conclusions: These results indicate that the presence of the G allele at position + 1174 of TLR9 predisposes humans to an increased risk of SLE. It is speculated that TLR9 normally prevents the development of human SLE.