Tao Kayoko, Fujii Mutsuko, Tsukumo Shin-ichi, Maekawa Yoichi, Kishihara Kenji, Kimoto Yasutaka, Horiuchi Takahiko, Hisaeda Hajime, Akira Shizuo, Kagami Shoji, Yasutomo Koji
Department of Immunology and Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
Ann Rheum Dis. 2007 Jul;66(7):905-9. doi: 10.1136/ard.2006.065961. Epub 2007 Mar 7.
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.
To investigate whether TLR9 polymorphisms are associated with an increased risk of SLE.
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.
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 -1486 (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.
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.
系统性红斑狼疮（SLE）的特征是自身反应性淋巴细胞和抗原呈递细胞的调节异常。作为固有免疫反应介质的Toll样受体9（TLR9）信号传导在树突状细胞和自身反应性B细胞的激活中起作用。
研究TLR9基因多态性是否与SLE风险增加相关。
从220例日本SLE患者（符合>4条美国风湿病学会SLE标准）和203例对照中获取DNA样本。通过PCR检测TLR9的基因变异，随后进行DNA测序。通过荧光素酶报告基因测定法测量TLR9的启动子和增强子活性。通过ELISA分析对照或TLR9缺陷小鼠血清中抗双链DNA抗体的滴度。
位于TLR9第1内含子的+1174位点的G等位基因与SLE风险增加密切相关（p = 0.029）。此外，SLE患者在-1486位点倾向于有C等位基因（p = 0.11）。通过报告基因测定，这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双链DNA血清抗体。
这些结果表明，TLR9第1174位点存在G等位基因使人类患SLE的风险增加。推测TLR9通常可预防人类SLE的发生。
