Christensen Sean R, Shupe Jonathan, Nickerson Kevin, Kashgarian Michael, Flavell Richard A, Shlomchik Mark J
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Immunity. 2006 Sep;25(3):417-28. doi: 10.1016/j.immuni.2006.07.013.
Antibodies (Abs) to RNA- and DNA-containing autoantigens are characteristic of systemic lupus erythematosus (SLE). We showed previously that Toll-like receptor (TLR) 9, recognizing DNA, is required for the spontaneous generation of DNA autoantibodies, but not for the development of lupus nephritis in susceptible mice. We report that lupus-prone mice deficient in TLR7, a receptor for ssRNA, failed to generate Abs to RNA-containing antigens (Ags) such as Smith (Sm) Ag. TLR9 and TLR7 also had dramatic effects on clinical disease in lupus-prone mice. In the absence of TLR9, autoimmune disease was exacerbated, lymphocytes and plasmacytoid DCs were more activated, and serum IgG and IFN-alpha were increased. In contrast, TLR7-deficient mice had ameliorated disease, decreased lymphocyte activation, and decreased serum IgG. These findings reveal opposing inflammatory and regulatory roles for TLR7 and TLR9, despite similar tissue expression and signaling pathways. These results have important implications for TLR-directed therapy of autoimmune disease.
针对含RNA和DNA自身抗原的抗体（Abs）是系统性红斑狼疮（SLE）的特征。我们先前表明，识别DNA的Toll样受体（TLR）9是DNA自身抗体自发产生所必需的，但对于易感小鼠狼疮性肾炎的发展并非必需。我们报告说，缺乏TLR7（一种单链RNA受体）的狼疮易感小鼠无法产生针对含RNA抗原（Ags）的抗体，如史密斯（Sm）抗原。TLR9和TLR7对狼疮易感小鼠的临床疾病也有显著影响。在缺乏TLR9的情况下，自身免疫性疾病会加剧，淋巴细胞和浆细胞样树突状细胞（pDC）的激活增加，血清IgG和IFN-α水平升高。相反，缺乏TLR7的小鼠病情有所改善，淋巴细胞激活减少，血清IgG水平降低。这些发现揭示了TLR7和TLR9在炎症和调节方面的相反作用，尽管它们在组织表达和信号通路方面相似。这些结果对自身免疫性疾病的TLR导向治疗具有重要意义。
