针对细胞表面 TLR7 治疗自身免疫性疾病。
Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases.
机构信息
1] Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan [2] Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan.
1] Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan [2] Japan Society for the Promotion of Science, 5-3-1, Kojimachi, Chiyodaku, Tokyo 102 0083, Japan.
出版信息
Nat Commun. 2015 Feb 4;6:6119. doi: 10.1038/ncomms7119.
Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that TLR7 is present on the cell surface of immune cells and that TLR7 responses can be inhibited by an anti-TLR7 antibody. The anti-TLR7 antibody is internalized with TLR7 and accumulates in endolysosomes as an immune complex. TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-TLR7 antibody. Furthermore, the anti-TLR7 antibody inhibits in vivo cytokine production induced by a TLR7 ligand. Spontaneous TLR7 activation in Unc93b1(D34A/D34A) mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-TLR7 antibody treatment. These results demonstrate that cell surface TLR7 is a promising target for therapeutic intervention in autoimmune diseases.
Toll 样受体 7（TLR7）可识别微生物源性 RNA，但也可能潜在地对自身源性 RNA 产生反应。为了防止自身免疫反应，TLR7 被认为定位于内溶酶体中。与这一观点相反，我们在此表明 TLR7 存在于免疫细胞的细胞表面，并且 TLR7 反应可被抗 TLR7 抗体抑制。抗 TLR7 抗体与 TLR7 一起内化，并作为免疫复合物积聚在内溶酶体中。抗 TLR7 抗体可抑制树突状细胞、巨噬细胞和 B 细胞中的 TLR7 反应。此外，抗 TLR7 抗体可抑制 TLR7 配体诱导的体内细胞因子产生。Unc93b1(D34A/D34A) 小鼠中自发的 TLR7 激活可导致致命性炎症。脾肿大、血小板减少和慢性活动性肝炎等进行性炎症可通过抗 TLR7 抗体治疗得到改善。这些结果表明，细胞表面 TLR7 是治疗自身免疫性疾病的有前途的治疗靶点。
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