Bochud Pierre-Yves, Hawn Thomas R, Aderem Alan
Institute for Systems Biology, Seattle, WA 98103-8904, USA.
J Immunol. 2003 Apr 1;170(7):3451-4. doi: 10.4049/jimmunol.170.7.3451.
Toll-like receptors (TLRs) are key mediators of the innate immune response to microbial pathogens. We investigated the role of TLRs in the recognition of Mycobacterium leprae and the significance of TLR2Arg(677)Trp, a recently discovered human polymorphism that is associated with lepromatous leprosy. In mice, TNF-alpha production in response to M. leprae was essentially absent in TLR2-deficient macrophages. Similarly, human TLR2 mediated M. leprae-dependent activation of NF-kappaB in transfected Chinese hamster ovary and human embryonic kidney 293 cells, with enhancement of this signaling in the presence of CD14. In contrast, activation of NF-kappaB by human TLR2Arg(677)Trp was abolished in response to M. leprae and Mycobacterium tuberculosis. The impaired function of this TLR2 variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy and may have important implications for understanding the pathogenesis of other mycobacterial infections.
Toll样受体（TLRs）是先天性免疫对微生物病原体反应的关键介质。我们研究了TLRs在麻风分枝杆菌识别中的作用以及TLR2 Arg(677)Trp的意义，TLR2 Arg(677)Trp是最近发现的一种与瘤型麻风相关的人类多态性。在小鼠中，TLR2缺陷型巨噬细胞对麻风分枝杆菌基本不产生肿瘤坏死因子-α。同样，人TLR2在转染的中国仓鼠卵巢细胞和人胚肾293细胞中介导了麻风分枝杆菌依赖性的核因子-κB激活，在存在CD14的情况下这种信号传导增强。相比之下，人TLR2 Arg(677)Trp对麻风分枝杆菌和结核分枝杆菌的反应中核因子-κB的激活被消除。这种TLR2变体功能受损为与瘤型麻风相关的细胞免疫反应不佳提供了一种分子机制，可能对理解其他分枝杆菌感染的发病机制具有重要意义。
