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首页> 外文期刊>American Journal of Physiology >Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease.
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Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease.

机译：显性阴性的TLR5多态性降低了对鞭毛蛋白的适应性免疫反应，并与克罗恩氏病呈负相关。

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Crohn's disease (CD) is associated with elevated adaptive immunity to commensal microbes, with flagellin being a dominant antigen. In light of heightened awareness of the importance of innate immunity in regulating adaptive immunity and ambiguity as to the role of CD-associated immune responses in CD pathophysiology, we sought to determine whether natural acquisition of immune responses to flagellin were regulated by the innate immune flagellin receptor toll-like receptor 5 (TLR5) and determine whether persons carrying a recently defined common dominant-negative TLR5 polymorphism (TLR5-stop) might be protected from developing CD. Carriage rates of a recently defined dominant-negative TLR5 polymorphism (TLR5-stop) and levels of serum immunoreactivity to bacterial products were measured in inflammatory bowel disease patients, first-degree relatives, and unrelated controls. We observed that, in healthy subjects, persons carrying TLR5-stop had significantly lower levels of flagellin-specific IgG and IgA but had similar levels of total and LPS-specific Ig. Moreover, we observed that, among Jewish subjects, the carriage rate of TLR5-stop (in heterozygous state) was significantly less in CD patients, but not ulcerative colitis (UC) patients, compared with unaffected relatives and unrelated controls (5.4, 0.9, 6.0, and 6.5% for unaffected relatives, CD, UC, and unrelated Jewish controls, respectively, n = 296, 215, 185, and 416, respectively; P = 0.037 by likelihood calculation for CD vs. controls), indicating that TLR5-stop can protect persons of Jewish ethnicity against CD. We did not observe a significant association of TLR5-stop with CD in a non-Jewish cohort (11.1, 10.4, and 11.7% for unaffected relatives, CD, and UC, respectively; n = 841, 543, and 300 for unaffected relatives, respectively). These results demonstrate that natural acquisition of immune responses to flagellin are regulated by TLR5 and suggest that immune responses to flagellin are not merely associated with CD but rather promote the pathogenic response.
机译：克罗恩氏病（CD）与对共生微生物的适应性免疫增强有关，鞭毛蛋白是主要抗原。鉴于人们越来越意识到先天免疫在调节适应性免疫中的重要性以及关于CD相关免疫反应在CD病理生理中的模糊性的重要性，我们试图确定先天免疫鞭毛蛋白是否能自然调节对鞭毛蛋白的免疫反应受体收费型受体5（TLR5），并确定是否具有最近定义的常见显性负性TLR5多态性（TLR5终止）的人是否可以免受CD的感染。在炎症性肠病患者，一级亲属和无关对照中，测定了最近定义的显性阴性TLR5多态性（TLR5终止）的携带率和血清对细菌产品的免疫反应水平。我们观察到，在健康受试者中，携带TLR5-stop的人的鞭毛蛋白特异性IgG和IgA含量明显降低，但总脂蛋白和LPS特异性Ig含量相似。此外，我们观察到，在犹太受试者中，与未受影响的亲戚和不相关的对照相比，CD患者而非杂合性结肠炎（UC）患者的TLR5终止（杂合状态）携带率显着降低（5.4、0.9，未受影响的亲戚，CD，UC和不相关的犹太对照分别为6.0和6.5％，n = 296、215、185和416;通过CD与对照的似然计算得出P = 0.037），表明TLR5-停止可以保护犹太人免受CD侵害。在非犹太人队列中，我们没有观察到TLR5终止子与CD有显着相关性（未受影响的亲戚，CD和UC分别为11.1、10.4和11.7％;未受影响的亲戚分别为841、543和300，分别）。这些结果表明，对鞭毛蛋白的免疫应答的自然获得受到TLR5的调节，并表明对鞭毛蛋白的免疫应答不仅与CD相关，而且还促进了致病应答。

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