Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease
Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease
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DOI：
10.1152/ajpgi.00544.2005
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发表时间：
2006-06-01
影响因子：
4.5
通讯作者：
Cho, JH
中科院分区：
文献类型：
--
作者：
Gewirtz, AT;Vijay-Kumar, M;Cho, JH
克罗恩病（CD）与对肠道微生物的适应性免疫增强有关，鞭毛蛋白是优势抗原。鉴于对先天免疫在调节适应性免疫中的重要性的认识提高以及CD相关免疫应答在CD病理生理学中的作用的模糊性，我们试图确定天然获得的对鞭毛蛋白的免疫应答是否受先天免疫鞭毛蛋白受体toll样受体5（TLR 5）的调节，并确定携带最近确定的常见显性阴性TLR 5多态性的人是否（TLR 5-stop）可以被保护免于显影CD。在炎症性肠病患者、一级亲属和无关对照组中测定了最近定义的显性阴性TLR 5多态性（TLR 5-stop）的携带率和对细菌产物的血清免疫反应性水平。我们观察到，在健康受试者中，携带TLR 5-stop的人具有显著较低水平的鞭毛蛋白特异性IgG和伊加，但具有相似水平的总Ig和LPS特异性IG。此外，我们观察到，在犹太受试者中，TLR 5-stop的携带率与未受影响的亲属和无关对照组相比，CD患者中（杂合状态）（未受影响的亲属、CD、UC和无关的犹太对照分别为5.4、0.9、6.0和6.5%，n = 296、215、185和416; P = 0.037，通过CD与对照的似然计算），表明TLR 5-stop可以保护犹太种族的人免受CD。在非犹太人队列中，我们没有观察到TLR 5-stop与CD的显著相关性（未受影响的亲属、CD和UC分别为11.1、10.4和11.7%;未受影响的亲属分别为n = 841、543和300）。这些结果表明，自然获得的鞭毛蛋白的免疫应答调节TLR 5，并表明，鞭毛蛋白的免疫应答不仅与CD，而是促进致病性反应。
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.