為什么有些人會(huì)自發(fā)地患上牛皮癬這樣一種慢性皮膚炎癥,？上周《自然—免疫學(xué)》上的一項(xiàng)研究報(bào)告給出了解釋,。
遭牛皮癬感染的皮膚會(huì)滲入大量的免疫細(xì)胞——包括可分泌產(chǎn)生促炎癥細(xì)胞因子調(diào)節(jié)物白細(xì)胞介素17（IL-17）和22（IL-22）的TH17細(xì)胞在內(nèi)。免疫細(xì)胞會(huì)幫助控制皮膚中的微生物感染,，但這種免疫反應(yīng)在牛皮癬中是極度活躍的,，容易導(dǎo)致皮膚表皮增厚和中性粒細(xì)胞的大量滲入，其中中性粒細(xì)胞會(huì)在皮膚損傷處釋放毒性中間體,。
Xiaoxia Li等人報(bào)告稱,，TH17細(xì)胞中的IL-17信號(hào)失調(diào)是致病因素之一。他們的研究采用了攜帶Act1蛋白特異突變的牛皮癬患病小鼠,，Act1蛋白是一種能與IL-17受體相互作用的蛋白,，其突變也存在于人類疾病中,。
正常的IL-17信號(hào)會(huì)誘發(fā)一種自我限制的炎癥反應(yīng)，但發(fā)生Act1蛋白突變的小鼠會(huì)自發(fā)產(chǎn)生慢性皮膚炎癥,。研究人員發(fā)現(xiàn)突變的Act1蛋白無(wú)法與可以消除炎癥反應(yīng)的伴侶蛋白hsp90發(fā)生結(jié)合,。因此，TH17細(xì)胞無(wú)法停止IL-22的產(chǎn)生,。研究人員還發(fā)現(xiàn),，利用中和抗體阻斷IL-22可減輕突變小鼠的病情。這些發(fā)現(xiàn)意味著在治療中采用抑制IL-22的方法可能對(duì)那些Act1蛋白表達(dá)存在缺陷的病人有幫助作用,。(生物谷Bioon.com)
doi:10.1038/ni.2479
PMC:
PMID:
The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90
Chenhui Wang, Ling Wu, Katarzyna Bulek, Bradley N Martin, Jarod A Zepp, Zizhen Kang,Caini Liu, Tomasz Herjan, Saurav Misra, Julie A Carman, Ji Gao, Ashok Dongre, Shujie Han,Kevin D Bunting, Jennifer S Ko, Hui Xiao, Vijay K Kuchroo, Wenjun Ouyang & Xiaoxia Li
Act1 is an essential adaptor in interleukin 17 (IL-17)-mediated signaling and is recruited to the receptor for IL-17 after stimulation with IL-17. Here we found that Act1 was a 'client' protein of the molecular chaperone hsp90. The D10N variant of Act1 (Act1(D10N)) that is linked to susceptibility to psoriasis was defective in its interaction with hsp90, which resulted in a global loss of Act1 function. Act1-deficient mice modeled the mechanistic link between loss of Act1 function and susceptibility to psoriasis. Although Act1 was necessary for IL-17-mediated inflammation, Act1-deficient mice had a hyperactive response of the TH17 subset of helper T cells and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17 signaling, IL-22 was the main contributor to skin inflammation, which provides a molecular mechanism for the association of Act1(D10N) with psoriasis susceptibility.
