为什么有些人会自发地患上牛皮癣这样一种慢性皮肤炎症？上周《自然—免疫学》上的一项研究报告给出了解释。
遭牛皮癣感染的皮肤会渗入大量的免疫细胞——包括可分泌产生促炎症细胞因子调节物白细胞介素17（IL-17）和22（IL-22）的TH17细胞在内。免疫细胞会帮助控制皮肤中的微生物感染，但这种免疫反应在牛皮癣中是极度活跃的，容易导致皮肤表皮增厚和中性粒细胞的大量渗入，其中中性粒细胞会在皮肤损伤处释放毒性中间体。
Xiaoxia Li等人报告称，TH17细胞中的IL-17信号失调是致病因素之一。他们的研究采用了携带Act1蛋白特异突变的牛皮癣患病小鼠，Act1蛋白是一种能与IL-17受体相互作用的蛋白，其突变也存在于人类疾病中。
正常的IL-17信号会诱发一种自我限制的炎症反应，但发生Act1蛋白突变的小鼠会自发产生慢性皮肤炎症。研究人员发现突变的Act1蛋白无法与可以消除炎症反应的伴侣蛋白hsp90发生结合。因此，TH17细胞无法停止IL-22的产生。研究人员还发现，利用中和抗体阻断IL-22可减轻突变小鼠的病情。这些发现意味着在治疗中采用抑制IL-22的方法可能对那些Act1蛋白表达存在缺陷的病人有帮助作用。(生物谷Bioon.com)
doi:10.1038/ni.2479
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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.
