美國和比利時(shí)科學(xué)家近日在小鼠免疫系統(tǒng)內(nèi)發(fā)現(xiàn)了一個(gè)特殊的機(jī)制，關(guān)閉這一機(jī)制會(huì)導(dǎo)致自體免疫疾病產(chǎn)生,。這一發(fā)現(xiàn)闡明了自體免疫性的產(chǎn)生過程,，對于研發(fā)新的藥物以加強(qiáng)對癌癥、艾滋等病的免疫響應(yīng)也有所啟示,。相關(guān)論文8月13日在線發(fā)表于《自然》（Nature）雜志上,。
美國國立衛(wèi)生研究院的科學(xué)家研究了免疫系統(tǒng)T細(xì)胞，特別是輔助T細(xì)胞,，并重點(diǎn)關(guān)注了furin蛋白,，這是一種在T細(xì)胞機(jī)能中發(fā)揮重要作用的酶。furin蛋白很難研究,，因?yàn)槠渌恍┟敢材軋?zhí)行與其相似的功能,，而且，furin蛋白對生命是必不可少的,，所以科學(xué)家無法創(chuàng)建一個(gè)小鼠模型,，使其不帶furin蛋白而能活過胚胎階段。
在最新的實(shí)驗(yàn)中,，研究人員別出心裁,，創(chuàng)建了一個(gè)僅T細(xì)胞不含furin的小鼠模型,。結(jié)果發(fā)現(xiàn),，這些小鼠產(chǎn)生了系統(tǒng)性自體免疫疾病。
論文第一作者,、美國國立關(guān)節(jié)炎,、肌與骨骼及皮膚病研究所（NIAMS）的Marko Pesu說：“我們已經(jīng)知道furin似乎在很多疾病中發(fā)揮著作用，如癌癥,、囊腫性纖維化以及傳染病,。此次發(fā)現(xiàn)說明，某些免疫細(xì)胞缺失furin會(huì)增加免疫響應(yīng)并導(dǎo)致小鼠患上自體免疫疾病,。”
研究人員還發(fā)現(xiàn),，刪除輔助T細(xì)胞中的furin會(huì)影響另兩種T細(xì)胞——調(diào)節(jié)性T細(xì)胞和效應(yīng)性T細(xì)胞的功能。前者借助Furin促進(jìn)機(jī)體組織與細(xì)胞的免疫耐受性,，后者缺乏furin會(huì)增加攻擊性,，易導(dǎo)致自體免疫性疾病和組織損傷。
文章另一位作者,、NIAMS的科學(xué)主任John J. O'Shea說：“抑制furin曾被認(rèn)為會(huì)減少惡性細(xì)胞的生長,，或通過阻礙病原體的活化來阻止感染。然而,，此次研究結(jié)果顯示,，藥物干預(yù)可能會(huì)產(chǎn)生意想不到的副作用——增加患自體免疫疾病的風(fēng)險(xiǎn),。”（生物谷Bioon.com）
生物谷推薦原始出處：
Nature，doi:10.1038/nature07210,，Marko Pesu,，John J. O'Shea
T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance
Marko Pesu1, Wendy T. Watford1, Lai Wei1, Lili Xu2, Ivan Fuss2, Warren Strober2, John Andersson3, Ethan M. Shevach3, Martha Quezado5, Nicolas Bouladoux4, Anton Roebroek6, Yasmine Belkaid4, John Creemers7 & John J. O'Shea1
Molecular Immunology and Inflammation Branch, National Institute for Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Mucosal Immunity Section, Laboratory of Host Defenses,
Cellular Immunology Section, Laboratory of Immunology
Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Experimental Mouse Genetics,
Laboratory for Biochemical Neuroendocrinology, K.U. Leuven and V.I.B., B-3000 Leuven, Belgium
Correspondence to: Marko Pesu1 Correspondence and requests for materials should be addressed to M.P. (Email: [email protected]).
Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins1. It is induced in activated T cells and is reported to process a variety of substrates including the anti-inflammatory cytokine transforming growth factor (TGF)-1 (refs 2–4), but the non-redundant functions of furin versus other proprotein convertases in T cells are unclear. Here we show that conditional deletion of furin in T cells allowed for normal T-cell development but impaired the function of regulatory and effector T cells, which produced less TGF-1. Furin-deficient T regulatory (Treg) cells were less protective in a T-cell transfer colitis model and failed to induce Foxp3 in normal T cells. Additionally, furin-deficient effector cells were inherently over-active and were resistant to suppressive activity of wild-type Treg cells. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its non-redundant, essential function in regulating TGF-1 production. Targeting furin has emerged as a strategy in malignant and infectious disease5, 6. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.
