美国和比利时科学家近日在小鼠免疫系统内发现了一个特殊的机制，关闭这一机制会导致自体免疫疾病产生。这一发现阐明了自体免疫性的产生过程，对于研发新的药物以加强对癌症、艾滋等病的免疫响应也有所启示。相关论文8月13日在线发表于《自然》（Nature）杂志上。
美国国立卫生研究院的科学家研究了免疫系统T细胞，特别是辅助T细胞，并重点关注了furin蛋白，这是一种在T细胞机能中发挥重要作用的酶。furin蛋白很难研究，因为其它一些酶也能执行与其相似的功能，而且，furin蛋白对生命是必不可少的，所以科学家无法创建一个小鼠模型，使其不带furin蛋白而能活过胚胎阶段。
在最新的实验中，研究人员别出心裁，创建了一个仅T细胞不含furin的小鼠模型。结果发现，这些小鼠产生了系统性自体免疫疾病。
论文第一作者、美国国立关节炎、肌与骨骼及皮肤病研究所（NIAMS）的Marko Pesu说：“我们已经知道furin似乎在很多疾病中发挥着作用，如癌症、囊肿性纤维化以及传染病。此次发现说明，某些免疫细胞缺失furin会增加免疫响应并导致小鼠患上自体免疫疾病。”
研究人员还发现，删除辅助T细胞中的furin会影响另两种T细胞——调节性T细胞和效应性T细胞的功能。前者借助Furin促进机体组织与细胞的免疫耐受性，后者缺乏furin会增加攻击性，易导致自体免疫性疾病和组织损伤。
文章另一位作者、NIAMS的科学主任John J. O'Shea说：“抑制furin曾被认为会减少恶性细胞的生长，或通过阻碍病原体的活化来阻止感染。然而，此次研究结果显示，药物干预可能会产生意想不到的副作用——增加患自体免疫疾病的风险。”（生物谷Bioon.com）
生物谷推荐原始出处：
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: pesum@mail.nih.gov).
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.
