日本科学技术振兴机构日前发表新闻公报说，东京大学的科学家发现了调控自身免疫耐受的髓质上皮细胞的分化和增殖机制，这有助于人们探究自体免疫疾病的原因，开发治疗过敏和癌症等疾病的新疗法。
正常的免疫系统不能耐受外界进入的抗原，对异己物质发生排斥反应，从而消除异己物质，如攻击并消灭入侵机体的细菌、病毒等。另一方面，免疫系统对自身的组织细胞具有耐受性，即表现出无免疫应答状态。这种免疫耐受一旦破裂，免疫系统就会攻击自身的组织细胞，导致自体免疫疾病。
新闻公报介绍说，在免疫反应中起重要作用的T细胞产生于胸腺，而且对自身脏器产生免疫应答的T细胞会被机体自然除去。如果这种自然除去的机制出现异常，免疫系统就会攻击自身脏器，导致自体免疫疾病。近年来的研究显示，胸腺细胞中的髓质上皮细胞在上述自然除去机制中起着非常重要的作用，但是髓质上皮细胞分化、增殖以及发挥作用的机制尚未得到充分解释。
东京大学医学研究所的秋山泰身等研究人员通过分析基因缺失的实验鼠以及进行胸腺组织培养实验，发现两种细胞表面受体——“核因子κB受体活化因子（RANK）”和“CD40”的特殊信号协调发挥作用，使胸腺髓质上皮细胞分化和增殖。如果诱导实验鼠髓质上皮细胞分化和增殖的信号缺失，那么它们体内就会产生对自身脏器产生免疫反应的T细胞。
公报说，这项研究成果有望帮助解开至今仍有诸多谜团的自体免疫疾病发病机制。此外，该研究使人工控制髓质上皮细胞的功能成为可能，有助于开发过敏和癌症等疾病的新疗法。
这项研究的相关论文已发表在最新一期美国《免疫》（Immunity）杂志的网络版上。（生物谷Bioon.com）
生物谷推荐原始出处：
Immunity，Vol 29, 423-437, 19 September 2008，Taishin Akiyama, Jun-ichiro Inoue
The Tumor Necrosis Factor Family Receptors RANK and CD40 Cooperatively Establish the Thymic Medullary Microenvironment and Self-Tolerance
Taishin Akiyama,1,2, Yusuke Shimo,1 Hiromi Yanai,1 Junwen Qin,1 Daisuke Ohshima,1Yuya Maruyama,1 Yukiko Asaumi,1 Juli Kitazawa,1 Hiroshi Takayanagi,3 Josef M. Penninger,4Mitsuru Matsumoto,5 Takeshi Nitta,6 Yousuke Takahama,6 and Jun-ichiro Inoue1
1 Division of Cellular and Molecular biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan
2 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012 Japan
3 Department of Cell Signaling, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-ku, Tokyo 113-8549, Japan
4 Institute of Molecular Biotechnology of the Austrian Academy Sciences, 1030 Vienna, Austria
5 Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan
6 Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan
Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens. However, signals underlying mTEC development remain largely unclear. Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-κB (RANK) and CD40 signals. Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment. Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-κB inducing kinase (NIK)-, and IκB kinase β (IKKβ)-dependent manner. These results show that developmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance.
