Anderson Mark S, Venanzi Emily S, Klein Ludger, Chen Zhibin, Berzins Stuart P, Turley Shannon J, von Boehmer Harald, Bronson Roderick, Dierich Andrée, Benoist Christophe, Mathis Diane
Section on Immunology and Immunogenetics, Joslin Diabetes Center; Department of Medicine, Brigham and Women's Hospital; Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA.
Science. 2002 Nov 15;298(5597):1395-401. doi: 10.1126/science.1075958. Epub 2002 Oct 10.
Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.
表达缺陷形式转录因子AIRE（自身免疫调节因子）的人类会患上多器官自身免疫性疾病。我们利用Aire基因缺陷小鼠来验证这一假说，即该转录因子通过促进外周组织限制性抗原在胸腺髓质上皮细胞中的异位表达来调节自身免疫。这一假说被证明是正确的。突变动物表现出特定的自身免疫性疾病谱，这取决于胸腺基质细胞中Aire的缺失。Aire基因缺陷的胸腺髓质上皮细胞显示出编码外周抗原的基因异位转录的特异性减少。这些发现突出了胸腺施加的“中枢”耐受性在控制自身免疫中的重要性。
