Gray Daniel H D, Gavanescu Irina, Benoist Christophe, Mathis Diane
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18193-8. doi: 10.1073/pnas.0709160104. Epub 2007 Nov 8.
The danger theory of immune tolerance asserts that environmental factors hold primacy over lymphocyte autoreactivity in initiating autoimmune disease. We sought to test this contention using the Aire-deficient mouse model of the human disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, a multiorgan autoimmune disorder rooted in a lesion in thymic tolerance. Compound screens stimulating a broad range of innate immune system pathways failed to show any modulation of disease characteristics in Aire(-/-) mice on either the C57BL/6 or NOD genetic backgrounds. Furthermore, deficiency in the Toll-like receptor adaptor Myd88 increased the lifespan of NOD.aire(-/-) mice but did not prevent the initiation of autoimmunity. Finally, germ-free NOD.aire(-/-) mice exhibited autoimmunity in all organs normally targeted in this model, indicating that microbial conditioning is not required for activation of autoreactive T cells relevant to this disease. Together, these data suggest that the stochastic genesis of dangerous T cell clones can initiate autoimmune disease without the need for environmental stimulation, underlining the importance of Aire-dependent thymic deletion.
免疫耐受的危险理论认为，在引发自身免疫性疾病方面，环境因素比淋巴细胞自身反应性更为重要。我们试图利用人类疾病自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良的Aire缺陷小鼠模型来验证这一观点，该疾病是一种多器官自身免疫性疾病，其根源在于胸腺耐受性的损伤。刺激广泛的先天免疫系统途径的化合物筛选未能显示出在C57BL/6或NOD遗传背景下的Aire(-/-)小鼠中疾病特征有任何调节。此外，Toll样受体衔接蛋白Myd88的缺陷延长了NOD.aire(-/-)小鼠的寿命，但并未阻止自身免疫的发生。最后，无菌的NOD.aire(-/-)小鼠在该模型中所有正常靶向的器官中都表现出自身免疫，这表明与该疾病相关的自身反应性T细胞的激活不需要微生物调节。总之这些数据表明，危险T细胞克隆的随机产生可以引发自身免疫性疾病，而无需环境刺激，这突出了Aire依赖性胸腺缺失的重要性。
