Zucchelli Silvia, Holler Phil, Yamagata Tetsuya, Roy Matthew, Benoist Christophe, Mathis Diane
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Immunity. 2005 Mar;22(3):385-96. doi: 10.1016/j.immuni.2005.01.015.
The genetic determinism of type-1 diabetes in NOD mice likely involves complementary defects in central T cell tolerance induction and peripheral immunoregulation. To study the contribution of the NOD genetic background to central tolerance, we followed the behavior of BDC2.5 clonotype thymocytes in fetal thymic organ cultures (FTOC). The NOD genetic background encodes a quantitative deficiency in the ability to delete these self-reactive thymocytes and to divert them to the CD8alphaalpha lineage. In genetic analyses, comparing NOD and B6.H2g7 FTOCs, the NOD defect incorporated the influence of several loci (notably ones on chr1 and 3). Microarray analyses assessing FTOCs from the same two strains argued that the NOD abnormality reflects the combined effects of turning down the gene expression program that provokes apoptosis and turning on a new program promoting cell survival. Intersection of the data from the two approaches points to a small set of attractive candidate genes.
非肥胖糖尿病（NOD）小鼠1型糖尿病的遗传决定因素可能涉及中枢T细胞耐受性诱导和外周免疫调节的互补缺陷。为了研究NOD遗传背景对中枢耐受性的影响，我们在胎儿胸腺器官培养物（FTOC）中追踪了BDC2.5克隆型胸腺细胞的行为。NOD遗传背景编码了一种数量缺陷，即缺乏删除这些自身反应性胸腺细胞并将它们转向CD8αα谱系的能力。在遗传分析中，比较NOD和B6.H2g7 FTOC，NOD缺陷包含了几个基因座（特别是位于1号和3号染色体上的基因座）的影响。评估来自相同两个品系的FTOC的微阵列分析表明，NOD异常反映了下调引发细胞凋亡的基因表达程序和开启促进细胞存活的新程序的综合作用。两种方法的数据交叉指向一小部分有吸引力的候选基因。
