Cellular Mechanisms of Restored a-Cell Tolerance Mediated by Protective Alleles of Idd3 and Idd5
Cellular Mechanisms of Restored a-Cell Tolerance Mediated by Protective Alleles of Idd3 and Idd5
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DOI：
10.2337/db11-0790
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发表时间：
2012-01-01
期刊：
影响因子：
7.7
通讯作者：
Sherman, Linda A.
中科院分区：
文献类型：
--
作者：
Hamilton-Williams, Emma E.;Cheung, Jocelyn;Sherman, Linda A.
白细胞介素(IL)-2、细胞毒性t淋巴细胞相关蛋白4 （CTLA-4）和天然耐药相关巨噬细胞蛋白（NRAMP1）通路中的1型糖尿病基因影响人类和NOD小鼠自身免疫性糖尿病的发展。在NOD小鼠中，编码IL-2、Idd3候选基因、CTLA-4、NRAMP1和乙酰辅酶A脱氢酶长链（ACADL） （Idd5.1、Idd5.2和Idd5.3亚区候选基因）的保护性等位基因一起存在时，提供了几乎完全的糖尿病保护。为了确定Idd3和Idd5亚区的保护性等位基因必须存在于何处以保护糖尿病和耐受胰岛特异性CD8(+) T细胞，对SCID小鼠进行了重组，使宿主和淋巴细胞表达Idd3和Idd5的各种保护性和易感等位基因组合。尽管淋巴细胞中的保护性Idd3等位基因和SCID宿主中的保护性Idd5等位基因对CD8耐受性的贡献最为显著，但在完整的Idd3/5小鼠中观察到的有效糖尿病保护作用，需要淋巴细胞和非淋巴细胞中同时存在这两个等位基因。我们的结论是，参与自身免疫性疾病的遗传区域并不局限于它们对个体细胞类型的影响。即使是单一的保护基因产物，如IL-2，也必须在淋巴细胞和树突状细胞中同时表达，才能充分发挥其疾病保护作用。这些研究强调了决定自身免疫性疾病易感性的基因的多效性。中国糖尿病杂志（英文版），2012
Type 1 diabetes genes within the interleulcin (IL)-2, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and natural resistance-associated macrophage protein (NRAMP1) pathways influence development of autoinunune diabetes in humans and NOD mice. In NOD mice, when present together, protective alleles encoding IL-2, Idd3 candidate gene, CTLA-4, NRAMP1, and acetyl-coenzyme A dehydrogenase, long-chain (ACADL) (candidate genes for the Idd5.1, Idd5.2, and Idd5.3 subregions) provide nearly complete diabetes protection. To define where the protective alleles of Idd3 and the Idd5 subregions must be present to protect from diabetes and tolerize islet-specific CD8(+) T cells, SCID mice were reconstituted so that the host and lymphocytes expressed various combinations of protective and susceptibility alleles at Idd3 and Idd5. Although protective Idd3 alleles in the lymphocytes and protective Idd5 alleles in the SCID host contributed most significantly to CD8 tolerance, both were required together in both lymphocyte and nonlymphocyte cells to recapitulate the potent diabetes protection observed in intact Idd3/5 mice. We conclude that genetic regions involved in autoimmune disease are not restricted in their influence to individual cell types. Even a single protective gene product, such as IL-2, must be expressed in both the lymphocytes and dendritic cells to exert its full extent of disease protection. These studies highlight the pleiotropic effects of genes that determine autoinunune disease susceptibility. Diabetes 61:166-174, 2012