Chamberlain Giselle, Wållberg Maja, Rainbow Dan, Hunter Kara, Wicker Linda S, Green E Allison
Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
J Immunol. 2006 Oct 15;177(8):5105-14. doi: 10.4049/jimmunol.177.8.5105.
Identification of candidate genes and their immunological mechanisms that control autoaggressive T cells in inflamed environments, may lead to novel therapies for autoimmune diseases, like type 1 diabetes (T1D). In this study, we used transgenic NOD mice that constitutively express TNF-alpha in their islets from neonatal life (TNF-alpha-NOD) to identify protective alleles that control T1D in the presence of a proinflammatory environment. We show that TNF-alpha-mediated breakdown in T cell tolerance requires recessive NOD alleles. To identify some of these recessive alleles, we crossed TNF-alpha-NOD mice to diabetes-resistant congenic NOD mice having protective alleles at insulin-dependent diabetes (Idd) loci that control spontaneous T1D at either the preinsulitis (Idd3.Idd5) or postinsulitis (Idd9) phases. No protection from TNF-alpha-accelerated T1D was afforded by resistance alleles at Idd3.Idd5. Lack of protection was not at the level of T cell priming, the efficacy of islet-infiltrating APCs to present islet peptides, nor the ability of high levels of CD4+ Foxp3+ T cells to accumulate in the islets. In contrast, protective alleles at Idd9 significantly increased the age at which TNF-alpha-NOD mice developed T1D. Disease delay was associated with a decreased ability of CD8+ T cells to respond to islet Ags presented by islet-infiltrating APCs. Finally, we demonstrate that the protective region on chromosome 4 that controls T1D in TNF-alpha-Idd9 mice is restricted to the Idd9.1 region. These data provide new evidence of the mechanisms by which selective genetic loci control autoimmune diseases in the presence of a strong inflammatory assault.
鉴定在炎症环境中控制自身攻击性T细胞的候选基因及其免疫机制，可能会带来针对自身免疫性疾病（如1型糖尿病，T1D）的新疗法。在本研究中，我们使用了从新生期开始就在胰岛中组成性表达肿瘤坏死因子-α（TNF-α）的转基因非肥胖糖尿病（NOD）小鼠（TNF-α-NOD），以鉴定在促炎环境下控制T1D的保护性等位基因。我们发现，TNF-α介导的T细胞耐受性破坏需要隐性NOD等位基因。为了鉴定其中一些隐性等位基因，我们将TNF-α-NOD小鼠与在胰岛素依赖型糖尿病（Idd）位点具有保护性等位基因的抗糖尿病近交系NOD小鼠杂交，这些位点在胰岛炎前期（Idd3、Idd5）或胰岛炎后期（Idd9）控制自发性T1D。Idd3、Idd5处的抗性等位基因对TNF-α加速的T1D没有保护作用。缺乏保护并非体现在T细胞启动水平、胰岛浸润抗原呈递细胞（APC）呈递胰岛肽的效力，也不是高水平的CD4+Foxp3+T细胞在胰岛中积累的能力上。相比之下，Idd9处的保护性等位基因显著提高了TNF-α-NOD小鼠发生T1D的年龄。疾病延迟与CD8+T细胞对胰岛浸润APC呈递的胰岛抗原作出反应的能力下降有关。最后，我们证明在TNF-α-Idd9小鼠中控制T1D的4号染色体上的保护区域仅限于Idd9.1区域。这些数据为在强烈炎症攻击下选择性基因位点控制自身免疫性疾病的机制提供了新证据。
