Transgenic expression of Hsc70 in pancreatic islets enhances autoimmune diabetes in response to beta cell damage.
Transgenic expression of Hsc70 in pancreatic islets enhances autoimmune diabetes in response to beta cell damage.
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DOI：
10.4049/jimmunol.0901288
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发表时间：
2009-11-01
期刊：
影响因子：
--
通讯作者：
Millar DG
中科院分区：
文献类型：
--
作者：
Alam MU;Harken JA;Knorn AM;Elford AR;Wigmore K;Ohashi PS;Millar DG
组织损伤后的炎症促进淋巴细胞募集、组织重塑和伤口愈合，同时保持自身耐受性。与组织损伤和细胞死亡相关的内源性信号被认为可以启动和指导损伤后的免疫反应。在这里，我们研究了一种候选内源性危险信号--热休克相关蛋白70(Hsc70)水平升高对刺激炎症和细胞损伤后自身免疫的影响。我们发现，在转基因小鼠模型中，表达额外胞浆Hsc70的胰腺β细胞的损伤会导致糖尿病发病率的增加。在链脲佐菌素诱导的β细胞死亡后，引流淋巴结中活化的APC和T细胞群的稳态水平增加，并进一步增加。此外，Hsc70转基因小鼠的促炎血清细胞因子和淋巴细胞募集增加。在β细胞损伤后，胰岛抗原特异性T细胞在表达Hsc70的小鼠的淋巴结中经历了更大程度的增殖，这表明在Hsc70存在的情况下释放抗原后抗原提呈增加。这些发现表明，在经历坏死性或凋亡性细胞死亡的细胞中，Hsc70含量的增加会增加无菌炎症的程度，并增加自身免疫的易感性。
Inflammation following tissue damage promotes lymphocyte recruitment, tissue remodelling, and wound healing while maintaining self tolerance. Endogenous signals associated with tissue damage and cell death have been proposed to initiate and instruct immune responses following injury. Here we have examined the effects of elevated levels of a candidate endogenous danger signal, heat shock cognate protein 70 (Hsc70), on stimulation of inflammation and autoimmunity following cell damage. We find that damage to pancreatic β-cells expressing additional cytosolic Hsc70 leads to an increased incidence of diabetes in a transgenic mouse model. Steady-state levels of activated APC and T cell populations in the draining lymph node were enhanced, which further increased following streptozotocin-induced β-cell death. In addition, pro-inflammatory serum cytokines, and lymphocyte recruitment were increased in Hsc70 transgenic mice. Islet-antigen-specific T cells underwent a greater extent of proliferation in the lymph nodes of mice expressing Hsc70 following β-cell damage, suggesting elevated antigen presentation following release of antigen in the presence of Hsc70. These findings suggest that an elevated content of Hsc70 in cells undergoing necrotic or apoptotic cell death can increase the extent of sterile inflammation and increase the susceptibility to autoimmunity.
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影响因子：
15.3
作者：
Ehl, S;Hombach, J;Aichele, P;Rülicke, T;Odermatt, B;Hengartner, H;Zinkernagel, R;Pircher, H
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15.3
作者：
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影响因子：
4.4
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影响因子：
5.4
作者：
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通讯作者：
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