Pechhold Klaus, Karges Wolfram, Blum Carmen, Boehm Bernhard O, Harlan David M
NIDDK Transplantation and Autoimmunity Branch, Bethesda, MD 20889, USA.
J Autoimmun. 2003 Feb;20(1):1-13. doi: 10.1016/s0896-8411(02)00105-1.
T cell responses toward pancreatic beta cell autoantigens arise spontaneously or on immunization in many mouse strains, yet sustained islet infiltration and progressive diabetes rarely ensues. Most mouse diabetes models overcome the innocuous coexistence of anti-islet specific T cells and endogenous islets via incompletely understood mechanisms (e.g. the spontaneous disease onset of the non-obese diabetic mouse) or depend on overwhelming numbers of peripheral islet-specific T cells. We report that insulin promoter murine CD80 (RIP-CD80) transgenic mice are extraordinarily susceptible to autoantigen-induced diabetes, while spontaneous disease is rare. Autoimmunity to the pancreatic beta cell-expressed glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) was elicited by a single injection of syngeneic fibroblastoid cell lines (FCL) loaded with the immunodominant LCMV-GP peptide, gp33. While both RIP-GP(+)and RIP-CD80(+)GP(+)mice mounted moderate CD4-independent CTL responses, only CD80(+)GP(+)mice developed severe insulitis and diabetes due to islet-infiltration of activated, gp33-specific, CD8(+)T cells. Strikingly, DNA immunization using plasmids encoding LCMV-GP or murine preproinsulin also efficiently induced Ag-specific RIP-CD80-dependent diabetes. We conclude that aberrant CD80-expression in a peripheral tissue disrupts that tissue's natural resistance to CD8 T cell-mediated autoimmune destruction. This rodent model thus represents a novel approach to identify beta cell-derived autoantigenic determinants involved in the pathogenesis of autoimmune diabetes, and may also serve as a prototype approach to uncover relevant autoantigens leading to a variety of organ-specific autoimmune disorders.
在许多小鼠品系中，T细胞对胰腺β细胞自身抗原的反应可自发出现或在免疫后产生，但很少会出现持续性胰岛浸润和进行性糖尿病。大多数小鼠糖尿病模型通过尚未完全了解的机制（如非肥胖糖尿病小鼠的自发性疾病发作）克服了抗胰岛特异性T细胞与内源性胰岛的无害共存，或依赖于大量外周胰岛特异性T细胞。我们报告，胰岛素启动子小鼠CD80（RIP-CD80）转基因小鼠极易受到自身抗原诱导的糖尿病影响，而自发性疾病很少见。通过单次注射负载免疫显性淋巴细胞脉络丛脑膜炎病毒（LCMV）糖蛋白（GP）肽gp33的同基因成纤维样细胞系（FCL），引发了对胰腺β细胞表达的LCMV糖蛋白（GP）的自身免疫。虽然RIP-GP(+)和RIP-CD80(+)GP(+)小鼠都产生了中等程度的不依赖CD4的CTL反应，但只有CD80(+)GP(+)小鼠因活化的gp33特异性CD8(+)T细胞浸润胰岛而出现严重的胰岛炎和糖尿病。引人注目的是，使用编码LCMV-GP或小鼠前胰岛素原的质粒进行DNA免疫也能有效诱导抗原特异性的RIP-CD80依赖性糖尿病。我们得出结论，外周组织中异常的CD80表达会破坏该组织对CD8 T细胞介导的自身免疫破坏的天然抵抗力。因此，这种啮齿动物模型代表了一种识别参与自身免疫性糖尿病发病机制的β细胞衍生自身抗原决定簇的新方法，也可能作为一种原型方法来揭示导致各种器官特异性自身免疫性疾病的相关自身抗原。
