Kay T W, Campbell I L, Oxbrow L, Harrison L C
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Diabetologia. 1991 Nov;34(11):779-85. doi: 10.1007/BF00408350.
Overexpression of class I major histocompatibility complex (MHC) proteins on pancreatic islet cells is a characteristic of autoimmune Type 1 (insulin-dependent) diabetes mellitus in humans and in animal models. Studies of post-mortem pancreases from humans with Type 1 diabetes suggest that overexpression of class I MHC proteins may precede mononuclear cell infiltration of the islets (insulitis). Pancreatic histology from the earliest stages of human Type 1 diabetes is rarely available. We have used the non-obese diabetic mouse, given cyclophosphamide to accelerate Beta-cell destruction, to investigate the temporal relationship between the overexpression of class I MHC protein and mRNA and other pathological changes associated with Beta-cell destruction. Prior to cyclophosphamide, immunoperoxidase staining showed that expression of class I MHC proteins was greater on islet cells and infiltrating inflammatory cells of the non-obese diabetic mouse than on islet cells of other mouse strains, whereas staining on exocrine cells was similar. On day three after cyclophosphamide administration, when insulitis had regressed, islet class I MHC protein expression had diminished. A dramatic increase in class I MHC protein expression occurred between days seven and nine, concomitant with reinfiltration of the islets by mononuclear cells; overexpression was seen both on islet cells and on surrounding exocrine cells, but only in the presence of mononuclear cell infiltration. By day 21, class I MHC protein overexpression was again confined to the islets, the exocrine pancreas being free of infiltration. Class I mRNA also increased dramatically by day eight but had virtually returned to normal by day 12.2+ effected by cytokines secreted by activated immuno-inflammatory cells. Class I MHC overexpression should enhance targeting of cytotoxic T cells to Beta cells bearing autoantigen.
I类主要组织相容性复合体（MHC）蛋白在胰岛细胞上的过度表达是人类和动物模型中自身免疫性1型（胰岛素依赖型）糖尿病的一个特征。对1型糖尿病患者尸检胰腺的研究表明，I类MHC蛋白的过度表达可能先于胰岛的单核细胞浸润（胰岛炎）。人类1型糖尿病最早阶段的胰腺组织学样本很少能获取到。我们使用非肥胖糖尿病小鼠，给予环磷酰胺以加速β细胞破坏，来研究I类MHC蛋白和mRNA的过度表达与β细胞破坏相关的其他病理变化之间的时间关系。在给予环磷酰胺之前，免疫过氧化物酶染色显示，非肥胖糖尿病小鼠的胰岛细胞和浸润的炎性细胞上I类MHC蛋白的表达高于其他小鼠品系的胰岛细胞，而外分泌细胞上的染色相似。在给予环磷酰胺后的第三天，当胰岛炎消退时，胰岛I类MHC蛋白表达减少。在第7天至第9天之间，I类MHC蛋白表达急剧增加，同时单核细胞再次浸润胰岛；在胰岛细胞和周围的外分泌细胞上均可见过度表达，但仅在有单核细胞浸润的情况下出现。到第21天，I类MHC蛋白的过度表达再次局限于胰岛，外分泌胰腺无浸润。I类mRNA在第8天也急剧增加，但在第12.2天几乎恢复正常，这是由活化的免疫炎性细胞分泌的细胞因子所影响。I类MHC的过度表达应会增强细胞毒性T细胞对携带自身抗原的β细胞的靶向作用。
