Study on the Pathogenesis of Type 1 Diabetes Mellitus

1型糖尿病发病机制研究

• 批准号: 01480290
• 负责人: HANAFUSA Toshiaki
• 金额: $ 4.29万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-01480290/
• 关键词: Type 1 diabetes; MHC antigens; Cytokines; Interferon-gamma; Pancreatic beta cells; Pathogenesis; Insulin secretion; Molecular biology; インスリノ-マ細胞; トランスフェクション; 遺伝子導入; FACS; 腫瘍壊死因子; Northern blotting

The pathogenic role of abnormal expression of major histocompatibility complex (MHC) antigens on pancreatic beta cells was studied using molecular biological techniques.We first tested which cytokines could induce MHC antigen expression on rat insulinoma cell line RINm5F. Messenger RNAs of class I and class II MHC molecules were examined by Northern analysis. The result showed that, in the absence of cytokines, 1) class I MHC antigen mRNA was constitutively expressed but 2) class II MHC mRNA was not detected in RINm5F cells. Class I mRNA was increased in response to either interferonーgamma (IFNgamma) or IFNgamma plus tumor necrosis factorーalpha (TNFalpha). However, no class II mRNA was detected after the challenge of any cytokines. On the other hand, insulin mRNA was decreased in the presence of either IFNgamma or IFNgamma+TNFalpha.We secondly examined the effect of MHC antigen expression on beta cell function, namely insulin secreting capacity. RINm5F cells were transfected with human MHC class I antigen (HLA-Cw2) gene and twelve clones with different degrees of expression of the transfectant were obtained. Insulin secreting capacity of the clones in response to glucose was negatively correlated with the amount of class I MHC antigen expressed.These results indicate that the expression of MHC antigen in beta cells is controlled by various cytokines and that insulin secreting capacity is impaired by the expression of MHC antigens in beta cells. This suggests the importance of MHC antigen expression in the pathogenesis of Type 1 diabetes mellitus.

为研究胰岛β细胞主要组织相容性复合体（MHC）抗原异常表达的致病作用，我们首先检测了哪些细胞因子能诱导大鼠胰岛瘤细胞系RINm 5 F表达MHC抗原。通过北方分析检测I类和II类MHC分子的信使RNA。结果表明，在无细胞因子存在的情况下，RINm 5 F细胞中I类MHC抗原mRNA呈组成性表达，而II类MHC mRNA未检测到。I类mRNA的增加是对干扰素γ（IFN γ）或IFN γ加肿瘤坏死因子α（TNF α）的反应。然而，在任何细胞因子的攻击后没有检测到II类mRNA。另一方面，在IFN γ或IFN γ + TNF α的存在下，胰岛素mRNA降低。我们其次检查了MHC抗原表达对β细胞功能的影响，即胰岛素分泌能力。将人MHC Ⅰ类抗原（HLA-Cw 2）基因转染RINm 5 F细胞，获得12个表达不同程度的克隆。胰岛素分泌能力与MHC Ⅰ类抗原表达量呈负相关，提示β细胞MHC抗原表达受多种细胞因子调控，胰岛素分泌能力受β细胞MHC抗原表达的影响。这表明MHC抗原表达在1型糖尿病发病机制中的重要性。

项目成果

T.Hanafusa,et al.: "Examination of islets in the pancreas biopsy specimens from newly diagnosed Type 1 (insulinーdependent) diabetic patients." Diabetologia. 33. 105-111 (1990)

T.Hanafusa 等人：“对新诊断的 1 型（胰岛素依赖型）糖尿病患者的胰腺活检标本中的胰岛进行检查。” 33. 105-111 (1990)。

K.Yamagata,et al.: "Expression of MHC antigens on islet cells in insulin-dependent diabetes mellitus:analysis of pancreas biopsy specimens and RINm5F cells." Proc.of the 2nd Japan/China Symp.on Diabetes Mellitus. (1990)

K.Yamagata 等人：“胰岛素依赖性糖尿病中胰岛细胞上 MHC 抗原的表达：胰腺活检标本和 RINm5F 细胞的分析。”

K.Yamagata,et al.: "HLAーDQ1^*1 contributes to resistance and A1^*3 confers susceptiーbility to Type 1 diabetes mellitus in Japanese subjects." Diabetologia. (1991)

K. Yamagata 等人：“HLA-DQ1^*1 有助于日本受试者抵抗，而 A1^*3 则增加对 1 型糖尿病的易感性”(1991)。

A.Miyazaki,et al.: "Demonstration of interleukin-1β on perifollicular endothelial cells in the thyroid glands of patients with Graves' disease." J.Clin.Endocrinol.Metab.69. 738-744 (1989)

A. Miyazaki 等人：“Graves 病患者甲状腺滤泡周围内皮细胞中白细胞介素 1β 的表现。J.Clin.Endocrinol.Metab.69 (1989)。

M.MoriーTanaka,et al.: "Inhibitory effect of ionophore A23187 on the release of thyroid hormone and colloid reabsorption in mouse thyroid glands." Acta Endocrinol.(1991)

M. Mori Tanaka 等人：“离子载体 A23187 对小鼠甲状腺激素释放和胶体重吸收的抑制作用”（Acta Endocrinol）。