RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes.
RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes.
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DOI：
10.2337/db10-0795
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发表时间：
2011-03
期刊：
影响因子：
7.7
通讯作者：
Kobayashi T
中科院分区：
文献类型：
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作者：
Aida K;Nishida Y;Tanaka S;Maruyama T;Shimada A;Awata T;Suzuki M;Shimura H;Takizawa S;Ichijo M;Akiyama D;Furuya F;Kawaguchi A;Kaneshige M;Itakura J;Fujii H;Endo T;Kobayashi T
在人类暴发型1型糖尿病中，先天免疫对侵袭性β细胞破坏的作用尚不清楚。研究了暴发型1型糖尿病发病2~5d后3例胰腺组织中Toll样受体(TLRs)、胞浆维甲酸诱导基因I(RIG-I)样受体、下游天然免疫标志物、获得性免疫介质和凋亡标志物的表达。在肠道病毒感染的3例胰腺组织中，RIG-I在β-细胞中均呈强阳性表达。黑色素瘤分化相关基因-5在胰岛细胞中高表达，包括β-和α-细胞。TLR3和TLR4在浸润性胰岛的单核细胞中表达。干扰素-α和干扰素-β在胰岛细胞中高表达。主要组织相容性复合体I类、干扰素-γ、白介素18和CXC基序配体10在受影响的胰岛中表达和共存。CD11c+MHC-II+树突状细胞和巨噬细胞亚群以胰岛细胞碎片为主，表现出明显的吞噬特征。受累胰岛内及周围未见CD4+叉头盒P3+调节性T细胞。单个核细胞表达Fas配体，大部分表达Fas的胰岛均有表达。维甲酸受体反应者3和活化的半胱氨酸蛋白酶8、9和3在β-细胞中优先表达。暴发型1型糖尿病患者血清干扰素-γ水平明显升高。这些发现表明，对肠道病毒感染存在特定的先天免疫反应，与增强的过继免疫途径有关，这些过继免疫途径对暴发型1型糖尿病的侵袭性β细胞毒性负责。
The contribution of innate immunity responsible for aggressive β-cell destruction in human fulminant type 1 diabetes is unclear. Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid–inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes. RIG-I was strongly expressed in β-cells in all three pancreata infected with enterovirus. Melanoma differentiation–associated gene-5 was hyperexpressed in islet cells, including β- and α-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN)-α and IFN-β were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-γ, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC-class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid–receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in β-cells. Serum levels of IFN-γ were markedly increased in patients with fulminant type 1 diabetes. These findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive β-cell toxicity in fulminant type 1 diabetes.