Defective function of the proteasome in autoimmunity: involvement of impaired NF-kappaB activation.
Defective function of the proteasome in autoimmunity: involvement of impaired NF-kappaB activation.
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DOI：
10.1089/15209150050194288
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发表时间：
2000-01-01
影响因子：
5.4
通讯作者：
Faustman, D
中科院分区：
文献类型：
--
作者：
Hayashi, T;Faustman, D
1型糖尿病（也称为胰岛素依赖型糖尿病或青少年发病型糖尿病）通常由T细胞介导的自身免疫引起，具有糖尿病前期状态，其特征在于产生对胰腺β细胞表达的蛋白质特异性的自身抗体。非肥胖糖尿病患者（NOD）小鼠是1型糖尿病的自发模型，具有强遗传成分，其映射到基因组的主要组织相容性复合体（MHC）区域。在NOD小鼠中，在选择的淋巴细胞和单核细胞谱系中已经鉴定出特异性蛋白酶体缺陷，其由蛋白酶体亚基LMP 2的表达下调引起，所述蛋白酶体亚基LMP 2由MHC基因组区域中的基因编码。这种缺陷阻止了转录因子核因子-κ B（NF-κ B）的产生和活化所需的蛋白水解加工，其在免疫和炎症反应中起重要作用，以及增加受影响细胞对肿瘤坏死因子-α（TNF-α）诱导的细胞凋亡的易感性。蛋白酶体在自身免疫功能障碍中的新作用被提出并记录为组织和发育阶段特异性的。我们提出蛋白酶体作为疾病发病机制和组织靶向的一个步骤的作用。
Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The nonobese patient with diabetes (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse in select lymphocytic and monocytic lineages that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). The novel role of the proteasome in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific. We propose a role of the proteasome as a step in disease pathogenesis and tissue targeting.