Genome and hormones: Gender differences in physiology selected contribution: Association of gender-related LMP2 inactivation with autoimmune pathogenesis
Genome and hormones: Gender differences in physiology selected contribution: Association of gender-related LMP2 inactivation with autoimmune pathogenesis
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DOI：
10.1152/jappl.2001.91.6.2804
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发表时间：
2001-12-01
影响因子：
3.3
通讯作者：
Faustman, DL
中科院分区：
文献类型：
--
作者：
Hayashi, T;Faustman, DL
自身免疫性糖尿病动物模型（非肥胖糖尿病（NOD）小鼠）的最新结果提出了一个假设来解释主要组织相容性复合体（MHC）在自身免疫中的作用。基因组 MHC 区域包含对于 T 细胞教育和 MHC 分子抗原呈递非常重要的免疫应答基因。编码 LMP2 和 LMP7 蛋白酶体亚基的两个这样的基因位于这个高风险 MHC 基因组区域。含有 LMP2 亚基的蛋白酶体对于 T 细胞教育至关重要，并通过蛋白水解激活转录因子核因子 -kappaB。具有明显女性疾病表达特异性的 NOD 小鼠的脾细胞 LMP2 表达有缺陷。 NOD 小鼠中自发缺陷的 LMP2 表达（性别偏向于女性群体）仅限于选定的淋巴和骨髓细胞，并且在发育过程中受到 LMP2 蛋白降低和肿瘤坏死因子-α 诱导的细胞凋亡增加的控制。这些缺陷仅在大约 7 周龄后才会显现出来。这些数据表明蛋白酶体在自身免疫进展中的作用，并且LMP2表达的性别发育和谱系限制可能导致在雌性NOD小鼠中优先观察到的多种自身免疫特征。
Recent results in an animal model of autoimmune diabetes, the nonobese diabetic (NOD) mouse, suggest a hypothesis to explain the role of major histocompatibility complex (MHC) in autoimmunity. The genome MHC region contains immune response genes that are important for T cell education and antigen presentation by MHC molecules. Two such genes encoding the LMP2 and LMP7 proteasome subunits are located in this high-risk MHC genomic region. Proteasome containing the LMP2 subunit is essential for T cell education and proteolytically activates transcription factor nuclear factor-kappaB. Splenocytes of NOD mouse with marked female specificity for disease expression are defective in LMP2 expression. The spontaneous defective LMP2 expression in NOD mice, which is gender biased toward female cohorts, is restricted to select lymphoid and myeloid cells and is developmentally controlled with lowered LMP2 protein and heightened tumor necrosis factor-alpha -induced apoptosis. These defects are apparent only after similar to7 wk of age. These data suggest a proteasome role in autoimmune progression, and a gender developmental and lineage restriction of LMP2 expression may contribute to the diverse autoimmune characteristics preferentially observed in female NOD mice.