Analysis of suscebility genes and pathogenesis of HTLV-I-associated Sjogren's syndrome

HTLV-I相关干燥综合征易感基因及发病机制分析

• 批准号: 13557042
• 负责人: EGUCHI Katsumi
• 金额: $ 6.46万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557042/
• 关键词: Sjogren's syndrome; IL-10; polymorphism; HTLV-I; toll-like receptor; apoptosis; HTLV I-associated myelopathy; SS-B; La; HTLV-I tax; ミトコンドリア; IL-18; GST; TAP; Sjogren症候群; HTLV-1

HTLV-I has been identified as a causative agent which initiates and/or perpetuates the process of Sjogren's syndrome (SS). A high seroprevalence of HTLV-I infection has been determined in SS patients in the HTLV I-endemic area of Nagasaki, Japan. Many patients with HTLV-I-associated myelopathy (HAM/TSP) have been complicated with SS. The present study was undertaken to clarify the involvement of HTLV-I infection on the development or perpetuation of SS. At first, we analyzed promoter region polymorphisms of the IL-10 gene. Our results suggest that the presence of the ATA haplotype of the IL-10 gene are associated with an increased susceptibility to primary SS. Moreover, IL-10 gene promoter region polymorphism affects the age at onset of SS, and the amounts of serum IgG. However, there is no association between the presence of anti-HTLV-I antibodies and IL-10 gene polymorphism. Next, two-color analysis by flow cytometry revealed a significantly high percentage of IL-12Rβl^+ cells in CD4 … More ^+T lymphocytes in HAM/TSP patients compared to the control. These results suggest Th1 immune activation in patients with HAM/TSP, which leads to chronic inflammation in the tissues, mediated by dysregulation of the IL-12/IL-12R. Furthermore, the sLe^<x+>+ cell population, which has features of activated Th1 cells with up-regulated expression of E-selectin and P-selectin ligands mediated by HTLV I infection, is increased in peripheral blood CD4^+T lymphocytes in HAM/TSP patients. These findings suggest their involvement in transmigration of T lymphocytes from peripheral blood into tissues. In addition, our results indicate that peripheral blood CD4^+T lymphocytes of HAM/TSP patients are resistant to apoptosis triggered through mitochondrial death pathway through up-regulations of expression of anti-apoptotic protein, Bcl-xL. We used HTLV-I tax transfectants to show that tax-mediated induction of Bcl-xL expression can protect cells from apoptotic stimuli in a mitochondria-dependent fashion. Compared with tax-negative JPX-9 cells, Bcl-xL expression was clearly augmented in tax-positive JPX-9 cells. These cells were resistant to both receptor-mediated apoptosis and chemical induced apoptosis. Theses results suggest that tax-mediated Bcl-xL expression inhibit apoptosis of activated T lymphocytes in HTLV-I-seropositive subjects, which consequently promotes the onset of autoimmune disorders such as SS. Finally, we demonstrated the expression of TLR-2, TLR-3 and TLR4 on the acinal and ductal cells, and infiltrated mononuclear cells from minor salivary glands of SS. When a human salivary glands (HSG) cell line were stimulated by peptidoglycan, poly I : C, or LPS, HSG cell line augmented the expression of CD54 and production of IL-6, through the phosphorylation of MAP kinase. From the above findings, the development and/or perpetuation of SS might be implicated with HTLV-I infection and the susceptibility genes. Less

HTLV-I已被鉴定为引发和/或延续干燥综合征（SS）过程的病原体。在日本长崎HTLV I型流行区的SS患者中已确定HTLV-I感染的高血清阳性率。许多HTLV-I相关性脊髓病（HAM/TSP）患者合并SS。本研究旨在阐明HTLV-I感染对SS发展或持续的影响。首先，我们分析了IL-10基因启动子区的多态性。我们的研究结果表明，ATA单倍型的IL-10基因的存在与原发性SS的易感性增加。此外，IL-10基因启动子区多态性影响SS的发病年龄和血清IgG水平。然而，抗HTLV-I抗体的存在与IL-10基因多态性之间没有关联。接下来，通过流式细胞术进行的双色分析显示，CD 4+细胞中IL-12 R βl^+细胞的百分比显著升高， ...更多信息 HAM/TSP患者与对照组相比的T淋巴细胞。这些结果表明HAM/TSP患者中的Th 1免疫活化，其导致组织中的慢性炎症，由IL-12/IL-12 R的失调介导。此外，HAM/TSP患者外周血CD 4 ^+T淋巴细胞中sLe^<x+>+细胞群增加，其具有由HTLV I感染介导的E-选择素和P-选择素配体表达上调的活化Th 1细胞的特征。这些发现表明它们参与外周血T淋巴细胞向组织的迁移。此外，我们的研究结果表明HAM/TSP患者外周血CD 4 ^+T淋巴细胞通过上调抗凋亡蛋白Bcl-xL的表达，抵抗线粒体死亡途径引发的凋亡。我们使用HTLV-I tax转染子来表明，tax介导的Bcl-xL表达诱导可以以依赖于细胞凋亡的方式保护细胞免受凋亡刺激。与tax阴性的JPX-9细胞相比，在tax阳性的JPX-9细胞中Bcl-xL表达明显增强。这些细胞对受体介导的凋亡和化学诱导的凋亡都有抗性。这些结果表明，Tax介导的Bcl-xL表达抑制HTLV-I血清阳性受试者中活化的T淋巴细胞的凋亡，从而促进自身免疫性疾病如SS的发作。最后，我们证明了TLR-2，TLR-3和TLR-4的表达腺泡和导管细胞，并从小唾液腺浸润的单个核细胞的SS。人唾液腺（HSG）细胞系在肽聚糖、poly I：C或LPS刺激下，通过MAP激酶的磷酸化，增加了CD 54的表达和IL-6的产生。从以上结果可以看出，SS的发生和/或持续可能与HTLV-Ⅰ的感染和易感基因有关。少

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