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; 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已被确定为一种因果剂，它启动和/或永久化了Sjogren综合征（SS）的过程。在日本长崎的HTLV I-末端区域的SS患者中，已经确定了HTLV-1感染的高血清阳性感染。许多患有HTLV-I相关性骨髓病（HAM/TSP）的患者与SS复杂。本研究的目的是阐明HTLV-I感染有关SS的发展或永久性的参与。首先，我们分析了IL-10基因的启动子区域多态性。我们的结果表明，IL-10基因的ATA单倍型的存在与对原代SS的敏感性增加有关。此外，IL-10基因启动子区域多态性会影响SS发作时的年龄和血清IgG的量。但是，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，通过流式细胞仪进行两种彩色分析显示，与对照相比，HAM/TSP患者中CD4中的IL-12RβL ^+细胞的比例明显很高。这些结果表明，HAM/TSP患者的Th1免疫激活，这会导致组织中的慢性炎症，这是由IL-12/IL-12R失调介导的。此外，在HAM/TSP患者中，在外周血CD4^+T淋巴细胞中增加了活性Th1细胞的SLE^<X+>+细胞群，其具有上调的E-选择蛋白和P-选择蛋白配体的表达的特征增加。这些发现表明它们参与了T淋巴细胞从外周血传播到组织中。此外，我们的结果表明，HAM/TSP患者的外周血CD4^+T淋巴细胞对通过线粒体死亡途径触发的凋亡具有抗性，这是通过对抗凋亡蛋白表达的上调BCl-XL的表达。我们使用HTLV-I税收转换物来表明，税收介导的BCl-XL表达可以以线粒体依赖性方式保护细胞免受凋亡刺激。与税收阴性JPX-9细胞相比，在税阳性JPX-9细胞中明显增强了BCL-XL表达。这些细胞对受体介导的凋亡和化学诱导的凋亡均具有抗性。这些结果表明，税收介导的BCL-XL表达抑制了HTLV-I - 膜阳离子受试者中活化T淋巴细胞的凋亡，从而促进了SS自身免疫性疾病（如SS）的发作。最后，我们证明了TLR-2，TLR-3和TLR4在刺激细胞和导管细胞上的表达，以及来自SS的次要唾液腺的浸润的单核细胞。当人类唾液腺（HSG）细胞系被辣椒，Poly I：C或LPS刺激时，HSG细胞系通过MAP激酶的磷酸化增强了CD54的表达和IL-6的产生。从上面的发现中，SS的发展和/或永久性可能与HTLV-I感染和易感基因有关。较少的