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 已被确定为引发和/或延续干燥综合征 (SS) 过程的病原体，在长崎 HTLV I 流行区的 SS 患者中已确定 HTLV-I 感染的血清阳性率较高。 ，日本，许多 HTLV-I 相关脊髓病 (HAM/TSP) 患者并发 SS。本研究旨在阐明 HTLV-I 感染的参与情况。首先，我们分析了 IL-10 基因的启动子区域多态性，结果表明 IL-10 基因 ATA 单倍型的存在与原发性 SS 的易感性增加有关。 IL-10基因启动子区多态性影响SS发病年龄和血清IgG量，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，与对照组相比，HAM/TSP 患者的 CD4… More ^+T 淋巴细胞中 IL-12Rβ1^+ 细胞的比例显着较高。这些结果表明，HAM/TSP 患者中的 Th1 免疫激活。 TSP，其通过IL-12/IL-12R失调介导而导致组织中的慢性炎症。此外，sLe^<x+++细胞群具有活化的Th1细胞的特征。 HAM/TSP 患者外周血 CD4+T 淋巴细胞中由 HTLV I 感染介导的 E-选择素和 P-选择素配体表达上调，这些发现表明它们参与 T 淋巴细胞从外周血迁移到组织的过程。此外，我们的结果表明，HAM/TSP患者的外周血CD4^+T淋巴细胞通过上调抗凋亡蛋白的表达来抵抗线粒体死亡途径引发的细胞凋亡， Bcl-xL。我们使用 HTLV-Itax 转染子表明，tax 介导的 Bcl-xL 表达诱导可以以线粒体依赖性方式保护细胞免受凋亡刺激，与 Tax 阴性 JPX-9 细胞相比，Bcl-xL 表达。 Tax 阳性 JPX-9 细胞中的 Bcl-xL 表达明显增强，这些细胞对受体介导的细胞凋亡和化学诱导的细胞凋亡具有抵抗力。 HTLV-I 血清阳性受试者，从而促进 SS 等自身免疫性疾病的发生。最后，我们证明了 TLR-2、TLR-3 和 TLR4 在腺泡和导管细胞以及小唾液腺浸润的单核细胞上的表达。当人唾液腺 (HSG) 细胞系受到肽聚糖、聚 I:C 或 LPS 刺激时，HSG 细胞系会增强 SS 的表达。 CD54 和 IL-6 的产生，通过 MAP 激酶的磷酸化从上述发现来看，SS 的发展和/或持续可能与 HTLV-I 感染和易感基因有关。

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