Role of adult T cell lymphotropic virus 1 on pathogenesis of Sjogren's syndrome.

成人 T 细胞嗜淋巴细胞病毒 1 在干燥综合征发病机制中的作用。

• 批准号: 05670426
• 负责人: EGUCHI Katsumi
• 金额: $ 1.28万
• 依托单位: The First Department of Internal Medicine, Nagasaki University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670426/
• 关键词: Sjogren's syndrome; HTLV-I; Tax gene; Anti-HTLV-I antibody; Vascular endothelial cell; Adhesion molecule; Cytokine; Syncytium formation; 抗HTLV-I抗体; シェーグレン症候群

Autoimmune diseases occur in a genetically susceptible patient after tiggering events including bacterial and viral infections, environmental insults, drugs or hormons.There is accumulating evidence that human T cell lymphotropic virus type-I (HTLV-I) infection contributes to the development of various inflammatory disorders. To elucidate the relation between the infection and Sjogren's syndrome (SjS), seroepidemiological and virological studies were conducted on patients with this syndrome. The HTLV-I seroprevalence rate among the patients with SjS was significantly higher than that among blood donors. Titers of serum antibodies in the HTLV-I seropositive patients with SjS were similar to those among patients with HTLV-I-associated myelopathy/tropical spatic paraparesis (HAM/TSP) and significantly higher than those among healthy carriers. IgM antibodies to HTLV-I were commonly detected in the sera of patients with SjS.Salivary IgA antibodies to HTLV-I were common among seropositive pa … More tients with SjS,which might be due to increased viral activity in the salivary glands. Those antibodies were barely detectable in HAM/TSP patients or healthy carriers.HTLV-IcDNA (gag, pol, Tax, LTR) was detected in salivary glands from patients with SjS by PCR.HTLV-I could infect the synovial cells and vascular endothelial cells, resulting the active production of cytokines such as granulocyte/macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 6. We presented that transient cotrasfection with the Tax-expression plasmid activated the transcription from the human IL-6 promotor in COS 1 cells. This finding directly indicates the potential of Tax for transactivating the human IL-6 gene. The analysis of a series of deletions of the IL-6 promoter suggested that the region (-105/-47) containing a NFkB site was crucial for the Tax responsivessess. From the above data, inflammaotry cytokines such as IL-6 produced through Tax-mediated transactivation is likely to play an important role in triggering and exacerbating SjS.SjS patients with anti-HTLV-I antibodies had increased prevalence of rucurrent fever, myositis and complication with HAM/TSP and uveitis as compared with SjS patients without these antibodies. Furthermore, we reported that interferon-alpha (IFN-alpha) was effective clinically in treating polyarthritis patients who were seropositive for anti-HTLV-I antibodies.Finally, we show that the fusion of HTLV-I-infected cells and target cells contribute to syncytium formation, and that a syncytium formation assay would be a model of HTLV-I transmission in vitro. Dextran sulfate, heparin, and anti-adhesion molecule antibodies including anti-CD18 and anti-CD50 (ICAM-3) monoclonal antibodies blocked HTLV-I-induced syncytium formation.In summary, our prosent results strongly suggest that HTLV-I is involved in the pathogenesis of the SjS. Less

自身免疫性疾病发生在遗传易感的患者中，包括细菌和病毒感染、环境损伤、药物或过敏性疾病。越来越多的证据表明，人类T细胞嗜淋巴细胞病毒I型（HTLV-I）感染有助于各种炎症性疾病的发展。为了阐明该感染与干燥综合征（SjS）的关系，对该综合征患者进行了血清流行病学和病毒学研究。SjS患者HTLV-I阳性率明显高于献血员。HTLV-I阳性的SjS患者血清抗体滴度与HTLV-I相关性脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）患者相似，但明显高于健康携带者。在SjS患者血清中普遍检测到抗HTLV-I的IgM抗体，在血清阳性患者中唾液中普遍检测到抗HTLV-I的伊加抗体。 ...更多信息 SjS患者，这可能是由于唾液腺中的病毒活性增加。PCR检测到SjS患者唾液腺中存在HTLV-IcDNA（gag、pol、Tax、LTR），HTLV-I可感染滑膜细胞和血管内皮细胞，并产生粒细胞/巨噬细胞集落刺激因子、粒细胞集落刺激因子和白细胞介素6等细胞因子。我们提出，瞬时共转染Tax表达质粒激活了COS 1细胞中人IL-6启动子的转录。这一发现直接表明Tax具有反式激活人IL-6基因的潜力。对IL-6启动子的一系列缺失的分析表明，含有NF κ B位点的区域（-105/-47）对Tax反应性至关重要。结论：Tax介导的IL-6等炎性细胞因子可能在SjS的发病和加重中起重要作用。与无抗HTLV-Ⅰ抗体的SjS患者相比，有抗HTLV-Ⅰ抗体的SjS患者的风疹、肌炎、HAM/TSP并发症和葡萄膜炎的患病率增加。此外，我们报道，干扰素-α（IFN-α）是有效的临床治疗多关节炎患者血清阳性的抗HTLV-I antibodies.Finally，我们表明，HTLV-I感染的细胞和靶细胞的融合有助于合胞体形成，合胞体形成试验将是一个模型的HTLV-I在体外传输。硫酸葡聚糖、肝素和抗粘附分子抗体（包括抗CD 18和抗CD 50（ICAM-3）单克隆抗体）阻断HTLV-I诱导的合胞体形成。少

项目成果

Izumi Yamashita,Katsumi Eguchi,et al: "Transactivation of the human interleukin-6 gene by the human T-lymphotropic virus type I" Blood. 84(5). 1573-1578 (1994)

Izumi Yamashita、Katsumi Eguchi 等人：“人类 T 淋巴细胞病毒 I 型对人类白细胞介素 6 基因的反式激活”血液。

Hiroaki Ida,Katsumi Eguchi,et al: "Proceeding of 5th International Conference on Human Differentiation Antigens:CD18 and CD50(ICAM-3)mAb block human T-cell lymphotropic virus type I(HTLV-I)-induced syncytium formation" (in press), (1994)

Hiroaki Ida、Katsumi Eguchi 等：“第五届人类分化抗原国际会议论文集：CD18 和 CD50(ICAM-3)mAb 阻断人类 T 细胞嗜淋巴细胞病毒 I 型 (HTLV-I) 诱导的合胞体形成”（载于

H.Ida, K.Eguchi, et al.: "CD18 and CD50 (ICAM-3) mAb block human T-cell lymphotropic virus type I (HTLV-I) -induced syncytium formation" Proceeding of 5th International Conference on Human Differentiation Antigens. (in press). (1995)

H.Ida、K.Eguchi 等人：“CD18 和 CD50 (ICAM-3) mAb 阻断人 T 细胞嗜淋巴细胞病毒 I 型 (HTLV-I) 诱导的合胞体形成”第五届人类分化抗原国际会议论文集

Izumi Yamashita,et al: "Transactivation of the human interleukin-6 gene by the human T-lymphotropic virus type I" Blood. 84(5). 1573-1578 (1994)

Izumi Yamashita 等人：“人类 T 淋巴细胞病毒 I 型对人类白细胞介素 6 基因的反式激活”血液。

Hiroaki Ida,et al: "Mechanism of inhibitory effect of dextran sulfate and heparin on human T-cell lymphotropic virus type I(HTLV-I)-induced syncytium formation in vitro:role of cell-to cell contact" Antiviral Research. (in press). (1994)

Hiroaki Ida等人：“硫酸葡聚糖和肝素对人T细胞嗜淋巴细胞病毒I型(HTLV-I)诱导的体外合胞体形成的抑制作用机制：细胞间接触的作用”抗病毒研究。