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

自身免疫性疾病发生在遗传易感的患者身上，触发事件包括细菌和病毒感染、环境损害、药物或激素。越来越多的证据表明，人类嗜T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血清阳性率明显高于献血者。htlv - 1血清阳性的SjS患者血清抗体滴度与htlv - 1相关脊髓病/热带空间性截瘫（HAM/TSP）患者相似，显著高于健康携带者。在SjS患者血清中常检测到HTLV-I的IgM抗体。唾液中针对HTLV-I的IgA抗体在血清阳性患者中较为常见，这可能是由于唾液腺病毒活性增加所致。这些抗体在HAM/TSP患者或健康携带者中几乎检测不到。应用PCR方法检测SjS患者唾液腺HTLV-IcDNA （gag, pol, Tax， LTR）。htlv - 1可感染滑膜细胞和血管内皮细胞，导致粒细胞/巨噬细胞集落刺激因子、粒细胞集落刺激因子、白细胞介素6等细胞因子的活性产生。我们发现，在COS - 1细胞中，短暂转染tax -表达质粒可激活人IL-6启动子的转录。这一发现直接表明了Tax具有激活人类IL-6基因的潜力。对IL-6启动子的一系列缺失的分析表明，包含NFkB位点的区域（-105/-47）对税收响应性至关重要。从上述数据来看，通过税收介导的反激活产生的炎症细胞因子如IL-6可能在SjS的触发和加重中发挥重要作用。与没有这些抗体的SjS患者相比，具有抗htlv - i抗体的SjS患者的复发性发热、肌炎、HAM/TSP并发症和葡萄膜炎的患病率增加。此外，我们报道了干扰素- α (ifn - α)在临床治疗血清抗htlv - i抗体阳性的多发性关节炎患者是有效的。最后，我们发现htlv - 1感染细胞和靶细胞的融合有助于合胞体的形成，合胞体形成试验将成为htlv - 1体外传播的模型。硫酸葡聚糖、肝素和抗黏附分子抗体（包括抗cd18和抗cd50 （ICAM-3）单克隆抗体）可阻断htlv -i诱导的合胞体形成。总之，我们目前的结果强烈提示HTLV-I参与了SjS的发病机制。少

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