Role of HTLV-I on pathegenesis of Sjogren's syndrome

HTLV-I 在干燥综合征发病机制中的作用

• 批准号: 09670482
• 负责人: EGUCHI Katsumi
• 金额: $ 2.24万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670482/
• 关键词: HTLV-I; Sjogren's syndrome; Apoptosis; Tax protein; NF-kB; HTLV-I associated myclopathy; FK506; activation induced cell death; アポト-シス; NF-κB; シェ-グレン症候群; NF-kB; カスペース; マトリックスメタロプロテアーゼ

Previously we have reported a high prevalence of HTLV-1 iiifcction in Sjogren's syndrome (SS). At first in the present study, we investigated whether SS was complicated with HTLV-l associated myclopathy (HAM). According to thc preliminary criteria for SS proposed by the European Community, definitive SS WaS (liagnosed in 6 of 10 patients. There was no significant difference in the prevalence of autoantibodies including rheumatoid factor, anti-nuclear antibody and anti-SS-A (Ro) antibody among HAM patients with definitive SS, HTLV-1 Seropositive and HTLV-I seronegative SS patients.Next, we ditermine the possible involvement of Fas and its ligand in salivary gland destruction. Several duetal epithelial cells. Acinal epithelial cells were also double-positive with Fas and FasL, aothough expression of FasL was localized at their apical border, suggest that apoptosis of acinal epithelial cells was mediated by FasL derived from either acinal epithelial cells or infiltrating mononuclear cells … More . Interestingly, Fas expression in ductal epithelial cells was licalized around the luman side of the ducts, indicating that FasL secreted from acinal epithelial cells may induce Fas-mediated apoptosis of ductal epithelial cells.We determined the role of interactions between CD4O and CD4O ligand (CD4OL) in these infiltrating lymphocytes on B cell differentiation. A clear expression of CD4OL and CD4O in infiltrating lymphocytes was demonstrated. The expression of Bcl-2 andBcl-X was colocalized with that of CD4O determined by mirror section technique. BcI-X was abduntly expressed on infiltrating mononuclear cells, but Bax expression was relatively less than that of Bc1-2 or Bc1-X.These findings suggest that signaling through CD4 O by means CD4OL increases the expression of Bcl-2 and Bcl-X in infiltrating lymphocytes, providing the resistance against apoptosis. Present results were commonly observed in SS patients irrespective of HTLV-I seropositivety.We examined the importance of in inhibiting activation of the caspase cascade, which operates a regulatory loop that prevent apoptosis. Apoptosis was induced in Jurkat cells and JPX-9 cells which Tax-expression plasmid pMAX-Neo is stably transfected in Jurkat by NF-_KB inhibitor. Preincubation of JPX-9 cells with CdCI_2, which induced Tax expression, significantly inhibited both the activation of caspases and apoptosis. The results suggest that apoptosis is initiated via activation of caspase cascade by inhibiting the activation. Furthermore, activation of NF-_KB via Tax protein in HTLV-I infected cells renders the cells resistant against apoptosis, resulting in an increase of cytokine production and cell proliferation, one of the proposed mechanisms that promotes autoimmune disorders such as Sjogren's syndrome (SS) found in HTLV-I seropositive subjects.Finally, we examined the mechanisms by which high-dose steroid and FK506 exerts the immunosuppressive actions. Peripheral blood T cells from normal subjects underwent DNA fragmentation following the in vitro exposure to 10^-^7M of dexametllasone for 30 min. FK506 synergistically enhanced this dexaniethazone-mediated apoptosis of human peripheral blood T cells. These results indicate that the induction of peripheral blood T cell apoptosis is an important mechanism contributing to the immunosuppression achieved by steroid and FK5O6. Less

以前我们曾报道过干燥综合征（SS）中HTLV-1感染的高患病率。首先，在本研究中，我们调查了SS是否并发HTLV-1相关性肌病（HAM）。根据欧共体提出的SS初步诊断标准，10例患者中有6例确诊为SS。HAM合并SS、HTLV-1阳性和HTLV-1阴性的SS患者中，类风湿因子、抗核抗体和抗SS-A（Ro）抗体的阳性率无显著性差异。几个绒毛上皮细胞。腺泡上皮细胞也呈Fas和FasL双阳性，尽管FasL的表达局限于腺泡上皮细胞的顶缘，但提示腺泡上皮细胞的凋亡是由来源于腺泡上皮细胞或浸润的单个核细胞的FasL介导的 ...更多信息 .有趣的是，Fas在导管上皮细胞的表达局限于管腔侧，表明从腺泡上皮细胞分泌的FasL可能诱导Fas介导的导管上皮细胞凋亡。我们确定了这些浸润淋巴细胞中的CD 4 O和CD 4 O配体（CD 4 OL）之间的相互作用对B细胞分化的作用。浸润淋巴细胞中CD 4 OL和CD 4 O表达明显。镜切法检测Bcl-2、Bcl-X与CD_（40）共定位表达。Bcl-X在浸润的单个核细胞上表达丰富，而Bax的表达较Bc 1 -2和Bc 1-X相对较低。这些结果表明，通过CD 4 OL介导的CD 4 O信号转导增加了浸润淋巴细胞中Bcl-2和Bcl-X的表达，从而提供了抗凋亡的能力。目前的结果通常在SS患者中观察到，无论HTLV-I血清学阳性与否。我们研究了抑制caspase级联反应激活的重要性，caspase级联反应是一个防止细胞凋亡的调节回路。NF-κ B抑制剂可诱导Jurkat细胞和JPX-9细胞凋亡。用CdCl_2预孵育JPX-9细胞，诱导Tax表达，显著抑制caspase的激活和凋亡。结果表明，细胞凋亡是通过激活caspase级联反应启动的。此外，NF-κ B通过Tax蛋白在HTLV-I感染的细胞中的活化使细胞抵抗凋亡，导致细胞因子产生和细胞增殖的增加，这是促进自身免疫性疾病如在HTLV-I血清阳性受试者中发现的干燥综合征（SS）的机制之一。正常人外周血T细胞在体外暴露于10^-^7 M地塞米松30分钟后发生DNA断裂。FK 506协同增强地塞米松介导的人外周血T细胞凋亡。这些结果表明，外周血T细胞凋亡的诱导是一个重要的机制，有助于实现类固醇和FK 5 O 6的免疫抑制。少

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