权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ROLE OF HUMAN T LYMPHOTROPIC VIRUS TYPE I ON PATHOGENESIS OF SJOGREN'S SYNDROME

I型人类T淋巴细胞病毒在干燥综合征发病机制中的作用

基本信息

批准号：
07670534
负责人：
EGUCHI Katsumi
金额：
$ 1.34万
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：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670534/
关键词：
HTLV-I Sjogren's syndrome Tax gene Anti-HTLV-I antibody Autoantibody Apoptosis HTLV-I associaed myelopathy lymphocyte migration T細胞レセプター

项目摘要

Human T-cell lymphotropic virus type I (HTLV-I) is a human retrovirus, originally identified as an aetiological agent of adult T cell leukemia, and closely associated with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We previously demonstrated that the HTLV-I seroprevalence in Sjogren's syndrome (SS) patients was 23.0%, which was significantly higher than those of the normal blood donors (3.4%). The age-adjusted summary odds ratio of HTLV-I infection in SS patients as compared with normal blood donors, estimated by the Mantel-Haenszel procedure, was 3.1. Furthermore, etiologic fraction, the proportion of SS patients attributable to HTLV-I infection, was estimated to be 17.6%.At first, we investigated whether SS was complicated with HAM patients. The clinical feature and histological findings of SS and the prevalence of serum autoantibodies were examined 14 patients with HAM.All patients with HAM histologically showed a mononuclear cell infiltration in the labial … More salivary glands. According to the preliminary criteria for SS proposed by the European Community, definitive SS was diagnosed in 8 patients and probable SS in 4 patients. There was no significant difference in the prevalence of autoantibodies including rheumatoid factor, anti-nuclear, anti-SS-A (Ro) and anti-SS-B (La) antibodies among 8 HAM patients with definitive SS,HTLV-I-seropositive and- seronegative SS patients. The CD4^+ T cells preferentially infiltrated into the salivary glands in HAM patients as well as the salivary glands of patients with HTLV-I-seropositive and -seronegative patients.Next, apoptosis in labial salivary glands from HTLV-I-seropositive and -seronegative SS patients was studied. Apoptotic cell death was detected in epithelial cells (acinus and ducts) of labial salivary glands. Fas antigen was found on epithelial cells in labial salivary glands. Fas ligand was stained in the infiltrated lymphocytes. There was no significant difference in above findings between HTLV-I-seropositive and -seronegative SS patients.We examined the presence of HTLV-I provirus DNA of both peripheral blood lymphocytes and labial salivary glands form 7 HTLV-I seropositive patients with SS by nested two-step PCR.All 4 independent regions of the HTLV-I genomic, including LTR,gag, pol and pX,were readily amplified from DNA of peripheral blood lymphocytes and tissues of all the seropositive patients. Next, we studied the copy number of HTLV-I in each sample DNA by semiquantitative PCR.The ratio of the copy number between tissue and lymphocytes was variable, but 3 out of 4 SS patients without HAM gene very high values. These findings suggest that HTLV-I infected cells may accumulate in the salivary gland of these patients. From the above findings, it seems likely that peripheral blood T cells from HAM patients preferentially infiltrate into the salivary glands, and then the infiltrated T cells induce SS the pathological changes in the exocrine organs. We studied, therefore, transmigratory activity of circulating T cells from HAM patients through reconstituted basement membrane. Transmigratory activity of lymphocytes was assayd in Transwell cell-culture chambers. We applied the circulating CD4^+ cells from patients with HAM and normal subjects on Transwell cell-culture chambers, and then counted the number of transmigrated cells. The percentage of transmigrated CD4^+ cells from HAM patients was significantly higher than that from normal subjects. Furthermore, HTLV-I proviral DNA quantified in the transmigrated CD4^+ cells from HAM patients were 2 to 8 fold more frequent than that in the non-transmigrated CD4^+ cells. These findings indicate that HTLV-I infected CD4^+ cells of HAM patients have up-regulated transmigratory activity through reconstituted basement membrane.In summary, our findings strongly support the idea that HTLV-I is involved in the pathogenesis of the disease in a subset of patients with SS in endemic areas. Less

人T淋巴细胞趋化病毒I型(HTLV-I)是一种人类逆转录病毒，最初被认为是成人T细胞白血病的病原体，与HTLV-I相关性脊髓病/热带痉挛麻痹(HAM/TSP)密切相关。我们先前证实干燥综合征(SS)患者HTLV-I血清阳性率为23.0%，显著高于正常献血员(3.4%)。用Mantel-Haenszel程序估计，SS患者与正常献血者相比，年龄调整后HTLV-I感染的汇总优势比为3.1。此外，病原学分数，即SS患者可归因于HTLV-I感染的比例，估计为17.6%。首先，我们调查了SS是否合并HAM患者。对14例HAM患者的临床表现、组织学特点及血清自身抗体的检测结果进行了分析。HAM患者的唇部…均有单个核细胞的浸润更多的唾液腺。根据欧洲共同体提出的SS初步诊断标准，确诊SS 8例，可能SS 4例。类风湿因子、抗核、抗SS-A(Ro)和抗SS-B(La)等自身抗体在8例确诊SS、HTLV-I阳性和血清阴性SS患者中的阳性率无显著差异。HAM患者的唾液腺和HTLV-I阳性及血清阴性患者的唾液腺中均有CD4~+T细胞优先渗入。唇腺上皮细胞(腺泡和导管)可见细胞凋亡。Fas抗原定位于唇涎腺上皮细胞。Fas配体在浸润性淋巴细胞中染色。用套式两步聚合酶链式反应检测了7例HTLV-I阳性SS患者外周血淋巴细胞和唾液腺组织中HTLV-I前病毒DNA的存在。接下来，我们用半定量聚合酶链式反应研究了HTLV-I在每个样本DNA中的拷贝数，组织和淋巴细胞的拷贝数比例是可变的，但4例无HAM基因的SS患者中有3例拷贝数很高。这些发现表明，HTLV-I感染细胞可能在这些患者的唾液腺中积聚。由此可见，HAM患者外周血中的T细胞可能首先侵入唾液腺，然后由浸润的T细胞引起外分泌器官病变。因此，我们研究了HAM患者循环T细胞通过重组基底膜的迁移活性。在Transwell细胞培养箱中检测淋巴细胞的迁移活性。我们将HAM患者和正常人的外周血中的CD4~+细胞置于Transwell细胞培养箱中，然后计数移植细胞的数量。HAM患者外周血中移行的CD4~+细胞百分率显著高于正常人。此外，HAM患者移行的CD4^+细胞中HTLV-I前病毒DNA定量的频率是未移行的CD4^+细胞的2~8倍。这些发现表明，HTLV-I感染的HAM患者的CD4^+细胞通过重组基底膜具有上调的迁移活性。综上所述，我们的研究结果有力地支持了HTLV-I参与了流行区SS患者亚群的疾病发病机制。较少