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

以前我们曾报道过干燥综合征（SS）中HTLV-1的高发率。在本研究中，我们首先调查了SS是否合并htlv - 1相关性肌病（HAM）。根据欧共体提出的SS初步标准，10例患者中有6例确诊为明确的SS。确诊性SS患者、HTLV-1血清阳性和HTLV-1血清阴性SS患者的自身抗体包括类风湿因子、抗核抗体和抗SS- a （Ro）抗体的患病率差异无统计学意义。接下来，我们确定Fas及其配体在唾液腺破坏中的可能参与。若干双上皮细胞。腺泡上皮细胞Fas和FasL也呈双阳性，尽管FasL的表达局限于腺泡上皮细胞的顶端边界，这表明腺泡上皮细胞的凋亡可能是由来源于腺泡上皮细胞或浸润性单核细胞的FasL介导的。有趣的是，Fas在导管上皮细胞中的表达在导管的人类一侧被激活，这表明从腺管上皮细胞分泌的FasL可能诱导Fas介导的导管上皮细胞凋亡。我们确定了CD4O和CD4O配体（CD4OL）在这些浸润淋巴细胞中相互作用对B细胞分化的作用。CD4OL和CD4O在浸润淋巴细胞中有明显表达。镜像切片法检测Bcl-2和bcl - x与cd40o的共定位表达。BcI-X在浸润的单核细胞上大量表达，而Bax的表达相对较少，Bc1-2或Bc1-X表达较少。这些发现表明，通过CD4OL通过CD4O信号传导可增加浸润淋巴细胞中Bcl-2和Bcl-X的表达，从而抵抗细胞凋亡。无论HTLV-I是否血清阳性，目前的结果在SS患者中普遍存在。我们研究了抑制caspase级联激活的重要性，caspase级联操作一个防止细胞凋亡的调节回路。用NF-_KB抑制剂稳定转染表达tax -表达质粒pMAX-Neo后，Jurkat细胞和JPX-9细胞均发生凋亡。CdCI_2预孵生JPX-9细胞，诱导Tax的表达，显著抑制caspase的激活和凋亡。结果表明，细胞凋亡是通过抑制caspase级联激活而启动的。此外，HTLV-I感染细胞中通过Tax蛋白激活NF-_KB使细胞抵抗凋亡，导致细胞因子产生和细胞增殖增加，这是HTLV-I血清阳性受试者中发现的促进自身免疫性疾病如干燥综合征（SS）的机制之一。最后，我们研究了大剂量类固醇和FK506发挥免疫抑制作用的机制。正常受试者外周血T细胞在体外暴露于10^-^7M的地塞米松30分钟后发生DNA断裂。FK506协同增强了这种地塞米松介导的人外周血T细胞凋亡。这些结果表明，诱导外周血T细胞凋亡是类固醇和FK5O6实现免疫抑制的重要机制。少

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