FALURE OF SELF TOLERANCE INDUCED BY ENVIRONMELAL SUBSTANCES : AUTOIMMUNE DYSREGULATION FOUND IN SILICOSIS PATIENIS AS A MODEL

矽肺患者不仅患有呼吸系统疾病，还患有自身免疫性疾病。由于Fas是调节T细胞自身免疫的重要分子之一，因此，为了阐明矽肺患者自身免疫的机制，我们一直关注Fas介导的凋亡途径中的Fas及其相关分子。结果表明，矽肺患者血清可溶性Fas水平升高，外周血单个核细胞可溶性Fas和dcr 3基因相对表达增加，Fas转录本的其他变异信息水平升高，几种生理抑制因子的表达相对降低（存活素和toso），以及淋巴细胞中较低膜Fas表达者的优势，其主要转录可溶性Fas。这些发现与已知的免疫学因素如血清免疫球蛋白G水平和抗核抗体滴度一致。 ...更多信息 矽肺患者的耳自身抗体另外，在矽肺患者血清中检测到抗caspase 8抗体和抗Fas抗体，功能性检测显示抗Fas抗体可刺激Fas介导的细胞凋亡。我们假设矽肺淋巴细胞有两个亚群。一种是长期部分，其包括显示较低水平的膜Fas和细胞外空间中Fas/Fas配体结合的抑制的自识别克隆。另一种是表现出由二氧化硅/硅酸盐引起的细胞凋亡的部分，从骨髓中募集，显示出较高水平的膜Fas，并且对抗Fas自身抗体敏感。需要进一步研究二氧化硅对人体免疫系统的影响，并分析石棉相关疾病如石棉肺（ASB）和恶性间皮瘤（MM）的免疫学改变可能影响癌症的进展。用10 ~ 10μg/ml温石棉-B（CB）连续暴露于人成T细胞白血病病毒永生化T细胞系（MT-2 T）。暴露至少8个月后，细胞中的凋亡变得非常低，该亚系被命名为MT-2 Rst）。MT-2 Rst细胞的特征在于：（i）通过siRNA减少bcl-2而增强bcl-2的表达，同时通过siRNA减少bcl-2而重新获得结肠炎敏感性，（ii）过量的IL-10分泌和表达，以及（iii）通过Src家族激酶的特异性抑制剂PP 2的抑制而激活STAT 3。这些结果提示，石棉与细胞接触后，可影响人体免疫系统，并引发Src家族激酶激活、IL-10增强、STAT 3激活和Bcl-2过表达等级联生物学事件。与ASB或健康供体相比，MM患者CD 4+外周血T细胞中bcl-2表达水平升高，部分证实了这一推测。未来的研究需要确保与石棉暴露诱导的肿瘤进展中的T细胞与增强的bcl-2表达的作用。少

Silicosis patients suffer not only from respiratory disorders but also from autoimmune diseases. To clarify the mechanisms involved in the of autoimmunity found in silicosis patients, we have been focusing on Fas and Fas-related molecules in the Fas-mediated apoptotic pathway, since Fas is one of the most important molecules regulating autoimmunity involving T cells. Our findings showed that silicosis patients exhibited elevated serum soluble Fas levels, an increased relative expression of the soluble fas and dcr3 genes in peripheral blood mononuclear cells, high levels if other variant messages of the fas transcript, relatively decreased expression of several physiological inhibitors (survivin and toso), and dominancy of lower membrane Fas expressers in lymphocytes, which transcribe soluble fas dominantly, in comparison with healthy donors. These findings are consistent with known features regarding immunological factors such as serum immunoglobulin G levels and the titer of anti-nucl … More ear autoantibodies in silicosis. In addition, anti-caspase 8 autoantibody and anti-Fas autoantibody were detected in serum from silicosis patients, and a functional assay showed that anti-Fas antibody stimulated Fas-mediated apoptosis. We hypothesize that there are two subpopulations of silicosis lymphocytes. One is a long-term fraction that includes self-recognizing clones showing lower levels of membrane Fas and inhibition of Fas/Fas ligand binding in extracellular spaces. The other is a fraction that exhibits apoptosis caused by silica/silicates, is recruited from bone marrow, shows higher levels of membrane Fas, and is sensitive to anti-Fas autoantibody. Further investigation should be performed to comfirm the effects of silica/silcates on the human immune system.In addition, too analyze the possibility of immunological alteration in asbestos-related diseases (ARD) such as asbestosis (ASB) and malignant mesothelioma (MM) may affect the progression of cancers, a human adult T cell leukemia virus-immortalized T cell line (MT-2Org) was continuously exposed to 10 10μg/ml of chrysotile-B (CB), an asbestos. After at least 8 months exposure, the apoptosis in the cells became very low and this subline was designated MT-2Rst). The MT-2Rst cells were characterized (i)enhanced expression of bcl-2 with regain of apoptotis-sensitivity by reduction of bcl-2 by siRNA, (ii)excess IL-10 secretion and expression, and (iii)activation of STAT3 with inhibition by PP2, a specific inhibitor of Src family kinases. These results suggested that the contact between cells and asbestos affect human immune system and trigger the cascade ob biological events such as activation of Src family kinases, enhancement of IL-10, STAT3 activation and Bcl-2 overexpression. This supeculation was partially confirmed by elevated bcl-2 expression levels in CD4+ peripheral blood T cells from patients with MM compared with those of ASB or healthy donors. Future study are required to ensure the role of T cells with enhanced bcl-2 expression in tumor progression induced by asbestos exposure. Less