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

矽肺病患者不仅患有呼吸系统疾病，还患有自身免疫性疾病。为了阐明矽肺患者自身免疫的机制，我们一直关注Fas和Fas介导的凋亡通路中的Fas相关分子，因为Fas是调节涉及T细胞的自身免疫的最重要分子之一。我们的研究结果表明，与健康供者相比，矽肺患者表现出血清可溶性Fas水平升高，外周血单个核细胞中可溶性Fas和dcr3基因的相对表达增加，Fas转录的其他变异信息水平较高，几种生理抑制剂（survivin和toso）的表达相对降低，淋巴细胞中低膜Fas表达者（主要转录可溶性Fas）占主导地位。这些发现与已知的免疫因素，如血清免疫球蛋白G水平和抗核抗体滴度一致。此外，在矽肺患者血清中检测到抗caspase 8自身抗体和抗fas自身抗体，功能分析显示抗fas抗体刺激fas介导的细胞凋亡。我们假设矽肺淋巴细胞有两个亚群。一个是长期片段，包括自我识别克隆，显示出较低水平的膜Fas和抑制细胞外空间Fas/Fas配体结合。另一种是由二氧化硅/硅酸盐引起的细胞凋亡，来自骨髓，显示出更高水平的膜Fas，并且对抗Fas自身抗体敏感。应该进行进一步的研究来证实二氧化硅/硅酸盐对人体免疫系统的影响。此外，为了分析石棉相关疾病（ARD）如石棉沉滞症（ASB）和恶性间皮瘤（MM）的免疫改变是否可能影响癌症的进展，将一个人成人T细胞白血病病毒永活T细胞系（MT-2Org）连续暴露于10个10μg/ml的温石棉- b （CB）和石棉中。暴露至少8个月后，细胞凋亡变得非常低，该亚系被命名为MT-2Rst)。MT-2Rst细胞的特点是：(i)通过siRNA减少bcl-2， bcl-2的表达增强，重新获得凋亡敏感性；（ii）过量的IL-10分泌和表达；（iii） STAT3的激活，被PP2 （Src家族激酶的特异性抑制剂）抑制。这些结果表明，细胞与石棉接触会影响人体免疫系统，引发Src家族激酶激活、IL-10增强、STAT3激活和Bcl-2过表达等级联生物学事件。与ASB或健康供者相比，MM患者CD4+外周血T细胞中bcl-2表达水平的升高部分证实了这种增殖。需要进一步的研究来确定bcl-2表达增强的T细胞在石棉暴露诱导的肿瘤进展中的作用。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