Research for immunodysregulation and acquisition of autoimmunity induced by silica compounds

我们一直在研究二氧化硅化合物诱导的免疫失调和自身免疫的获得，并观察到以下发现：i)与膜Fas信息相比，矽肺患者外周血单个核细胞（PBMC）可溶性Fas相对表达增加，ii)矽肺患者与健康志愿者（HV）总Fas或Fas配体表达无差异，iii)矽肺患者血清可溶性Fas升高，iv)外周血淋巴细胞表面膜Fas无差异，v)血清可溶性Fas配体无差异。v)用二氧化硅化合物、温石棉B培养PBMC诱导凋亡，vi)通过添加Fas/Fas配体途径抗体和抗caspase 8中和抗体抑制PBMC凋亡，vii)在二氧化硅诱导的凋亡过程中，Fas、Fas配体、caspase、1、3和8基因上调，viii)二氧化硅比人造矿物纤维更强的诱导凋亡，ix)检测SIL诱导的PBMC中选择性剪接的变异信息。这些结果表明，尽管健康的淋巴细胞容易进入fas介导的凋亡途径，并因暴露于二氧化硅而激活后死亡，但在职业性和慢性暴露二氧化硅时，会出现抵抗二氧化硅诱导的凋亡的淋巴细胞。这些抗性克隆可能包括自我识别克隆的亚群，它们可能产生可溶性Fas，这些可溶性Fas可以与膜Fas拮抗，与Fas配体结合，使自我识别克隆存活更长时间。这些克隆可能对矽肺患者获得自身免疫具有重要作用。

We have been studying the immunodysregulation and acquisition of autoimmunity induced by silica compounds and have observed following findings ; i) increase of relative expression of soluble Fas as compared with membrane Fas message in peripheral blood mononuclear cells (PBMC) from silicosis cases (SIL), ii) No difference of total Fas or Fas ligand expression between SIL and healthy volunteers (HV), iii) elevation of serum soluble Fas in SIL, iv) No difference of membrane Fas on the surface of peripheral blood lymphocytes (PBL), v) NO difference of serum soluble Fas ligand, v) induction of apoptosis of PBMC cultured with silica compound, chrysotile B, vi) inhibition of this apoptosos by addition of antibodies for Fas/Fas ligand pathway, and anti-caspase 8 neutralizing antibody, vii) upregulatlon of Fas, Fas ligand, caspase, 1, 3, and 8 genes during apoptosis induced by silica, viii) stronger inducibility of apoptosis by silica than man-made mineral fibers, ix) detection of alternatively spliced variant messages in PBMC from SIL.These findings indicate that lymphocytes which are resistant to the silica-induced apoptosis will appear during exposure of silica compounds occupationally and chronically, although healthy lymphocytes easily enter the Fas-mediated apoptosis pathway and die after activation due to silica exposure. These resistant clones may include subpopulation of self-reccgnizing clones and they may produce soluble Fas which may antagonize with membrane Fas to bind with Fas ligand and make self-recognize clones to survive longer. These clones may possess an important role to acquire autoimmunity in cases with silicosis.