THE IMMUNOBIOLOGY OF CARCINOGENESIS (EVANS)

戏剧性和特征性组织的致病基础 与自身免疫性Graves病相关的重塑 眼病最有可能在于成纤维细胞的相互作用 免疫活性细胞，包括B和T淋巴细胞、肥大细胞 和单核细胞。这些细胞一旦被贩卖到轨道上 启动导致成纤维细胞活化和积聚的过程 透明质酸正是透明质酸的高度亲水性， 导致眼眶内容物部分挤出， 眼球突出的表现。Leukoregulin，一种50千道尔顿的抗癌药物 由淋巴细胞分泌的细胞因子，可以通过以下方式增加透明质酸的合成： 在眼眶成纤维细胞中超过15倍。这件事的重要性 这种增加在哺乳动物细胞系统中是前所未有的， 白细胞调节蛋白作为激活的候选分子触发剂， Graves眼病中的眼眶成纤维细胞另一个引人注目的特点是 活动期的眼病是一种强烈的炎症反应， 反应Leukoregulin显著增加前列腺素E2（PGE 2） 在眼眶成纤维细胞中合成;这种上调是通过 - 诱导牛肝菌素-内过氧化物H合酶-2（PGHS-2）， 炎性环氧化酶PGHS-2表达的增加引起了 白细胞调节素在眼眶成纤维细胞中的作用可能是两者共同作用的结果。 转录和转录后效应。这些观察结果 有助于阐明与强烈的 与Graves眼病相关的炎症。淋巴细胞 被贩运到眼眶组织中，通过 它们释放的细胞因子， 自身免疫性疾病眼眶成纤维细胞的高敏感性 白细胞调节素的差异基因调节作用，此外， 让人想起宫颈癌、白血病和其他 肿瘤细胞对这种细胞因子。因此，眼眶成纤维细胞可能 为细胞因子应答性肿瘤的研究提供了独特的新资源 细胞属性和标记。

The pathogenic basis for the dramatic and characteristic tissue remodeling associated with the autoimmuine disease Graves' ophthalmopathy most likely resides in the interaction of fibroblasts with immunocompetent cells, including B and T lymphocytes, mast cells and monocytes. Once trafficked to the orbit these cells apparently initiate processes leading to fibroblast activation and the accumulation of hyaluronan. It is the profound hydrophilicity of hyaluronan that results in the partial extrusion of orbital contents and the manifestation of proptosis. Leukoregulin, a 50 kiloDalton anti-cancer cytokine secreted by lymphocytes, can increase hyaluronan synthesis by greater than 15-fold in orbital fibroblasts. The magnitude of this increase is unprecedented in mammalian cell systems and implicates leukoregulin as a candidate molecular trigger in the activation of orbital fibroblasts in Graves' ophthalmopathy. Another striking feature of the active phase of ophthalmopathy is an intense inflammatory reaction. Leukoregulin dramatically increases prostaglandin E2 (PGE2) synthesis in orbital fibroblasts; this up-regulation is mediated through an induction of prostaglandin-endoperoxide H synthase-2 (PGHS-2), the inflammatory cycoloxygenase. The increased PGHS-2 expression elicited by leukoregulin in orbital fibroblasts may be a consequence of both transcriptional and post-transcriptional effects. These observations help clarify the pathogenic mechanisms relevant to the intense inflammation associated with Graves' ophthalmopathy. Lymphocytes trafficked to orbital tissues have a putative role, through the cytokines they release, in the activation of fibroblasts in this autoimmune disease. The heightened sensitivity of orbital fibroblasts to the differential gene regulatory action of leukoregulin, moreover, is reminiscent of the response of cervical carcinoma, leukemia and other tumor cells to this cytokine. Orbital fibroblasts, therefore, may provide a unique new resource for the study of cytokine responsive tumor cell properties and markers.