Mountz J D, Zhang H G, Hsu H C, Fleck M, Wu J, al-Maini M H, Zhou T
Department of Medicine, University of Alabama, Birmingham 35294-0007, USA.
Recent Prog Horm Res. 1999;54:235-68; discussion 269.
Inflammatory diseases of the endocrine system--such as thyroiditis, diabetes, and Graves' disease--are considered to be autoimmune in origin. More recently, these and other autoimmune diseases have been associated with defects in Fas apoptosis. The mutation of the Fas or Fas ligand (FasL) has been observed in a minority of patients with autoimmune disease. However, dysfunction of the Fas apoptosis signaling pathway or production of soluble factors, including sFas and sFasL, may be more prevalent. Certain endocrine tissues, such as the testes, are immune privilege sites. Defects in Fas and FasL expression in immune privilege sites can trigger an inflammatory response. Other factors that trigger inflammatory diseases of the thyroid or islets may be loss of self tolerance, leading to an autoimmune response. An infectious trigger or other environmental agent can initiate organ damage, leading to release of new antigens that initiate the autoreactive process. We have developed a murine cytomegalovirus model of Sjögren's syndrome in which defects in the Fas/FasL pathway are necessary to enable chronic inflammation, even after the initial virus has been cleared. Another interaction between the endocrine system and apoptosis is by direct hormone interaction. This is exemplified by the orphan steroid receptor Nur77. Nur77 is important for T cell apoptosis after signaling through CD3. We have demonstrated that a dominant-negative Nur77 transgenic mouse exhibits a defect in thymic selection of T cells. Therefore, there are many potential mechanisms by which endocrine glands or hormones can affect the Fas apoptosis pathway, resulting in either cell death or a chronic inflammatory disease in the endocrine system, leading to hypothyroidism and diabetes. This inflammatory dysfunction can be reversed by a dominant-negative I kappa B that prevents nuclear translocation of NF-kappa B. We have developed antigen-specific, antigen-presenting cells that express high levels of FasL that can prevent tissue-specific inflammatory disease. Treatment with these cells prevents development of diabetes in NOD mice. Further understanding of the role and regulation of apoptosis in diseases of the endocrine system (e.g., diabetes, thyroiditis) should lead to better methods of treatment and prevention of these diseases.
内分泌系统的炎症性疾病，如甲状腺炎、糖尿病和格雷夫斯病，被认为起源于自身免疫。最近，这些以及其他自身免疫性疾病与Fas凋亡缺陷有关。在少数自身免疫性疾病患者中观察到了Fas或Fas配体（FasL）的突变。然而，Fas凋亡信号通路功能障碍或可溶性因子（包括sFas和sFasL）的产生可能更为普遍。某些内分泌组织，如睾丸，是免疫赦免部位。免疫赦免部位Fas和FasL表达缺陷可引发炎症反应。引发甲状腺或胰岛炎症性疾病的其他因素可能是自身耐受性丧失，导致自身免疫反应。感染触发因素或其他环境因素可引发器官损伤，导致新抗原释放，从而启动自身反应过程。我们已经开发出一种干燥综合征的小鼠巨细胞病毒模型，其中Fas/FasL途径的缺陷对于引发慢性炎症是必要的，即使在初始病毒已被清除之后也是如此。内分泌系统与凋亡之间的另一种相互作用是通过直接的激素相互作用。孤儿类固醇受体Nur77就是一个例子。Nur77在通过CD3发出信号后对T细胞凋亡很重要。我们已经证明，显性负性Nur77转基因小鼠在T细胞的胸腺选择中存在缺陷。因此，内分泌腺或激素有许多潜在机制可影响Fas凋亡途径，导致内分泌系统中的细胞死亡或慢性炎症性疾病，进而导致甲状腺功能减退和糖尿病。这种炎症功能障碍可通过阻止NF-κB核转位的显性负性IκB来逆转。我们已经开发出表达高水平FasL的抗原特异性抗原呈递细胞，其可预防组织特异性炎症性疾病。用这些细胞进行治疗可预防非肥胖糖尿病（NOD）小鼠患糖尿病。进一步了解凋亡在内分泌系统疾病（如糖尿病、甲状腺炎）中的作用和调节，应能带来更好的治疗和预防这些疾病的方法。
