Molecular Mechanisms Of Autoimmune Lymphoproliferative

该项目基于我们的发现，即控制淋巴细胞程序性死亡或凋亡的分子中的基因突变是导致自身免疫性淋巴细胞增生性综合征（ALPS）的原因。ALPS是一种影响儿童的疾病，导致正常淋巴细胞稳态丧失，导致淋巴腺和器官肿大。因为淋巴细胞是介导免疫反应的主要细胞，这种过量的淋巴细胞会导致患者自身组织的病理性自身免疫攻击。我们已经确定了死亡诱导细胞表面受体Fas（也称为APO-1或CD95）和其他调节细胞凋亡的分子中的突变。我们还确定了一种新的疾病实体，称为“caspase-8缺陷状态”（CEDS），这是由于caspase-8的遗传缺陷造成的。这种疾病包括凋亡控制和淋巴细胞扩张的丧失，以及正常淋巴细胞通过抗原受体激活的失败。其结果是一种严重的免疫缺陷状态，而新的认识是，迄今为止仅被认为是一种诱导细胞死亡的蛋白酶，在抗原受体信号传导中起关键作用，特别是在诱导一种称为NF-kB的基因调节因子方面。这些研究有望为自身免疫和免疫缺陷疾病的分子机制提供新的见解，并揭示淋巴细胞程序性细胞死亡途径的关键步骤。我们目前正在研究一类被称为ALPS III型的患者，这些患者在Fas受体、其配体（Fas配体）或caspase-10中不显示突变。我们正在使用各种分子分析来确定导致ALPS III型疾病的基因突变。我们的指导原则是，如果在分子水平上进行适当的研究，来自鲜为人知的疾病的患者标本可以对疾病机制和正常生理学产生有价值的见解。

This project is based on our discovery that genetic mutations in molecules that control the programmed death, or apoptosis, of lymphocytes is responsible for the Autoimmune Lymphoproliferative Syndrome (ALPS). ALPS is a disease affecting children that leads to loss of normal lymphocyte homeostasis leading to swollen lymph glands and organs. Because lymphocytes are the primary cell mediating immune reactions, this excess of lymphocytes leads to a pathological autoimmune attack on the patient's own tissues. We have identified mutations in a death-inducing cell surface receptor termed Fas (also known as APO-1 or CD95) and in other molecules that regulate apoptosis. We have also identified a new disease entity called, "Caspase-eight deficiency state" (CEDS) that is due to a genetic deficiency of caspase-8. This disease involves a loss of apoptotic control and lymphocyte expansion combined with a failure of normal lymphocyte activation through the antigen receptors. The consequence of this is a profound immunodeficiency state and the new insight the capase-8, heretofore regarded solely as a cell death inducing protease, has a key role in antigen receptor signaling particularly for the induction of a gene regulatory factor called NF-kB. These studies promise to provide new insights into the molecular mechanisms that underlie autoimmune and immunodeficiency disease as well as revealing crucial steps in the pathway of programmed cell death in lymphocytes. We are presently studying a class of these patients called ALPS Type III which do not display mutations in the Fas receptor, its ligand (Fas ligand), or caspase-10. We are using a variety of molecular analyses to determine the gene mutation that underlies disease in ALPS Type III. Our guiding principle is that patient specimens from poorly understood diseases can yield valuable insights into disease mechanisms and normal physiology if investigated properly at the molecular level.