Molecular Mechanisms Of The Autoimmune Lymphoproliferative Syndrome

这个项目是基于我们的发现，即控制淋巴细胞程序性死亡或凋亡的分子的基因突变是自身免疫性淋巴增殖综合征(Alps)的原因。阿尔卑斯病是一种影响儿童的疾病，会导致正常淋巴细胞稳态丧失，导致淋巴腺和器官肿大。由于淋巴细胞是介导免疫反应的主要细胞，淋巴细胞的过剩会导致患者自身组织的病理性自身免疫攻击。我们已经确定了一种名为Fas(也称为APO-1或CD95)的死亡诱导细胞表面受体以及其他调节细胞凋亡的分子中的突变。我们还发现了一种新的疾病实体，称为Caspase-8缺乏状态(CEDS)，它是由于Caspase-8的遗传缺陷造成的。这种疾病包括失去对凋亡的控制和淋巴细胞的扩张，并通过抗原受体失去正常的淋巴细胞激活。其结果是一种严重的免疫缺陷状态和新的见解，即caspase-8，到目前为止仅被认为是一种细胞死亡诱导蛋白酶，在抗原受体信号转导中具有关键作用，特别是在诱导一种称为核因子-kB的基因调控因子方面。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中的关键步骤。在其他相关研究中，我们已经证明在阿尔卑斯患者中Fas和caspase-10的突变可以共同遗传。我们还发现，导致阿尔卑斯综合征的Fas配体突变具有显性干扰特性，从而解释了为什么这些突变的等位基因在杂合状态下会致病。 我们目前正在研究一类被称为Alps III型的患者，这种患者不显示Fas受体及其配体(Fas配体)或caspase-10的突变。我们正在使用各种分子分析来确定阿尔卑斯III型疾病背后的基因突变。这些实验已经成功地揭示了一种新的疾病--阿尔卑斯IV型疾病的分子基础。这种疾病的患者具有典型的自身免疫和淋巴细胞稳态异常的临床特征，这在阿尔卑斯山、I型和II型都可以检测到。然而，这些患者的不同之处在于，他们的死亡率显著减少，这是对细胞因子的退出的反应，而不是死亡受体凋亡的缺陷。这种疾病的分子基础是由于N-RAS癌基因的遗传性胚系突变导致凋亡蛋白Bim减少。我们计划继续研究不寻常的阿尔卑斯山III型病例，以了解它们的分子基础。我们的指导原则是，如果在分子水平上进行适当的研究，来自知之甚少的疾病的患者样本可以对疾病机制和正常生理产生有价值的见解。我们扩大了研究范围，试图了解BIM在淋巴细胞凋亡中的作用。我们已经发现，Bim可以传递参与T细胞受体参与的本体杀伤性调节的凋亡信号。Bim的作用与Fas受体是互补的，前者对CD8T细胞的凋亡更为重要，而后者对CD4T细胞的凋亡更为重要。

This project is based on our discovery that genetic mutations in molecules that control the programmed death, or apoptosis, of lymphocytes are 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 patients 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-8 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 a new insight that caspase-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. In other related studies, we have shown that mutations in Fas and caspase-10 can be co-inherited in ALPS patients. We have also found that mutations in Fas ligand that cause ALPS have dominant-interfering properties thus explaining why such mutant alleles are disease-causing in a heterozygous state. 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. These experiments have been successful in uncovering the molecular basis of a new class of this disease, ALPS type IV. Patients with this disorder have typical clinical features of autoimmunity and abnormal lymphocyte homeostasis that are detected in ALPS, type I and II. however, these patients differ in that they have a strikingly decreased death in response to cytokine withdrawal rather than a defect in death receptor apoptosis. The molecular basis of this disorder is a reduction in the apoptosis protein Bim due to an inherited germline mutation in the N-Ras oncogene. We plan to continue to examine unusual Alps Type III cases to understand their molecular basis. 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. we have extended the studies to try to understand the role of Bim in lymphocyte apoptosis. We have found that Bim can convey apoptotic signals involved in propriocidal regulation caused by T cell receptor engagement. The role of Bim is complementary to the Fas receptor with the former being more important for CD8 T cell apoptosis whereas the latter is more important for CD4 T cell apoptosis.