Molecular Mechanisms Of The Autoimmune Lymphoproliferative Syndrome

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。由于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的遗传缺陷引起的。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和新的见解，即caspase-8，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。在其他相关研究中，我们已经证明Fas和caspase-10的突变可以在ALPS患者中共同遗传。我们还发现导致ALPS的Fas配体突变具有显性干扰特性，从而解释了为什么这种突变等位基因在杂合状态下致病。

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.