Characterization of an apoptotic defect in patients with ALPS Type 3

自身免疫性淋巴增殖性综合征(ALPS)是一种人类疾病，其原因是淋巴细胞凋亡缺陷，导致淋巴细胞稳态异常。这会导致淋巴结病、自身免疫和淋巴瘤风险增加。用于诊断阿尔茨海默病的诊断标准包括三个方面的表现：淋巴结病，循环中的α-β双阴性T细胞增加，以及体外Fas介导的淋巴细胞凋亡缺陷。大多数阿尔卑斯病患者的Fas(CD95)编码基因存在杂合性突变，少数患者存在Fas配体或caspase 10基因突变。然而，相当数量的阿尔卑斯病患者没有上述基因突变，被归类为阿尔卑斯病3型，并无特征性缺陷。我们已经开始了对阿尔卑斯3型患者的系统评估，首先收集了所有在阿尔卑斯3型患者中被确认为异常的各种实验室数据，看看这些发现在阿尔卑斯3型患者中是否不同。此外，我们已经开始对参与细胞凋亡过程的细胞内蛋白进行系统评估。这些研究的目标是评估死亡诱导信号复合体(DISC)以及控制最终导致细胞死亡的凋亡级联反应的下游事件和蛋白质的组合。我们还试图识别有类似临床发现的亲属的阿尔卑斯3型患者，试图确定与疾病发展有关的基因联系。最后，我们正在着手对阿尔卑斯3型患者进行表达芯片评估，最初关注的是未激活的T细胞，并计划也评估激活的T细胞。

The autoimmune lymphoproliferative syndrome (ALPS) is a human disorder due to defective lymphocyte apoptosis resulting in abnormalities in lymphocyte homeostasis. This produces a combination of lymphadenopathy, autoimmunity and increased risk of lymphoma. The diagnostic criteria used to diagnose ALPS include a triad of findings: lymphadenopathy, increased circulating alpha-beta double negative T cells and defective in vitro Fas mediated lymphocyte apoptosis. The majority of patients with ALPS have been found to have a heterozygous mutation in the gene encoding Fas (CD95) while a small number of patients have been found to have mutations in Fas ligand or caspase 10. However, a sizeable number of ALPS patients do not have mutations in the genes noted about and are categorized as having ALPS type 3 with an uncharacterized defect. We have begun a systematic evaluation of ALPS type 3 patients by first collecting all the various laboratory data that has been identified as abnormal in ALPS type 1a to see if these findings differ in ALPS type 3 patients. In addition, we have begun a systenatic evaluation of intracellular proteins involved with the apoptotic process. These are targeted at assessing the assemblage of the Death Inducing Signalling Complex (DISC) and downstream events and proteins that control the apoptotic cascade that ultimately results in cell death. We are also attempting to identify ALPS type 3 patients who have relatives with similar clinical findings in an attempt to identify genetic links to disease development. Finally, we are embarking on an expression microarray evaluation of ALPS type 3 patients focusing intitially on non-activated T cells with plans to also evaluate activated T cells.