Investigations into XIAP-deficient X-linked Lymphoproliferative Disease

描述（由申请人提供）：Rigaud等人于2006年报告了X连锁细胞凋亡抑制剂（XIAP）缺乏症，作为X连锁细胞增生综合征（XLP）的第二个已知原因。XLP是一种罕见的原发性免疫缺陷，其特征为淋巴细胞功能缺陷和与EBV感染相关的噬血细胞性嗜组织细胞增多症（HLH）的显著易感性。HLH是一种危及生命的疾病，其特征是严重的全身炎症和多器官衰竭，如果不治疗。12例报告的XIAP缺陷患者中有11例报告发生HLH，其中4例死亡。我们最近诊断出几例XIAP缺乏症患者。目前对这种新发现的XLP病因的自然史和临床表型范围知之甚少，XIAP缺陷导致免疫缺陷和HLH的机制仍有待阐明。因此，很难告知患者和父母预计的结果，除了预防感染性并发症和治疗HLH之外，没有疾病特异性治疗。虽然骨髓移植通常被认为是SAP缺陷型XLP的情况下，因为死亡率的显着风险，太少知道XIAP缺陷型XLP，以确定是否移植的好处是值得的风险。我们建议的工作涉及三大范畴。第一个是具有特定基因突变和蛋白质表达的患者的临床和免疫学结果的相关性。这是为了进一步确定这种新认识的免疫缺陷的表现，并根据特定的基因突变改善对患者结局的预测。还开始了流式细胞术筛查分析的工作，以帮助快速诊断患者。其次，我们将调查这些患者发生HLH的原因。原发性HLH通常是由杀死病毒感染细胞的缺陷引起的。因此，我们将查找与此过程相关的缺陷。我们还将努力确定XIAP患者免疫细胞经历程序性细胞死亡的易感性是否增加，因为Rigaud等人先前在XIAP缺陷患者中发现了这一点，并且可能有助于HLH的发展。第三，我们将寻找SAP和XIAP缺陷XLP患者之间的重叠。这是合理的，因为这些患者有相似的临床疾病，他们可能是由相同的信号通路的缺陷引起的。总之，这项工作将进一步定义XIAP缺陷的疾病特征，扩大为什么免疫缺陷和HLH在这些患者中发展的理解，并可能发现SAP缺陷XLP和XIAP缺陷XLP之间的联系。这些发现将使识别患者谁应该评估XIAP缺陷，并使追求疾病特异性治疗的基础上的潜在发病机制。 公共卫生相关性：对XIAP缺陷型X连锁恶性肿瘤增殖性疾病的研究直接关系到公共卫生和个体患者的护理。这是一种新认识的疾病，在受影响的患者中具有显著的相关死亡率。该项目的目的是进一步定义疾病，提高对患者的识别和诊断，并研究疾病的潜在机制，这将加强未来XLP特异性干预措施的开发和实施，从而改善患者结局。

DESCRIPTION (provided by applicant): X-Linked Inhibitor of Apoptosis (XIAP) deficiency was reported in 2006 as the second known cause of X-linked Lymphoproliferative Syndrome (XLP) by Rigaud et al. XLP is a rare primary immunodeficiency characterized by defects in lymphocyte function and a striking susceptibility to develop Hemophagocytic Lymphohistiocytosis (HLH) in association with EBV infection. HLH is a life-threatening disorder characterized by severe systemic inflammation and multi-organ failure if left untreated. 11 out of the 12 reported XIAP deficient patients reported developed HLH, and 4 of these patients died. We have recently diagnosed several patients with XIAP deficiency. Little is currently known about the natural history and range of clinical phenotypes of this newly discovered cause of XLP, and the mechanisms by which defects of XIAP lead to immunodeficiency and HLH remain to be elucidated. Thus, it is difficult to advise patients and parents of projected outcome, and there are no disease-specific treatments other than prevention of infectious complications and treatment of HLH should it occur. While bone marrow transplant is typically considered in cases of SAP-deficient XLP because of the significant risk of mortality, too little is known about XIAP deficient XLP to determine if the benefit of transplant is worth the risks involved. The work that we propose involves three major areas. The first is the correlation of clinical and immunologic findings among patients with specific genetic mutations and protein expression. This is in an effort to both further define the manifestations of this newly recognized immunodeficiency and to improve prediction of patient outcome based on specific genetic mutations. Work has also begun on a flow cytometric screening assay to aid in the rapid diagnosis of patients. Second, we will investigate the reason for the development of HLH in these patients. Primary HLH is generally caused by defects in the killing of virus infected cells. Thus, we will look for defects related to this process. We will also work to determine if there is an increase in the susceptibility of XIAP patient immune cells to undergo programmed cell death, as this was previously found in XIAP deficient patients by Rigaud et al, and may contribute to the development of HLH. Third, we will look for overlaps between SAP and XIAP deficient XLP patients. It is reasonable that since these patients have similar clinical diseases that they may be caused by defects in the same signaling pathways. In summary, this work will further define disease characteristics of XIAP deficiency, expand understanding of why immunodeficiency and HLH develop in these patients, and possibly discover a connection between SAP deficient XLP and XIAP deficient XLP. These findings will enable identification of patients who should be evaluated for XIAP deficiency and enable the pursuit of disease-specific therapies based on the underlying pathogenesis. PUBLIC HEALTH RELEVANCE: Investigations into XIAP-deficient X-linked Lymphoproliferative Disease directly relates to public health and individual patient care. This is a newly recognized disease with significant associated mortality among affected patients. The aims of this project will further define the disease, improve recognition and diagnosis of patients, and investigate the underlying mechanisms of disease which will potentiate development and implementation of future XLP-specific interventions, thus improving patient outcome.