Investigations into XIAP-deficient X-linked Lymphoproliferative Disease

描述(由申请人提供)：Rigaud等人在2006年报道X连锁淋巴增殖性综合征(XLP)的第二大已知原因是X连锁凋亡抑制因子(XIAP)缺乏。XLP是一种罕见的原发免疫缺陷，以淋巴细胞功能缺陷为特征，极易发生与EBV感染相关的噬血细胞性淋巴组织细胞增多症(HLH)。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，如果不治疗的话。在报告的12例XIAP缺陷患者中，有11例发生HLH，其中4例死亡。我们最近诊断出了几名XIAP缺乏症患者。目前对这种新发现的XLP的自然病史和临床表型范围以及XIAP缺陷导致免疫缺陷和HLH的机制尚不清楚。因此，很难向患者和父母提供预测结果的建议，而且除了预防感染并发症和治疗HLH外，没有针对疾病的治疗方法。虽然骨髓移植通常被认为是SAP缺陷的XLP病例，因为存在显著的死亡风险，但对XIAP缺陷的XLP知之甚少，无法确定移植的好处是否值得承担相关风险。我们建议的工作涉及三个主要方面。第一个是具有特定基因突变和蛋白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发现的免疫缺陷的表现，并根据特定的基因突变改进对患者预后的预测。流式细胞仪筛查分析的工作也已经开始，以帮助患者快速诊断。其次，我们将探讨这些患者发生高促黄体生成素的原因。原发HLH通常是由病毒感染细胞的杀伤缺陷引起的。因此，我们将寻找与此过程相关的缺陷。我们还将致力于确定XIAP患者免疫细胞是否像Rigaud等人以前在XIAP缺陷患者中发现的那样，增加了经历程序性细胞死亡的敏感性，并可能有助于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，因为这些患者都有相似的临床疾病，他们可能是由相同的信号通路缺陷引起的。综上所述，这项工作将进一步明确XIAP缺乏症的疾病特征，扩大对免疫缺陷和HLH在这些患者中发生的理解，并可能发现SAP缺陷XLP和XIAP缺陷XLP之间的联系。这些发现将有助于确定哪些患者应该接受XIAP缺乏症的评估，并能够根据潜在的发病机制寻求疾病特异性治疗。公共卫生相关性：对XIAP缺陷X连锁淋巴增殖性疾病的调查直接关系到公共卫生和个别患者的护理。这是一种新发现的疾病，在受影响的患者中具有显著的相关死亡率。该项目的目标将进一步定义疾病，提高对患者的认识和诊断，并调查疾病的潜在机制，这将加强未来针对XLP的干预措施的开发和实施，从而改善患者的预后。

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.