Investigations into XIAP-deficient X-linked Lymphoproliferative Disease

XIAP 缺陷型 X 连锁淋巴增殖性疾病的研究

基本信息

批准号：
7533920
负责人：
Rebecca Marsh
金额：
$ 7.5万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7533920
关键词：
Affect Apoptosis Area Biological Assay Bone Marrow Transplantation Caring Cell surface Cells Child Clinic Clinical Cytotoxic T-Lymphocytes Defect Development Diagnosis Disease Effector Cell Employee Strikes Epstein-Barr Virus Infections Exposure to Flow Cytometry Future Gene Mutation Genes Genetic Genotype Grant Hemophagocytic Lymphohistiocytoses Human Herpesvirus 4 Immune Immunity Immunologic Deficiency Syndromes Immunologics In Vitro Incentives Individual Infectious Mononucleosis Inflammation Intervention Investigation Knowledge Lead Left Life Location Lymphocyte Lymphocyte Function Mediating Mind Mutation Natural History Natural Killer Cells Numbers Organ failure Outcome Pathogenesis Pathway interactions Patient Care Patient Transfer Patients Phenotype Play Population Predisposition Prevention Process Production Proteins Public Health Range Regulation Reporting Resources Ring Finger Domain Risk Role Screening procedure Signal Pathway Signal Transduction Small Interfering RNA Standards of Weights and Measures Stimulus Stratification T-Cell Receptor Time Transplantation Ubiquitination Viral Virus Work X-Linked lymphoproliferative disorders apoptosis in lymphocytes base cell killing cell mediated lymphocytolysis test clinical phenotype congenital immunodeficiency crosslink cytokine cytotoxic disease characteristic granzyme B human BIRC4 protein improved killings mortality novel parent project protein expression rapid diagnosis ubiquitin ligase

项目摘要

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.

描述（由申请人提供）：Rigaud等人在2006年报告了X连锁凋亡（XIAP）缺陷抑制剂（XIAP）缺乏症是X连锁淋巴增生综合征（XLP）的第二个已知原因。 XLP是一种罕见的原发性免疫缺陷，其特征是淋巴细胞功能缺陷和与EBV感染相关的淋巴细胞淋巴淋巴结症（HLH）的惊人敏感性。 HLH是一种威胁生命的障碍，其特征是如果未治疗，则以严重的全身性炎症和多器官衰竭。据报道，有11个报告说，XIAP缺乏症患者报告了HLH发生了HLH，其中4例死亡。我们最近诊断出几名XIAP缺乏症患者。目前，关于这种新发现的XLP原因的自然历史和临床表型的范围知之甚少，XIAP导致免疫缺陷和HLH的缺陷的机制仍有待阐明。因此，很难为患者和父母提供预测的预期结果，除了预防感染并发症和HLH治疗外，没有其他特异性治疗方法。虽然由于死亡率很大，因此通常在SAP缺陷XLP的情况下通常考虑骨髓移植，但对XIAP缺陷XLP的了解很少，以确定移植的益处是否值得涉及的风险。我们提出的工作涉及三个主要领域。首先是具有特定基因突变和蛋白质表达的患者中临床和免疫学发现的相关性。这是为了进一步定义这种新认识的免疫缺陷的表现，并基于特定的遗传突变改善患者结果的预测。还开始进行流式细胞仪筛查测定法，以帮助患者的快速诊断。其次，我们将研究这些患者中HLH发展的原因。原发性HLH通常是由杀死感染细胞的缺陷引起的。因此，我们将寻找与此过程相关的缺陷。我们还将努力确定XIAP患者免疫细胞发生程序性细胞死亡的敏感性是否有所提高，因为这是Rigaud等人在XIAP缺乏的患者中发现的，并且可能有助于HLH的发展。第三，我们将寻找SAP和XIAP缺乏XLP患者之间的重叠。合理的是，由于这些患者患有相似的临床疾病，因此它们可能是由同一信号通路中的缺陷引起的。总而言之，这项工作将进一步定义XIAP缺乏症的疾病特征，扩大对这些患者的免疫缺陷和HLH为何发展的理解，并可能发现SAP缺乏XLP和XIAP缺乏XLP之间的联系。这些发现将使应评估应评估XIAP缺乏症的患者，并基于潜在的发病机理对疾病特异性疗法进行追求。公共卫生相关性：对缺乏XIAP的X连锁淋巴增生性疾病的调查直接与公共卫生和个体患者护理有关。这是一种新认可的疾病，受影响的患者的死亡率显着。该项目的目的将进一步定义疾病，改善患者的识别和诊断，并研究疾病的潜在机制，这些机制将增强和实施未来XLP特定的干预措施，从而改善患者的预后。