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 等人于 2006 年报道，X 连锁凋亡抑制剂 (XIAP) 缺乏是 X 连锁淋巴增殖综合征 (XLP) 的第二个已知原因。 XLP 是一种罕见的原发性免疫缺陷病，其特征是淋巴细胞功能缺陷，并且极易发生与 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，如果不及时治疗，其特征是严重的全身炎症和多器官衰竭。报告的 12 名 XIAP 缺陷患者中，有 11 名报告出现 HLH，其中 4 名患者死亡。我们最近诊断出几位患有 XIAP 缺乏症的患者。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，很难向患者和家长告知预计的结果，并且除了预防感染性并发症和在发生 HLH 时进行治疗之外，没有针对疾病的治疗方法。虽然由于死亡风险显着，SAP 缺陷型 XLP 病例通常会考虑骨髓移植，但对 XIAP 缺陷型 XLP 知之甚少，无法确定移植的益处是否值得承担所涉及的风险。我们建议的工作涉及三个主要领域。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。这是为了进一步定义这种新发现的免疫缺陷的表现，并改善基于特定基因突变的患者结果预测。流式细胞术筛查分析的工作也已开始，以帮助患者快速诊断。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 等人之前在 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 缺陷的 XLP 患者之间的重叠。有理由认为，由于这些患者具有相似的临床疾病，因此他们可能是由相同信号通路的缺陷引起的。总之，这项工作将进一步明确 XIAP 缺陷的疾病特征，扩大对这些患者为何发生免疫缺陷和 HLH 的理解，并可能发现 SAP 缺陷型 XLP 和 XIAP 缺陷型 XLP 之间的联系。这些发现将能够识别出应该评估 XIAP 缺陷的患者，并能够根据潜在的发病机制寻求针对疾病的特异性治疗。公共卫生相关性：对 XIAP 缺陷型 X 连锁淋巴增殖性疾病的调查直接关系到公共卫生和个体患者护理。这是一种新发现的疾病，与受影响患者的死亡率显着相关。该项目的目标将进一步明确疾病，提高对患者的识别和诊断，并研究疾病的潜在机制，这将促进未来 XLP 特异性干预措施的开发和实施，从而改善患者的治疗结果。