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

• 批准号: 7686748
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686748
• 关键词: Affect; Apoptosis; Area; Biological Assay; Bone Marrow Transplantation; 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; 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; Organ failure; Outcome; Pathogenesis; Pathway interactions; Patient Care; Patient Transfer; Patients; Phenotype; Play; Population; Predisposition; Prevention; Process; Production; Proteins; Public Health; Regulation; Reporting; Resources; Ring Finger Domain; Risk; Role; Screening procedure; Signal Pathway; Signal Transduction; Small Interfering RNA; 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 care; clinical phenotype; congenital immunodeficiency; crosslink; cytokine; cytotoxic; disease characteristic; granzyme B; human BIRC4 protein; improved; killings; mortality; novel; parent project; protein expression; public health relevance; rapid diagnosis; ubiquitin ligase

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）：2006年，Rigaud等人报道X-Linked Inhibitor of Apoptosis （XIAP）缺乏症是X-Linked lymphoprolifative Syndrome （XLP）的第二大已知病因。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感染相关的噬血细胞性淋巴组织细胞病（HLH）的显著易感性。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。12例报告的XIAP缺陷患者中有11例报告发生了HLH，其中4例死亡。我们最近诊断了几例XIAP缺乏症患者。目前对这种新发现的XLP病因的自然历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期的结果，并且除了预防感染并发症和发生HLH时的治疗之外，没有针对疾病的治疗方法。由于存在显著的死亡风险，在sap - XLP缺陷的病例中通常考虑进行骨髓移植，但对于XIAP - XLP缺陷的了解太少，无法确定移植的益处是否值得所涉及的风险。我们提出的工作主要涉及三个方面。首先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认识的免疫缺陷的表现，并根据特定的基因突变改进对患者结果的预测。流式细胞术筛选试验也已开始进行，以帮助快速诊断患者。其次，我们将探讨这些患者发生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患者免疫细胞对程序性细胞死亡的易感性是否增加，正如之前由Rigaud等人在XIAP缺陷患者中发现的那样，这可能有助于HLH的发展。第三，我们将寻找SAP和XIAP缺陷XLP患者之间的重叠。由于这些患者具有相似的临床疾病，因此它们可能是由相同信号通路的缺陷引起的，这是合理的。总之，这项工作将进一步定义XIAP缺乏症的疾病特征，扩大对为什么免疫缺陷和HLH在这些患者中发展的理解，并可能发现SAP缺乏症XLP和XIAP缺乏症XLP之间的联系。这些发现将有助于识别XIAP缺乏的患者，并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连锁淋巴增生性疾病的调查与公共卫生和个体患者护理直接相关。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，提高对患者的认识和诊断，并研究疾病的潜在机制，这将有助于开发和实施未来针对xlp的干预措施，从而改善患者的预后。

项目成果

A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency.

• DOI: 10.1002/cyto.b.20473
• 发表时间: 2009-09
• 期刊: CYTOMETRY PART B-CLINICAL CYTOMETRY
• 影响因子: 3.4
• 作者: Marsh, Rebecca A.;Villanueva, Joyce;Zhang, Kejian;Snow, Andrew L.;Su, Helen C.;Madden, Lisa;Mody, Rajen;Kitchen, Brenda;Marmer, Dan;Jordan, Michael B.;Risma, Kimberly A.;Filipovich, Alexandra H.;Bleesing, Jack J.
• 通讯作者: Bleesing, Jack J.