The mechanism of NK cell defects in human NEMO deficiency
人类NEMO缺陷导致NK细胞缺陷的机制
基本信息
- 批准号:7629124
- 负责人:
- 金额:$ 20.56万
- 依托单位:
- 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:2008-07-01 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAnimal ModelAreaBiochemicalBiological AssayCell modelCell physiologyCellsConfocal MicroscopyCytomegalovirusCytoplasmic GranulesDataDefectDependenceDevelopmentDiseaseElementsGenerationsGenesGenetic TranscriptionGenus MycobacteriumHealthHumanImmuneImmune systemImmunityImmunologic Deficiency SyndromesImmunologyIn VitroInfectionInterleukin-2InterruptionLaboratoriesLeadLigationLymphocyteLyticMediatingMutationNK Cell ActivationNatural Killer CellsPathway interactionsPatientsPhysiological ProcessesPredispositionProcessProtein BiosynthesisProteinsReceptor ActivationRegulationRoleSignal TransductionSmall Interfering RNAStagingTechniquesTestingTherapeuticVirusWorkcytotoxicityimmunological synapseimmunological synapse formationinhibitor/antagonistinsightinterestkillingsnovelpathogenpublic health relevanceresearch studytranscription factor
项目摘要
DESCRIPTION (provided by applicant): Human primary immunodeficiency caused by hypomorphic mutation of the NF-?B essential modifier (NEMO) gene impairs several immunological functions and leads to grave infectious susceptibilities. The disease resulting from these mutations (NEMO-ID) arises from an inability of NEMO to effectively perform its typical function enabling activation of the NF-?B transcription factor after ligation of key immunoreceptors. Patients with NEMO-ID are vulnerable to infection with cytomegalovirus, which has led us to identify their having a defect of NK cell cytotoxicity. NK cells are lymphocytes of the innate immune system that are capable of killing through the process of directed secretion of lytic granules onto a target cell after forming an immunological synapse (IS). NK cells are especially useful in defense against cytomegalovirus and other viruses that employ strategies to evade adaptive immunity. This is underscored by several other primary immunodeficiencies affecting NK cells. Although a number of the immunological deficits in NEMO-ID are understood at a mechanistic level, that of NK cell cytotoxicity is not. Through the work proposed in this application we will determine the mechanism of the NK cell defect in NEMO-ID. This is relevant as NK cell deficiency adversely affects the health of patients with NEMO-ID and understanding its mechanism will likely suggest therapeutic strategies to specifically overcome it. Defining the mechanism of NK cell deficiency in NEMO-ID will also provide unexpected and novel insight into the function of cytolytic cells and the IS. In our studies of NK cells from NEMO-ID patients we have found that the defect is specific and can be circumvented after IL-2 stimulation. Thus it is unlikely that the NK cells are developmentally abnormal and a mechanism in which NEMO serves an acute role in NK cell cytotoxicity is likely. Through in vitro preliminary studies we have found that the NEMO-dependent NF-?B pathway is rapidly induced in NK cells after activation receptor ligation. This leads to rapid NF-?B-dependent gene transcription and synthesis of new proteins in a timeframe consistent with the cytolytic process. Using several approaches we have identified a limited number of NEMO- and NF-?B-dependent rapidly synthesized proteins in NK cells and are pursuing their role in enabling cytotoxicity and the lytic IS. Thus, our long term objective is to further establish this paradigm of NEMO function in NK cells and define a role for NEMO-dependent rapidly synthesized proteins in formation of the IS and cytotoxicity. Specifically we will: 1) define the stage of the NK cell IS that depends upon NEMO function and NF-?B activation; 2) determine the role of rapidly synthesized NEMO-dependent proteins in NK cell function; 3) determine if IL-2 can restore the expression of critical NEMO/NF-?B dependent proteins in NK cells with blocked NF-?B signaling. Cumulatively, these studies will determine the mechanism of NK cell deficiency in NEMO-ID, define a novel pathway of regulating cytolytic function and provide insight into potentially useful therapy for NEMO-ID patients. PUBLIC HEALTH RELEVANCE: Our proposal, "The Mechanism of NK Cell Defects in Human NEMO Deficiency", is aimed at understanding why patients with hypomorphic mutations in the NEMO gene have defective NK cell function. We believe the answer is that NEMO serves a surprising role in rapid transcription and protein synthesis to enable NK cell cytotoxicity. Our work will test this hypothesis and be of broad relevance in that it will define a novel mechanism by which immunological function can be regulated as well as more specific insight into NK cells in NEMO deficiency that may allow for rational therapies.
描述(由申请人提供):由核因子-?B基本修饰物(NEMO)基因亚型突变引起的人类初级免疫缺陷损害了几种免疫功能,并导致严重的感染易感性。由这些突变引起的疾病(NEMO-ID)是由于NEMO不能有效地执行其典型功能,即在连接关键免疫受体后激活核因子?B转录因子。NEMO-ID患者容易感染巨细胞病毒,这使得我们发现他们存在NK细胞杀伤缺陷。NK细胞是天然免疫系统中的淋巴细胞,在形成免疫突触(IS)后,通过将裂解颗粒定向分泌到靶细胞上而产生杀伤作用。NK细胞在防御巨细胞病毒和其他采用策略逃避获得性免疫的病毒方面特别有用。其他几种影响NK细胞的原发免疫缺陷也突显了这一点。虽然NEMO-ID的一些免疫学缺陷是在机制水平上被理解的,但NK细胞的细胞毒性却不是。通过本申请中提出的工作,我们将确定NEMO-ID中NK细胞缺陷的机制。这是相关的,因为NK细胞缺乏对Nemo-ID患者的健康造成不利影响,了解其机制可能会提出专门克服它的治疗策略。明确NEMO-ID中NK细胞缺陷的机制也将为了解细胞溶解细胞和IS的功能提供意想不到的新见解。在我们对NEMO-ID患者的NK细胞的研究中,我们发现这种缺陷是特异的,在IL-2刺激后可以绕过。因此,NK细胞不太可能是发育异常的,NEMO在NK细胞细胞毒性中起重要作用的机制可能是可能的。通过体外初步研究,我们发现在NK细胞中,激活受体结合后能迅速诱导NEMO依赖的核因子-βB途径。这导致依赖于核因子?B的基因在与细胞溶解过程一致的时间框架内快速转录和合成新的蛋白质。使用几种方法,我们已经在NK细胞中鉴定了数量有限的依赖于NEMO和NF?B的快速合成的蛋白质,并正在研究它们在实现细胞毒性和裂解IS方面的作用。因此,我们的长期目标是进一步建立NK细胞中NEMO功能的这一范例,并确定依赖NEMO的快速合成蛋白在IS形成和细胞毒性中的作用。具体地说,我们将:1)确定NK细胞的阶段是取决于Nemo功能和NF-β激活的;2)确定快速合成的Nemo依赖蛋白在NK细胞功能中的作用;3)确定IL-2是否能在阻断了NF-?B信号的NK细胞中恢复关键的Nemo/NF-?B依赖蛋白的表达。总而言之,这些研究将确定NEMO-ID患者NK细胞缺陷的机制,定义一条调节细胞溶解功能的新途径,并为NEMO-ID患者提供潜在有用的治疗方法。公共卫生相关性:我们的提案《人类NEMO缺乏症中NK细胞缺陷的机制》旨在了解NEMO基因低形态突变患者NK细胞功能缺陷的原因。我们认为答案是NEMO在快速转录和蛋白质合成方面发挥了令人惊讶的作用,从而使NK细胞具有细胞毒作用。我们的工作将检验这一假说,并具有广泛的相关性,因为它将定义一种新的机制,通过它可以调节免疫功能,以及对NEMO缺乏症中的NK细胞进行更具体的洞察,从而允许合理的治疗。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels.
NEMO 谷氨酸 223 的先天性改变会导致少汗性外胚层发育不良和血清 IgG 水平正常的免疫缺陷。
- DOI:10.1016/j.anai.2011.03.009
- 发表时间:2011
- 期刊:
- 影响因子:0
- 作者:Karamchandani-Patel,Gital;Hanson,EricP;Saltzman,Rushani;Kimball,CEve;Sorensen,RicardoU;Orange,JordanS
- 通讯作者:Orange,JordanS
Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO and EDA mutations.
- DOI:10.3389/fimmu.2011.00061
- 发表时间:2011
- 期刊:
- 影响因子:7.3
- 作者:Keller MD;Petersen M;Ong P;Church J;Risma K;Burham J;Jain A;Stiehm ER;Hanson EP;Uzel G;Deardorff MA;Orange JS
- 通讯作者:Orange JS
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Jordan Scott Orange其他文献
Jordan Scott Orange的其他文献
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{{ truncateString('Jordan Scott Orange', 18)}}的其他基金
GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY
人类 NK 细胞缺陷的遗传、免疫学和机制基础
- 批准号:
10363767 - 财政年份:2016
- 资助金额:
$ 20.56万 - 项目类别:
GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY
人类 NK 细胞缺陷的遗传、免疫学和机制基础
- 批准号:
10490860 - 财政年份:2016
- 资助金额:
$ 20.56万 - 项目类别:
GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY
人类 NK 细胞缺陷的遗传、免疫学和机制基础
- 批准号:
10686199 - 财政年份:2016
- 资助金额:
$ 20.56万 - 项目类别:
GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY
人类 NK 细胞缺陷的遗传、免疫学和机制基础
- 批准号:
9205454 - 财政年份:2016
- 资助金额:
$ 20.56万 - 项目类别:
GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY
人类 NK 细胞缺陷的遗传、免疫学和机制基础
- 批准号:
9003675 - 财政年份:2016
- 资助金额:
$ 20.56万 - 项目类别:
Directing Function at the Natural Killer Cell Secretory Immunological Synapse
自然杀伤细胞分泌免疫突触的指导功能
- 批准号:
8308767 - 财政年份:2011
- 资助金额:
$ 20.56万 - 项目类别:
Directing Function at the Natural Killer Cell Secretory Immunological Synapse
自然杀伤细胞分泌免疫突触的指导功能
- 批准号:
7875101 - 财政年份:2009
- 资助金额:
$ 20.56万 - 项目类别:
The mechanism of NK cell defects in human NEMO deficiency
人类NEMO缺陷导致NK细胞缺陷的机制
- 批准号:
7530223 - 财政年份:2008
- 资助金额:
$ 20.56万 - 项目类别:
Directing Function at the Natural Killer Cell Secretory Immunological Synapse
自然杀伤细胞分泌免疫突触的指导功能
- 批准号:
7650556 - 财政年份:2008
- 资助金额:
$ 20.56万 - 项目类别:
Directing Function at the Natural Killer Cell Secretory Immunological Synapse
自然杀伤细胞分泌免疫突触的指导功能
- 批准号:
8448575 - 财政年份:2007
- 资助金额:
$ 20.56万 - 项目类别:
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