FAIM in Immunity and Autoimmunity
免疫和自身免疫中的 FAIM
基本信息
- 批准号:7987067
- 负责人:
- 金额:$ 41.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAntibodiesAntibody FormationAntibody-Producing CellsAntigensApoptosisAttentionAutoantibodiesAutoimmune DiseasesAutoimmune ProcessAutoimmunityAutologousB cell differentiationB-Cell ActivationB-LymphocytesBindingBiological ModelsBiologyBloodCell physiologyCellular biologyClinicalComplexDevelopmentDiseaseDown-RegulationDysplasiaEvolutionFaceGenesGoalsGrantHumanIRF4 geneImmuneImmune responseImmunityImmunoglobulinsIn VitroLaboratoriesLettersLeukocytesLocationLower OrganismLupusLupus ErythematosusMature B-LymphocyteModelingMolecular StructureMolecular TargetMusParticipantPatientsPersonal CommunicationPhysiologyPlasma CellsPlayPoriferaProcessProductionProtein RegionProteinsPublishingResearch PersonnelRestRoleSequence HomologySignal TransductionSpecificityStructureStructure of germinal center of lymph nodeSystemTNFRSF5 geneTimeVirus DiseasesWorkantimicrobialfascinatefeedinggene cloninggene discoveryin vivolupus prone micenew therapeutic targetnoveloverexpressionplasma cell differentiationpublic health relevancetherapeutic targettranscription factor
项目摘要
DESCRIPTION (provided by applicant): Like the two faces of Janus, antibodies can be a gateway to anti-microbial immunity or to autoantibody- associated disease. The recent successful use of anti-CD20 to treat patients with autoimmune dyscrasias has re-focused attention on the role of B cells as therapeutic targets. Mature B cells become antibody secreting plasma cells through a complex process that begins in the germinal center and involves alterations in multiple transcription factors. Work from this laboratory has identified a new player in B cell activation and differentiation, namely the novel gene, Faim. FAIM is unique; it is highly evolutionarily conserved, yet does not contain sequence homology, or structural homology, with any other protein. In B cells FAIM acts as a force multiplier. It boosts CD40 signaling by enhancing CD40L-stimulated increases in NF-:B and IRF4, and, it enhances the CD40L-stimulated decline in BCL-6. As expected from the extra increase in IRF4 and decline in BCL-6 (as well as its location in the germinal center) FAIM overexpression augments the plasma cell compartment in chimeric mice. FAIM expression is stimulated by IRF4 and so once triggered FAIM is involved in a "feed-forward" positive re-inforcing mechanism. The long term objective of this proposal is two-fold: to understand normal B cell biology focusing on how "resting" B cells become effectors, and to determine the points at which these processes go awry resulting in autoantibody production and autoimmunity. The near term objective of this work is to define the role of FAIM in facilitating immunity and regulating autoimmunity, with the goal of identifying a new therapeutic target. The specific aims of this proposal are to: 1) conduct a careful molecular structure/function analysis to identify and characterize the unique FAIM effector motif; and, 2) evaluate the influence of FAIM on the quality and selection of antibody produced in a model normal immune response, and on checkpoint integrity in a model system of spontaneous autoantibody production, and elucidate the physiology of FAIM expression in the germinal center. The results of this work are highly likely to provide completely new and fundamental information about how signaling in B cells is promoted, and about how plasma cell differentiation is regulated. Moreover, the recent finding by other investigators (unpublished) that SNPs proximal to, and within, the FAIM sequence are strongly associated with human lupus disease indicates that the mechanisms revealed by this study are highly likely to be relevant to understanding clinical autoimmunity and may provide a new target for therapeutic manipulation.
PUBLIC HEALTH RELEVANCE: Antibodies are proteins in the blood that are made by B lymphocytes, which are a kind of white blood cell. Antibodies bind to and help defeat bacterial and viral infections. However, antibodies are not always beneficial; sometimes B lymphocytes make antibodies against self, and these autoreactive antibodies, or autoantibodies, can cause serious autoimmune diseases such as system lupus erythematosus. Recently we found new and important activities produced by a gene that we discovered 10 years ago. This gene, termed FAIM, makes B cells hyperresponsive to some kinds of activation signals and increases the number of antibody producing cells. This gene is fascinating because it is found throughout evolution in both higher and lower organisms (even sponge has a similar gene), but its mechanism of action is unknown. We have found that FAIM is a force multiplier for B lymphocyte responsiveness and development into antibody producing cells. As such, FAIM is likely to play a role in autoimmune disease. Our goal in this work is to determine: how FAIM affects B lymphocytes by identifying the active region of the protein, whether effect of FAIM on antibody producing cells alters which cells produce antibody, and whether FAIM influences the level of spontaneous autoantibodies during autoimmune disease. If our work is successful, we will identify a new molecular target through which it should be possible to regulate B cell activity and antibody production, up to treat immune deficiency, and down to treat autoimmune disease.
描述(由申请人提供):就像两面神的两个面孔一样,抗体可以成为抗微生物免疫或自身抗体相关疾病的门户。最近成功使用抗 CD20 治疗自身免疫性恶液质患者,使人们重新将注意力集中在 B 细胞作为治疗靶点的作用上。成熟的 B 细胞通过一个复杂的过程成为分泌抗体的浆细胞,该过程始于生发中心,涉及多种转录因子的改变。该实验室的工作已经确定了 B 细胞激活和分化的新参与者,即新基因 Faim。 FAIM 是独一无二的;它在进化上高度保守,但不包含与任何其他蛋白质的序列同源性或结构同源性。在 B 细胞中,FAIM 充当力量倍增器。它通过增强 CD40L 刺激的 NF-:B 和 IRF4 增加来增强 CD40 信号传导,并且增强 CD40L 刺激的 BCL-6 下降。正如 IRF4 的额外增加和 BCL-6(及其在生发中心的位置)下降所预期的那样,FAIM 过表达增强了嵌合小鼠中的浆细胞区室。 FAIM 表达受 IRF4 刺激,因此一旦触发,FAIM 就会参与“前馈”正强化机制。该提案的长期目标有两个:了解正常 B 细胞生物学,重点关注“静止”B 细胞如何成为效应细胞,并确定这些过程出错的点,从而导致自身抗体产生和自身免疫。这项工作的近期目标是确定 FAIM 在促进免疫和调节自身免疫方面的作用,以期确定新的治疗靶点。该提案的具体目标是:1)进行仔细的分子结构/功能分析,以识别和表征独特的 FAIM 效应基序; 2) 评估 FAIM 对正常免疫反应模型中产生的抗体的质量和选择的影响,以及对自发自身抗体产生模型系统中检查点完整性的影响,并阐明生发中心 FAIM 表达的生理学。这项工作的结果很可能提供有关如何促进 B 细胞信号传导以及如何调节浆细胞分化的全新基本信息。此外,其他研究人员最近发现(未发表)FAIM 序列附近和内部的 SNP 与人类狼疮疾病密切相关,表明这项研究揭示的机制很可能与理解临床自身免疫相关,并可能为治疗操作提供新的靶点。
公共卫生相关性:抗体是血液中由 B 淋巴细胞(白细胞的一种)产生的蛋白质。抗体结合并帮助战胜细菌和病毒感染。然而,抗体并不总是有益的。有时B淋巴细胞会产生针对自身的抗体,这些自身反应性抗体或自身抗体可引起严重的自身免疫性疾病,例如系统性红斑狼疮。最近,我们发现了 10 年前发现的一个基因产生的新的重要活性。这种被称为 FAIM 的基因使 B 细胞对某些类型的激活信号过度反应,并增加产生抗体的细胞数量。这个基因很有趣,因为它在高等和低等生物的整个进化过程中都被发现(甚至海绵也有类似的基因),但其作用机制尚不清楚。我们发现 FAIM 是 B 淋巴细胞反应性和发育成抗体产生细胞的力量倍增器。因此,FAIM 很可能在自身免疫性疾病中发挥作用。我们这项工作的目标是确定:FAIM 如何通过识别蛋白质的活性区域来影响 B 淋巴细胞,FAIM 对抗体产生细胞的影响是否会改变哪些细胞产生抗体,以及 FAIM 是否会影响自身免疫性疾病期间自发性自身抗体的水平。如果我们的工作成功,我们将确定一个新的分子靶标,通过它应该可以调节 B 细胞活性和抗体产生,向上治疗免疫缺陷,向下治疗自身免疫性疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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THOMAS L ROTHSTEIN其他文献
THOMAS L ROTHSTEIN的其他文献
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{{ truncateString('THOMAS L ROTHSTEIN', 18)}}的其他基金
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Human B1-like Cells and Pneumococcal Defense in the Elderly
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