Testing a role for activation-induced deaminase in Omenns syndrome B-cell autoimm
测试激活诱导的脱氨酶在 Omenns 综合征 B 细胞自身免疫中的作用
基本信息
- 批准号:8176094
- 负责人:
- 金额:$ 8.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-20 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnti-DNA AntibodiesAntibodiesAntibody-Producing CellsAntigen-Antibody ComplexAutoantibodiesAutoimmune DiseasesAutoimmunityB cell differentiationB-Cell DevelopmentB-LymphocytesBiological AssayBone MarrowCellsChromatinCoupledDevelopmentDiseaseExhibitsFailureGene MutationGene ProteinsGene TargetingGenerationsGenesGeneticGenetic RecombinationGermHumanImmune responseImmunoglobulin Class SwitchingImmunologic Deficiency SyndromesInfectionLeadLupus ErythematosusLymphocyteLymphoid TissueLymphopeniaMature B-LymphocyteMature LymphocyteMature T-LymphocyteMeasuresModelingMouse StrainsMusMutationOrganParentsPatientsPeripheralPersonsProcessRNAReceptor GeneReportingResearchResearch DesignRoleSerumSurfaceSyndromeSystemT-LymphocyteTestingTissuesVariantactivation-induced cytidine deaminasecentral tolerancecytokinefightinghuman diseaseinterleukin-21mouse modelmutantreceptor
项目摘要
DESCRIPTION (provided by applicant): Omenn syndrome is a human disease that exhibits an unusual combination of immunodeficiency coupled with autoimmunity. Patients have few mature T cells or B cells, and have poor immune responses. On the other hand, patients show substantial serum antibodies with elevated levels of self-reactive antibodies. Hypomorphic mutations in recombination-activating genes (RAG) are some of the best-characterized genetic defects associated with Omenn syndrome. RAG proteins are critical for recombination of receptor genes during development of B and T lymphocytes and hypomorphic RAG mutations lead to limited generation of mature lymphocytes. However, the causes of autoimmunity in the disease are not clear. During the past several years, our research groups have collaborated on studies of B cell differentiation and tolerance during early B cell development. We have recently shown that isotype switching occurs even in immature B cells in the bone marrow, counter to the prevailing paradigm that switching was limited to activated mature B cells. We have also found that immature B cell switching is greatly elevated in a mouse strain (564Igi strain) that models human System Lupus Erythematosus (SLE), and develops autoimmune disease. Because isotype switched B cells respond more strongly to stimulation, we have hypothesized that isotype switching in immature B cells can lead to a breakdown of central tolerance checkpoints and can result in autoimmune disease. We have also developed mutant 564Igi variants that either can or cannot undergo isotype switching in immature B cells. Preliminary studies indicate that autoimmunity is greatly reduced in 564Igi mice that lack early B-cell isotype switching, supporting our hypothesis that early B-cell switching can circumvent tolerance and can lead to autoimmune disease. The SLE-like 564Igi mouse model effectively reproduces many features of human SLE, but the gene- targeted anti-RNA antibody genes in the 564Igi strain are a genetic construct that is not found in human SLE patients. We want to test the role of early B-cell switching in the development of autoimmunity arising from a genetic mutation known to be involved in human autoimmunity. Recent reports have described mouse models of the human Omenn syndrome disease. These have a gene-targeted hypomorphic RAG gene and, thereby, are analogous to patients with hypomorphic RAG. The mouse models replicate the lymphopenia, the serum antibody levels, and the autoimmunity of the human disease. Furthermore, some features of Omenn syndrome, such as anti-RNA, anti-chromatin and anti-DNA antibodies, as well as elevated serum cytokines that regulate isotype switching, are shared with SLE. We will use Omenn syndrome mouse model variants that cannot undergo isotype switching in immature B cells to test whether these exhibits reduced autoimmunity. Our tests will indicate whether or not tolerance breakdown through isotype switching might be a common feature of various B cell autoimmune diseases.
PUBLIC HEALTH RELEVANCE: Antibody producing cells (B cells) are critical for making antibodies to fight infections from many different germs. B cells are born in the bone marrow; in the process of making B cells that can attack many different germs, the body makes many B cells that could attack a person's own cells and organs (self-reactive B cells). Self-reactive B cells are known to be deleted or inactivated in the bone marrow, this process is called tolerance. Sometimes tolerance fails and this can cause autoimmunity. In one mouse model of autoimmunity, we have found that tolerance failure appears to be caused by B cells that change one of their surface receptors in a particular way. Our proposed studies are designed to find out whether this mechanism for tolerance failure is a general one that occurs in other B cell autoimmune diseases.
描述(由申请人提供):Omenn综合征是一种人类疾病,其免疫缺陷与自身免疫性相结合。患者的成熟T细胞或B细胞很少,免疫反应较差。另一方面,患者表现出大量的血清抗体,自反应抗体水平升高。重组激活基因(RAG)中的型型突变是与Omenn综合征相关的一些特征最佳的遗传缺陷。抹布蛋白对于在B和T淋巴细胞的发育过程中重组受体基因至关重要,而型型rag突变导致成熟淋巴细胞的产生有限。但是,疾病自身免疫的原因尚不清楚。 在过去的几年中,我们的研究小组在早期B细胞开发过程中研究了B细胞分化和耐受性的研究。我们最近表明,即使在骨髓中未成熟的B细胞中,同种型切换也会发生,这与现行的范式相反,即开关仅限于活化的成熟B细胞。我们还发现,在小鼠菌株(564igi菌株)中,未成熟的B细胞转换大大升高,该菌株模拟了人类系统红斑狼疮(SLE),并发展自身免疫性疾病。由于同种型切换B细胞对刺激的反应更强烈,因此我们假设未成熟B细胞中的同型切换会导致中央耐受性检查点的分解,并可能导致自身免疫性疾病。我们还开发了突变体564IGI变体,这些变体可以或无法在未成熟的B细胞中进行同种异体转换。初步研究表明,缺乏早期B细胞同种型切换的564IGI小鼠中自身免疫大大降低,这支持了我们的假设,即早期的B细胞转换可以避免耐受性并可能导致自身免疫性疾病。 类似SLE的564igi小鼠模型有效地再现了人类SLE的许多特征,但是564IGI菌株中基因靶向抗RNA抗体基因是人类SLE患者中未发现的遗传构建体。我们想测试早期B细胞转换在人类自身免疫中涉及的基因突变引起的自身免疫发展中的作用。 最近的报道描述了人类奥蒙综合征疾病的小鼠模型。这些具有靶向基因的肌片基因,因此类似于患有肌张力的患者。小鼠模型复制淋巴细胞减少症,血清抗体水平和人类疾病的自身免疫性。此外,Omenn综合征的某些特征,例如抗RNA,抗染色质和抗DNA抗体,以及调节同种型切换的升高的血清细胞因子,与SLE共享。我们将使用无法在未成熟的B细胞中进行同种型切换的Omenn综合征鼠标模型变体,以测试这些表现是否会降低自身免疫性。我们的测试将指示通过同种型切换通过同种型切换的耐受性分解可能是各种B细胞自身免疫性疾病的常见特征。
公共卫生相关性:产生抗体细胞(B细胞)对于制造抗体来抵抗许多不同细菌的感染至关重要。 B细胞出生在骨髓中。在制造可以攻击许多不同细菌的B细胞的过程中,人体会产生许多B细胞,这些B细胞可能会攻击一个人自己的细胞和器官(自我反应性B细胞)。已知自反应性B细胞在骨髓中被删除或灭活,该过程称为耐受性。有时耐受性失败,这可能会导致自身免疫性。在一种自身免疫性的小鼠模型中,我们发现公差失败似乎是由B细胞引起的,B细胞以特定方式改变其表面受体之一。我们提出的研究旨在找出这种耐受性衰竭机制是否是发生在其他B细胞自身免疫性疾病中的一般性。
项目成果
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ERIK SELSING其他文献
ERIK SELSING的其他文献
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{{ truncateString('ERIK SELSING', 18)}}的其他基金
Testing a role for activation-induced deaminase in Omenns syndrome B-cell autoimm
测试激活诱导的脱氨酶在 Omenns 综合征 B 细胞自身免疫中的作用
- 批准号:
8304205 - 财政年份:2011
- 资助金额:
$ 8.25万 - 项目类别:
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