Itch Ubiquitin Ligase and Germinal Center B cells
痒泛素连接酶和生发中心 B 细胞
基本信息
- 批准号:9977374
- 负责人:
- 金额:$ 16.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmericanAntibodiesAntibody FormationAntibody ResponseAntigensAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityB-Cell Antigen ReceptorB-LymphocytesB-cell receptor repertoire sequencingBindingBiological Response ModifiersBiologyCell CountCell Surface ReceptorsCellsCellular biologyCollaborationsComputational BiologyComputer ModelsConfocal MicroscopyDataDevelopmentEndocytosisEnsureExcisionFailureFlow CytometryFoundationsFutureGenerationsGoalsHemagglutininHumanImmune responseImmunizationImmunizeImmunoglobulin Somatic HypermutationImpairmentInfluenza A virusKineticsKnockout MiceLabelLigandsLinkLysosomesModelingMolecularMolecular TargetMusMutateMutationMutation AnalysisNatureNeutralization TestsPathologicPathologyPathway interactionsPlasma CellsProteinsProteomicsPruritusRNA vaccineReceptor GeneRegulationResearchRiskRoleSerumShapesSignal TransductionSomatic MutationSpecificityStructure of germinal center of lymph nodeSurfaceSystemTechniquesTestingTherapeuticTrainingUBB geneUnited States National Institutes of HealthVariantantigen bindingantigen testautoreactive B cellbasecross reactivitycrosslinkdeep sequencingdesignfunctional outcomesneutralizing antibodynext generation sequencingnovel therapeuticspreventprogramsreceptor internalizationrecruitresponserisk minimizationtherapeutic targettraffickingubiquitin ligaseubiquitin-protein ligase
项目摘要
PROJECT SUMMARY/ABSTRACT
The NIH estimates that up to 23.5 million Americans suffer from autoimmune disease, driven in large part
by germinal center (GC)-derived pathologic autoantibodies. GC B cells undergo iterative rounds of somatic
hypermutation of B cell receptor (BCR) genes, and selection based on BCR-antigen affinity. The random nature
of somatic hypermutation allows emergence of autoreactive B cells, but these cells die because they have lost
antigen specificity, and fail to be selected. Without a stringent selection threshold, autoreactive B cells may
survive and become long-lived plasma cells. Regulation of surface BCR turnover is critical for faithful antigen-
driven selection. During each round of somatic hypermutation and selection, the pre-mutated BCR must be
removed and replaced with the newly-mutated BCR to ensure that the genetically encoded BCR dictates
selection. Failure to remove previous “versions” of the BCR could allow selection of a BCR that has not been
tested for antigen affinity. BCR turnover is an integral component of the current model of GC selection, yet this
has never been fully explored.
The ubiquitin ligase Itch prevents humoral autoimmunity in humans and mice, but how Itch limits antibody
production is unclear. I have recently determined that Itch functions in B cells to limit GC B cells, plasma cells,
and antibody production, aligning with its role in preventing autoimmunity. Through analysis of somatic mutations
in GC B cells, I now show that Itch supports stringent selection of GC B cells. After immunization, I identified
Itch deficient GC B cells bearing antigen-specific surface BCRs, yet containing nonproductive BCR genes.
These data support the idea that Itch prevents survival of B cells acquiring detrimental BCR mutations and
promotes pre-mutated BCR removal after mutation. Itch has been shown to regulate BCR internalization and
trafficking to lysosomes in naïve B cells. It is unknown how Itch controls BCR turnover in GCs, and how this
impacts GC selection. In this proposal I will test the hypothesis that Itch regulates surface BCR turnover in GC
B cells to ensure stringent selection and prevent the emergence of autoantibody. I will use B cell specific Itch
knockout mice and analysis of antigen-specific GC B cell somatic mutations to model GC dynamics and
determine how Itch regulates selection. Additionally, I will define the role of Itch in GC BCR removal and
replacement using cell biology approaches to probe surface BCR removal/replacement in GC B cells. To
complete these studies, I have formed collaborations with experts in immunoreceptor biology, intracellular
trafficking, next generation sequencing, and computational modeling. These studies will advance the
understanding of mechanisms regulating selection in GCs, and provide a unique system in which to study the
link between BCR turnover, GC B cell selection, and antibody responses.
项目概要/摘要
美国国立卫生研究院 (NIH) 估计,多达 2350 万美国人患有自身免疫性疾病,这在很大程度上是由
由生发中心 (GC) 衍生的病理性自身抗体产生,GC B 细胞经历迭代轮的体细胞。
B 细胞受体 (BCR) 基因的超突变,以及基于 BCR 抗原亲和力的选择 随机性。
体细胞超突变允许自身反应性 B 细胞出现,但这些细胞会死亡,因为它们失去了
抗原特异性,如果没有严格的选择阈值,自身反应性 B 细胞可能无法被选择。
存活并成为长寿的浆细胞,表面 BCR 更新的调节对于忠实的抗原至关重要。
在每轮体细胞超突变和选择期间,突变前的 BCR 必须是驱动选择。
删除并替换为新突变的 BCR,以确保基因编码的 BCR 指示
如果未能删除 BCR 的先前“版本”,则可能会选择尚未删除的 BCR。
抗原亲和力测试是当前 GC 选择模型的一个组成部分,但这
从未被充分探索过。
泛素连接酶 Itch 可预防人类和小鼠的体液自身免疫,但 Itch 如何限制抗体
我最近确定,Itch 在 B 细胞中发挥着限制 GC B 细胞、浆细胞、
和抗体的产生,通过体细胞突变分析与其预防自身免疫的作用相一致。
在 GC B 细胞中,我现在表明 Itch 支持 GC B 细胞的严格选择。
瘙痒缺陷型 GC B 细胞带有抗原特异性表面 BCR,但含有非生产性 BCR 基因。
这些数据支持这样的观点:瘙痒会阻止获得不健康 BCR 突变的 B 细胞的存活,并且
Itch 已被证明可以调节 BCR 内化和突变后去除突变前的 BCR。
目前尚不清楚 Itch 如何控制 GC 中的 BCR 周转,以及它是如何控制的。
在本提案中,我将测试 Itch 调节 GC 中表面 BCR 周转的假设。
为了确保严格选择B细胞并防止自身抗体的出现,我将使用B细胞特异性Itch。
敲除小鼠并分析抗原特异性 GC B 细胞体细胞突变以模拟 GC 动力学和
确定 Itch 如何调节选择此外,我将定义 Itch 在 GC BCR 去除和中的作用。
使用细胞生物学方法探测 GC B 细胞中表面 BCR 去除/替代的替代。
完成这些研究后,我与免疫受体生物学、细胞内
这些研究将推动贩运、下一代测序和计算模型的发展。
了解 GC 中调节选择的机制,并提供一个独特的系统来研究
BCR 周转、GC B 细胞选择和抗体反应之间的联系。
项目成果
期刊论文数量(0)
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Emily K. Moser其他文献
Emily K. Moser的其他文献
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{{ truncateString('Emily K. Moser', 18)}}的其他基金
Itch Ubiquitin Ligase and Germinal Center B cells
痒泛素连接酶和生发中心 B 细胞
- 批准号:
10322084 - 财政年份:2021
- 资助金额:
$ 16.2万 - 项目类别:
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