Decay Accelerating Factor and B cell Immunity
衰变加速因子和 B 细胞免疫
基本信息
- 批准号:10623288
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-17 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAlternative Complement PathwayAntibodiesAntibody AffinityAntibody FormationAntibody ResponseAntibody titer measurementAntigensAutoimmuneAutoimmunityB Cell ProliferationB-Cell ActivationB-LymphocytesBCL6 geneBiologicalBiologyC3AR1 geneC5a anaphylatoxin receptorCD55 AntigensCell SurvivalCell surfaceCellular biologyChromosome 1ComplementComplement 3 ConvertaseComplement 3aComplement 3d ReceptorsComplement 5aComplement ActivationDataDevelopmentDiseaseDown-RegulationEnhancersEventFollicular Dendritic CellsFutureGenerationsGenesGenetic TranscriptionHumoral ImmunitiesImmune responseImmunityImmunizationImmunoglobulin Somatic HypermutationImpairmentInfectionLiftingLigationLightLinkMediatingMediatorMemory B-LymphocyteModelingMolecularMusOutcomeOutputPIK3CG genePathogenicityPhysiologicalPlasma CellsProcessProductionReactionReagentReceptor SignalingRegulationRepressionResearchRoleSignal PathwaySignal TransductionSolidStructure of germinal center of lymph nodeSystemT-LymphocyteTestingTransgenic OrganismsTransplantationVaccineschronic graft versus host diseasecomplement C3d,gcomplement pathwaygene repressiongenetic regulatory proteinin vivoinsightlymphoid structuresmembernovelorgan transplant rejectionoverexpressionpathogenpreventprogramspromoterreceptorresponserestrainttransmission processvaccine strategy
项目摘要
Project Summary
Humoral immunity crucially protects against pathogens but can function as a pathogenic mediator of multiple
autoimmune and alloimmune disease processes, the latter including chronic graft vs. host disease and
antibody-mediated solid organ transplant rejection. Development of antigen-specific antibody responses
requires T cell-dependent B cell activation and the formation of germinal centers (GC), transient lymphoid
structures where somatic hypermutation and affinity maturation events result in the generation of high affinity,
antibody-producing plasma cells (PC) and memory B cells (Bmem). The physiological signals that control GC
formation and GC B cell fates are incompletely characterized. Our preliminary data identify a previously
unappreciated role for decay accelerating factor (DAF or CD55), a cell surface-expressed complement
regulatory protein, in controlling GC reactions and their resultant output, the production of PC and Bmem. Our
data support the hypothesis that optimal GC function requires downregulation of cell surface expressed DAF
on responding B cells, a process that lifts restraint on local, alternative pathway complement activation and
facilitates C3- and C5-convertase formation and production of C3 and C5 cleavage products. This process
promotes C3a/C3aR1 and C5a/C5aR1 ligations on GC B cells, which would in turn transduce signals
controlling GC B cell proliferation, survival, somatic hypermutation, and/or affinity maturation, and as a
consequence, influence differentiation into memory B cells and/or plasma cells. We will test this paradigm-
shifting hypothesis using unique biological reagents and through 3 interactive aims: 1) To determine the effects
of B cell-expressed DAF, C3aR1 and C5aR1 on T cell-dependent humoral immune responses and distinguish
them from the effects of B cell-expressed CD21. 2) To determine the cellular and molecular mechanisms
through which DAF downregulation and enhanced signaling through C3aR1/C5aR1 in B cells drive affinity
maturation. 3) To determine the molecular basis of DAF downregulation on B cells. This comprehensive
analysis performed by a multi-PI team with expertise in complement biology (Heeger) and B cell biology
(Dominguez-Sola) is likely to provide new insight into fundamental mechanisms of GC dynamics and function.
The results have the potential to guide second order studies aimed at exploiting the complement/B cell axis to
either inhibit development of pathogenic B cell responses (e.g. in transplantation or autoimmunity) or augment
B cell response (e.g. in response to vaccines).
项目摘要
体液免疫力至关重要地预防病原体,但可以充当多重病原体的介体
自身免疫性和同种免疫性疾病过程,后者包括慢性移植与宿主疾病和
抗体介导的固体器官移植排斥。抗原特异性抗体反应的发展
需要T细胞依赖性B细胞激活和生发中心(GC)的形成,瞬态淋巴样
体细胞超成熟和亲和力成熟事件导致高亲和力产生的结构,
产生抗体的浆细胞(PC)和记忆B细胞(BMEM)。控制GC的生理信号
形成和GC B细胞命运未完全表征。我们的初步数据确定了先前的
衰减加速因子(DAF或CD55)的未欣赏角色,一种细胞表面表达的补体
调节蛋白在控制GC反应及其产量时,PC和BMEM的产生。我们的
数据支持最佳GC功能需要下调细胞表面表达DAF的假设
在响应B细胞时,该过程可以限制局部替代途径补充激活和
促进C3-和C5-转化酶形成以及C3和C5裂解产品的产生。这个过程
在GC B细胞上促进C3A/C3AR1和C5A/C5AR1绑扎,这又会传输信号
控制GC B细胞增殖,存活,体细胞超成名和/或亲和力成熟,并作为A
结果,影响分化为记忆B细胞和/或浆细胞。我们将测试此范式 -
使用独特的生物试剂转移假设,并通过3个交互式目的:1)确定影响
B细胞表达的DAF,C3AR1和C5AR1在T细胞依赖性体液免疫反应上的
它们来自B细胞表达的CD21的影响。 2)确定细胞和分子机制
通过在B细胞中通过C3AR1/C5AR1通过C3AR1/C5AR1的DAF下调和增强的信号传导驱动亲和力
成熟。 3)确定B细胞上DAF下调的分子基础。这个全面
由具有补体生物学专业知识(HEEGER)和B细胞生物学专业知识的多PI团队进行的分析
(Dominguez-Sola)可能会提供有关GC动力学和功能基本机制的新见解。
结果有可能指导旨在利用补体/B细胞轴的二阶研究
抑制致病性B细胞反应的发展(例如,移植或自身免疫性)或增强
B细胞反应(例如,对疫苗的响应)。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cleaving It All Behind: ADAMTS7 Degrades Factor H.
- DOI:10.1681/asn.0000000000000030
- 发表时间:2023-02
- 期刊:
- 影响因子:0
- 作者:P. Heeger;P. Cravedi
- 通讯作者:P. Heeger;P. Cravedi
Effects of the complement system on antibody formation and function: implications for transplantation.
- DOI:10.1097/mot.0000000000001002
- 发表时间:2022-10-01
- 期刊:
- 影响因子:2.2
- 作者:Cumpelik, Arun;Heeger, Peter S.
- 通讯作者:Heeger, Peter S.
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David Dominguez-Sola其他文献
David Dominguez-Sola的其他文献
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{{ truncateString('David Dominguez-Sola', 18)}}的其他基金
Decay Accelerating Factor and B cell Immunity
衰变加速因子和 B 细胞免疫
- 批准号:
10406250 - 财政年份:2019
- 资助金额:
$ 42.38万 - 项目类别:
Role of FOXO1 mutations in the pathogenesis of B cell non-Hodgkin lymphomas
FOXO1突变在B细胞非霍奇金淋巴瘤发病机制中的作用
- 批准号:
10334435 - 财政年份:2018
- 资助金额:
$ 42.38万 - 项目类别:
Role of FOXO1 mutations in the pathogenesis of B cell non-Hodgkin lymphomas
FOXO1突变在B细胞非霍奇金淋巴瘤发病机制中的作用
- 批准号:
10087895 - 财政年份:2018
- 资助金额:
$ 42.38万 - 项目类别:
ROLE OF REPLICATION STRESS DURING MYC-DEPENDENT LYMPHOMAGENESIS
复制应激在 MYC 依赖性淋巴细胞生成过程中的作用
- 批准号:
8146177 - 财政年份:2010
- 资助金额:
$ 42.38万 - 项目类别:
ROLE OF REPLICATION STRESS DURING MYC-DEPENDENT LYMPHOMAGENESIS
复制应激在 MYC 依赖性淋巴细胞生成过程中的作用
- 批准号:
7962386 - 财政年份:2010
- 资助金额:
$ 42.38万 - 项目类别:
Role of Replication Stress during Myc-dependent Lymphomagenesis
复制应激在 Myc 依赖性淋巴瘤发生过程中的作用
- 批准号:
8785173 - 财政年份:2010
- 资助金额:
$ 42.38万 - 项目类别:
Role of Replication Stress during Myc-dependent Lymphomagenesis
复制应激在 Myc 依赖性淋巴瘤发生过程中的作用
- 批准号:
8819518 - 财政年份:2010
- 资助金额:
$ 42.38万 - 项目类别:
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