Neutrophil plasticity in autoimmune disease
自身免疫性疾病中的中性粒细胞可塑性
基本信息
- 批准号:10326852
- 负责人:
- 金额:$ 64.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-10 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AbbreviationsAcuteAntibodiesAntigen-Antibody ComplexAntigen-Presenting CellsAntigensAutoantibodiesAutoimmuneAutoimmune DiseasesAutomobile DrivingAutophagocytosisBehaviorBiological AssayBloodBlood VesselsCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCategoriesCellsCharacteristicsChronic DiseaseClinicalComplexCoupledCrohn&aposs diseaseDataDendritic CellsDepositionDiseaseEnd stage renal failureEvolutionExposure toFluorescein-5-isothiocyanateFrequenciesGenerationsGenesGlomerulonephritisGoodpasture SyndromeGranulocyte-Macrophage Colony-Stimulating FactorHeart DiseasesHumanIgG ReceptorsImmune responseImmunizeImmunoglobulin GImmunosuppressive AgentsIn VitroInflammationInflammatoryInjectionsInjuryInjury to KidneyKidneyLinkLupusLupus NephritisMalignant NeoplasmsMediatingModelingMolecularMusNephritisNeutrophil ActivationOrganOvalbuminPatientsPhasePhenotypePolysaccharidesPopulationProcessPropertyProteinsReporterRheumatoid ArthritisRiskRoleSerumSpleenSystemic Lupus ErythematosusT-Cell ProliferationT-LymphocyteTestingTherapeutic InterventionTubulointerstitial NephritisTumor Immunityacquired immunityantigen bindingautoimmune pathogenesisbasecell killingchemokine receptorchronic autoimmune diseasecytokinedifferential expressiondraining lymph nodehuman tissuehumanized mouseimmunogenicimprintin vivoinhibitorinsightintravital microscopymigrationmouse modelnephrotoxicityneutrophilnovelorgan injuryphenotypic biomarkerpreventreceptorrecruitrenal damageresponsesingle-cell RNA sequencingsystemic autoimmune diseasetissue injurytraffickingtranscription factortranscriptometranscriptome sequencingtranscriptomicstransdifferentiationuptake
项目摘要
Autoimmune disease is the third most common disease category after cancer and heart disease. Current
therapies often rely on broad-spectrum immunosuppressive drugs to reduce inflammation and thus prevent
permanent organ damage and chronic disease. Neutrophils are considered short-lived cells with degradative
properties that associate with organ damage in diseases ranging from rheumatoid arthritis and Crohn’s to
lupus nephritis. Deletion of activating FcγRs, receptors for IgG protects from organ damage in many mouse
models of autoimmune diseases and FcγR SNPs are linked to rheumatoid arthritis, lupus and other
autoimmune disorders. We have shown that IgG-immune complex deposition within blood vessels triggers
rapid neutrophil capture via their own FcγRs and subsequent renal injury in a model of glomerulonephritis,
suggesting that neutrophil FcγRs serve as a key link between IgG deposition and organ damage. What is the
fate of activated neutrophils? Neutrophils can transdifferentiate into dendritic cells (DC) in response to
cytokines in vitro and neutrophils with DC markers (nDC) are observed in inflamed mouse and human
tissues. This suggests that the neutrophil imprint may go beyond the acute stages of inflammation. Based
on preliminary data in mouse models and lupus patient blood we propose the following. Neutrophil FcγR
engagement with multivalent IgG-complexed antigen induces neutrophil transdifferentiation into
immunogenic, antigen cross-presenting nDCs that elicit T cell dependent acquired immunity and organ
damage, which contributes to the transition from acute to chronic autoimmune disease. This hypothesis will
be tested using our humanized FcγR mice, neutrophil reporter mice, mouse models of autoimmune target
organ injury and systemic lupus erythematosus (SLE) patient blood coupled with transcriptome profiling,
functional assays and multiphoton intravital microscopy. In specific aims, we propose to understand the
molecular underpinnings of the FcγR dependent neutrophil to DC transition, the evolution of nDC fate,
trafficking and immunogenic profile during the course of IgG mediated inflammation and the role of nDCs in
promoting organ damage. Here, we will focus on nephrotoxic nephritis, a model of glomerulonephritis that
mimics aspects of the effector phase of lupus nephritis, and T cell mediated tubulointerstitial nephritis, which
are leading causes of end stage renal disease, but fully anticipate a broader applicability of our results to
other IgG-mediated autoimmune diseases. Successful completion of our aims will lead to the characterization
of a unique population of potent antigen presenting cells that develop from neutrophils exposed to
autoantibody-ICs and may provide evidence that they establish a feed forward loop that fuels inflammation
and thus increases the risk for transition to chronic autoimmune disease. We anticipate that this will lay the
groundwork for elucidating novel points for therapeutic intervention in autoimmune disorders.
自身免疫性疾病是仅次于癌症和心脏病的第三大常见疾病。当前的
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)
专利数量(0)
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Tanya N Mayadas其他文献
Tanya N Mayadas的其他文献
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{{ truncateString('Tanya N Mayadas', 18)}}的其他基金
Neutrophil plasticity in autoimmune disease
自身免疫性疾病中的中性粒细胞可塑性
- 批准号:
10569637 - 财政年份:2020
- 资助金额:
$ 64.84万 - 项目类别:
TNFR2 Regulation of Leukocyte Recruitment in Glomerulonephritis
肾小球肾炎中白细胞募集的 TNFR2 调节
- 批准号:
8821615 - 财政年份:2014
- 资助金额:
$ 64.84万 - 项目类别:
TNFR2 Regulation of Leukocyte Recruitment in Glomerulonephritis
肾小球肾炎中白细胞募集的 TNFR2 调节
- 批准号:
9456733 - 财政年份:2014
- 资助金额:
$ 64.84万 - 项目类别:
cAMP Control of Endothelial Barrier and T Cell Migration
cAMP 控制内皮屏障和 T 细胞迁移
- 批准号:
7753048 - 财政年份:2009
- 资助金额:
$ 64.84万 - 项目类别:
Endothelia mechanisms of leukocyte accumulation in glomerulonephritis
肾小球肾炎白细胞积聚的内皮机制
- 批准号:
7903751 - 财政年份:2009
- 资助金额:
$ 64.84万 - 项目类别:
Endothelia mechanisms of leukocyte accumulation in glomerulonephritis
肾小球肾炎白细胞积聚的内皮机制
- 批准号:
7620123 - 财政年份:2007
- 资助金额:
$ 64.84万 - 项目类别:
Endothelia mechanisms of leukocyte accumulation in glomerulonephritis
肾小球肾炎白细胞积聚的内皮机制
- 批准号:
7322748 - 财政年份:2007
- 资助金额:
$ 64.84万 - 项目类别:
Mac-1 (CR3) and Fc gamma receptors in immune-mediated neutrophil cytotoxicity
Mac-1 (CR3) 和 Fc gamma 受体在免疫介导的中性粒细胞细胞毒性中的作用
- 批准号:
8209095 - 财政年份:2003
- 资助金额:
$ 64.84万 - 项目类别:
Mac-1 (CR3) and Fc gamma receptors in immune-mediated neutrophil cytotoxicity
Mac-1 (CR3) 和 Fc gamma 受体在免疫介导的中性粒细胞细胞毒性中的作用
- 批准号:
7582061 - 财政年份:2003
- 资助金额:
$ 64.84万 - 项目类别:
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