Newly Identified T Peripheral Helper (Tph) Cells in Rheumatoid Arthritis
新发现的类风湿关节炎外周辅助 T (Tph) 细胞
基本信息
- 批准号:10436186
- 负责人:
- 金额:$ 51.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-13 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnti-Tumor Necrosis Factor TherapyAntibodiesAntibody FormationAutoantibodiesAutoimmune DiseasesAutoimmunityB-LymphocytesBLR1 geneBiological Response Modifier TherapyCD4 Positive T LymphocytesCRISPR/Cas technologyCXCL13 geneCell CountCell Differentiation processCell MaturationCell SurvivalCell physiologyCellsCharacteristicsChemotactic FactorsChronicClinicalCollaborationsCytokine SignalingDataDiseaseFrequenciesGenetic TranscriptionHelper-Inducer T-LymphocyteHeterogeneityHomingHumanHyperplasiaIn VitroInflammationInflammatoryInterferon Type IInterferonsInterruptionJointsKnowledgeLeukocytesLymphocyteLymphoidLymphoid FollicleLymphoid TissueMHC Class II GenesMaintenanceMediatingNaturePRTN3 genePainPathologicPathway interactionsPatientsPeripheralPhenotypePlayPopulationProductionResolutionRheumatoid ArthritisRheumatoid FactorRoleSTAT3 geneSignal TransductionSiteSjogren&aposs SyndromeStructureSushi DomainSwellingSynovial FluidSynovial MembraneSystemic Lupus ErythematosusT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTNFSF5 geneTestingTissuesWorkarthritis therapyautoreactive T cellchemokine receptorcitrullinated proteincohortcytokineexhaustimmunopathologyin vivoinsightjoint inflammationjoint injuryprogrammed cell death protein 1receptorresponserituximabseropositivetargeted treatmenttranscriptome sequencingtranscriptomics
项目摘要
Rheumatoid arthritis (RA) is a prototypical autoimmune disease characterized by
activation of autoreactive T cells and B cells, production of autoantibodies, and accumulation of
lymphocyte aggregates within the synovium. Recently, we described a population PD-1hi CD4+
T cells that we called T `peripheral helper' (Tph) cells that is markedly expanded within RA
synovium and possesses the capacity to infiltrate inflamed tissues and promote B cell
maturation and antibody production (Rao et al., Nature, 2017). Tph cells share several features
with T follicular helper (Tfh) cells, the principal T cell subset known to drive B cell maturation in
secondary lymphoid tissues. Like Tfh cells, synovial Tph cells express high levels of IL-21,
which promotes B cell survival, and CXCL13, a B cell chemoattractant. Yet, Tph cells differ from
Tfh cells in expression of chemokine receptors for homing to inflammatory sites and in
transcriptional regulators.
The discovery of Tph cells has clinical implications for diseases that involve
autoantibody production within tissues, including RA and SLE. Selective targeting of Tph cells
could potentially interrupt local production of autoantibodies and downstream inflammatory
cascades. However, such targeting will require a precise characterization of the phenotype of
pathologic Tph cells and a more complete understanding of the factors that drive Tph cell
differentiation and expansion. Our current knowledge of Tph cells is limited.
We propose in Aim 1 to define the heterogeneity and subpopulations of Tph cells using
unbiased single cell transcriptomics followed by isolation of distinct subpopulations for functional
analysis including cytokine production. In Aim 2, we gain insight into how cytokine signaling
may alter Tph cells in vivo by tracking changes in Tph cell numbers and function in response to
currently used targeted therapies for RA. Finally, in Aim 3 we determine what drives Tph cell
differentiation and maturation. Together, these studies will advance our knowledge of the
nature of newly identified Tph cells in RA and provide information critical to understanding their
role in the immunopathogenesis of RA and potential applications for therapy.
风湿性关节炎(RA)是一种典型的自身免疫性疾病,其特征在于:
自身反应性T细胞和B细胞的活化,自身抗体的产生,
淋巴细胞在滑膜内聚集。最近,我们描述了一个群体PD-1hi CD 4 +
我们称之为T“外周辅助”(Tph)细胞的T细胞在RA中显著扩增
滑膜,并具有浸润发炎组织和促进B细胞增殖的能力
成熟和抗体产生(Rao等人,Nature,2017)。Tph细胞有几个共同的特点
与T滤泡辅助细胞(Tfh),已知的驱动B细胞成熟的主要T细胞亚群,
次级淋巴组织与Tfh细胞一样,滑膜Tph细胞表达高水平的IL-21,
其促进B细胞存活,和CXCL 13,一种B细胞化学引诱物。然而,Tph细胞不同于
Tfh细胞表达趋化因子受体,归巢至炎症部位,
转录调节因子。
Tph细胞的发现对涉及以下疾病的临床意义
组织内自身抗体的产生,包括RA和SLE。选择性靶向Tph细胞
可能会中断自身抗体和下游炎症的局部产生,
瀑布然而,这样的靶向将需要精确表征的表型,
病理性Tph细胞和驱动Tph细胞的因素的更完整的理解
差异化和扩张。我们目前对Tph细胞的了解是有限的。
我们在目标1中提出使用以下方法定义Tph细胞的异质性和亚群:
无偏的单细胞转录组学,然后分离不同的亚群用于功能性
包括细胞因子产生的分析。在目标2中,我们深入了解了细胞因子信号传导
可能通过跟踪Tph细胞数量和功能的变化来改变体内Tph细胞,
目前用于RA的靶向治疗。最后,在目标3中,我们确定是什么驱动Tph细胞
分化和成熟。总之,这些研究将促进我们对
RA中新发现的Tph细胞的性质,并提供了解其
在RA免疫发病机制中的作用和潜在的治疗应用。
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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Michael B. Brenner其他文献
Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions
不变自然杀伤 T 细胞:一种与多种效应功能相关的先天性激活方案
- DOI:
10.1038/nri3369 - 发表时间:
2013-01-21 - 期刊:
- 影响因子:60.900
- 作者:
Patrick J. Brennan;Manfred Brigl;Michael B. Brenner - 通讯作者:
Michael B. Brenner
Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis
脂肪细胞相关的糖皮质激素信号调节正常成纤维细胞功能,而在炎性关节炎中该功能丧失
- DOI:
10.1038/s41467-024-52586-x - 发表时间:
2024-11-14 - 期刊:
- 影响因子:15.700
- 作者:
Heather J. Faust;Tan-Yun Cheng;Ilya Korsunsky;Gerald F. M. Watts;Shani T. Gal-Oz;William V. Trim;Suppawat Kongthong;Anna Helena Jonsson;Daimon P. Simmons;Fan Zhang;Robert Padera;Susan Chubinskaya;Kevin Wei;Soumya Raychaudhuri;Lydia Lynch;D. Branch Moody;Michael B. Brenner - 通讯作者:
Michael B. Brenner
Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin
上皮细胞与 T 淋巴细胞之间通过 E-钙黏蛋白和αEβ7 整合素介导的黏附
- DOI:
10.1038/372190a0 - 发表时间:
1994-11-10 - 期刊:
- 影响因子:48.500
- 作者:
Karyn L. Cepek;Sunil K. Shaw;Christina M. Parker;Gary J. Russell;Jon S. Morrow;David L. Rimm;Michael B. Brenner - 通讯作者:
Michael B. Brenner
CD1 antigen presentation: how it works
CD1 抗原呈递:它是如何运作的
- DOI:
10.1038/nri2191 - 发表时间:
2007-12-01 - 期刊:
- 影响因子:60.900
- 作者:
Duarte C. Barral;Michael B. Brenner - 通讯作者:
Michael B. Brenner
Assembly and retention of CD1b heavy chains in the endoplasmic reticulum.
CD1b 重链在内质网中的组装和保留。
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:4.4
- 作者:
Masahiko Sugita;S. Porcelli;Michael B. Brenner - 通讯作者:
Michael B. Brenner
Michael B. Brenner的其他文献
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{{ truncateString('Michael B. Brenner', 18)}}的其他基金
CD8 T cell derived Granzyme K activates complement that drives synovial fibroblast inflammation
CD8 T 细胞衍生的颗粒酶 K 激活补体,驱动滑膜成纤维细胞炎症
- 批准号:
10733690 - 财政年份:2023
- 资助金额:
$ 51.06万 - 项目类别:
Single cell and spatial genomic analyses of specimens from patients with autoimmune diseases (Technology Core)
自身免疫性疾病患者标本的单细胞和空间基因组分析(技术核心)
- 批准号:
10595635 - 财政年份:2022
- 资助金额:
$ 51.06万 - 项目类别:
Single cell and spatial genomic analyses of specimens from patients with autoimmune diseases (Technology Core)
自身免疫性疾病患者标本的单细胞和空间基因组分析(技术核心)
- 批准号:
10451924 - 财政年份:2022
- 资助金额:
$ 51.06万 - 项目类别:
Role of fibroblastic stromal cells and notch signaling in tissue inflammation in RA and SLE
成纤维基质细胞和 Notch 信号在 RA 和 SLE 组织炎症中的作用
- 批准号:
10427147 - 财政年份:2021
- 资助金额:
$ 51.06万 - 项目类别:
Differentiation of immune cells and fibrobalsts in inflamed tissue in RA and SLE
RA 和 SLE 炎症组织中免疫细胞和成纤维细胞的分化
- 批准号:
10427141 - 财政年份:2021
- 资助金额:
$ 51.06万 - 项目类别:
Role of fibroblastic stromal cells and notch signaling in tissue inflammation in RA and SLE
成纤维基质细胞和 Notch 信号在 RA 和 SLE 组织炎症中的作用
- 批准号:
10088790 - 财政年份:2021
- 资助金额:
$ 51.06万 - 项目类别:
Role of fibroblastic stromal cells and notch signaling in tissue inflammation in RA and SLE
成纤维基质细胞和 Notch 信号在 RA 和 SLE 组织炎症中的作用
- 批准号:
10598101 - 财政年份:2021
- 资助金额:
$ 51.06万 - 项目类别:
Differentiation of immune cells and fibrobalsts in inflamed tissue in RA and SLE
RA 和 SLE 炎症组织中免疫细胞和成纤维细胞的分化
- 批准号:
10598093 - 财政年份:2021
- 资助金额:
$ 51.06万 - 项目类别: