The role of cytotoxic T cells in rheumatoid arthritis pathogenesis
The role of cytotoxic T cells in rheumatoid arthritis pathogenesis
批准号:
10276979
负责人:
Erika Darrah
金额:
$60.85万
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
项目状态:
未结题
起止时间:
2021-09-01 至 2026-08-31
关键词:
AddressAllelesAntibodiesAntigen TargetingAntigen-Presenting CellsAntigensArthritisAutoantibodiesAutoantigensAutoimmuneAutoimmunityB-LymphocytesCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCalciumCessation of lifeCitrullineCleaved cellClonal ExpansionClonalityClone CellsComplexCytolysisCytoplasmic GranulesCytotoxic T-LymphocytesDNA Sequence AlterationDataDendritic CellsDevelopmentDiseaseEnzymesEpitopesEtiologyGenerationsGeneticGoalsGranzymeHLA-DRB1HumanImmune TargetingImmune responseInflammationIsoenzymesJointsKiller CellsKnowledgeLaboratoriesLeadLinkLymphocyteMaintenanceMediatingMethodsModelingMutationNatural Killer CellsNeutropeniaPathogenesisPathogenicityPathway interactionsPatientsPhenotypeProcessProtein-arginine deiminaseProteinsPublishingRheumatoid ArthritisRoleSeriesSerologyShapesSpecificityStat3 proteinSubgroupT-Cell Large Granular LymphocyteTechnologyTestingTherapeutic InterventionUniversitiesVirginiaWorkantigen processingarthropathiesautoreactivitychronic T-cell leukemiacitrullinated proteincohortcytotoxiccytotoxic CD8 T cellsenzyme mechanismhuman modelimmunogenicinnovationinsightleukemiamonocyteneutrophilnovelnovel therapeutic interventionpatient subsetsperforinpreventive intervention
中文摘要
项目摘要/摘要
大量数据表明,抗瓜氨酸蛋白自身抗体在类风湿关节炎发病机制中起作用。
瓜氨酸氨基精氨酸脱亚胺酶4(PAD4)的自身抗体也存在于
患有最严重关节疾病的患者。瓜氨酸化是一种依赖钙离子的多肽-
精氨酸通过PAD酶转化为瓜氨酸,但启动对瓜氨酸的免疫反应的机制-
相关的自身抗原知之甚少。虽然已经提出了几种不同的机制,但我们的
已发表的和初步的数据表明,细胞毒性淋巴细胞介导的中性粒细胞在世代中的杀伤
瓜氨酸自身抗原和免疫原性PAD4在RA患者中的亚群。一个致病的角色
在这一过程中的细胞毒性T淋巴细胞(CTL)得到了我们对T细胞患者的初步研究的有力支持
细胞性大颗粒淋巴细胞白血病(T-LGLL),是一种罕见的白血病形式,20%-30%的患者发生在这种白血病中
RA(T-LGLL/RA)。本病的特点是CD8+T细胞克隆性增殖、中性粒细胞减少和体细胞
激活STAT3中的突变。有趣的是,我们发现了惊人的自身免疫和遗传相似性
T-LGLL/RA和抗PAD4抗体阳性的RA亚群之间存在共同的致病机制
关节炎在这两种疾病中的发展。重要的是,这些发现使T-LGLL/RA成为一种强大的
简化致病CTL驱动的人体模型,研究RA的新致病机制。在……里面
在这个项目中,我们将使用独特的RA和T-LGLL/RA患者队列,以及创新和状态
ART技术,以检验新的假设,即致病CTL杀死中性粒细胞是一个中心
在独特的血清学上不同的RA亚群中促进对自身抗原缺乏耐受性的机制。至
针对这一假设,我们将定义:1)与自身反应性CTL扩增有关的常见致病机制
以及指示RA和T-LGLL/RA中CTL驱动疾病的血清学特征;2)细胞毒性淋巴细胞如何
颗粒途径塑造从垂死的中性粒细胞到自身反应性CD4+的自身抗原库
3)自身反应性CD8+T细胞的克隆性、特异性和效应功能
RA和T-LGLL/RA中的细胞。我们的长期目标是应用这些知识来定义精确的机械制导
类风湿关节炎的预防和治疗干预。
英文摘要
PROJECT SUMMARY/ABSTRACT
Significant data implicate a role for autoantibodies to citrullinated proteins in RA pathogenesis, and
autoantibodies to the citrullinating enzyme peptidylarginine deiminase 4 (PAD4) are also found in a subset of
patients with the most severe joint disease. Citrullination is the calcium-dependent conversion of peptidyl-
arginine to citrulline by the PAD enzymes, but the mechanisms that initiate immune responses to citrullination-
associated autoantigens are poorly understood. While different several mechanisms have been proposed, our
published and preliminary data implicate cytotoxic lymphocyte-mediated killing of neutrophils in the generation
of citrullinated autoantigens and immunogenic PAD4 in a subset of patients with RA. A pathogenic role for
cytotoxic T lymphocytes (CTLs) in this process is strongly supported by our preliminary work on patients with T
cell large granular lymphocyte leukemia (T-LGLL), a rare form of leukemia in which 20-30% of patients develop
RA (T-LGLL/RA). This disease is characterized by clonal expansion of CD8+ T cells, neutropenia and somatic
activating mutations in STAT3. Interestingly, we have found striking autoimmune and genetic similarities between
T-LGLL/RA and the anti-PAD4 antibody positive subgroup of RA, suggesting a common pathogenic origin for
the development of arthritis in these two diseases. Importantly, these findings make T-LGLL/RA a powerful yet
simplified human model driven by pathogenic CTLs, in which to study novel pathogenic mechanisms in RA. In
this project, we will use unique cohorts of patients with RA and T-LGLL/RA, as well as innovative and state of
the art technologies, to examine the novel hypothesis that killing of neutrophils by pathogenic CTLs is a central
mechanism promoting the lack of tolerance to autoantigens in a unique serologically distinct RA subset. To
address this hypothesis we will define: 1) common pathogenic mechanisms linked to autoreactive CTL expansion
and serological profiles indicative of CTL-driven disease in RA and T-LGLL/RA; 2) how the cytotoxic lymphocyte
granule pathway shapes the repertoire of autoantigens presented from dying neutrophils to autoreactive CD4+
T cells by antigen presenting cells; and 3) the clonality, specificity and effector functions of autoreactive CD8+ T
cells in RA and T-LGLL/RA. Our long-term goal is to apply this knowledge to define precise mechanism-guided
preventive and therapeutic interventions in RA.
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会议论文
The Immunopathogenic role of XIST in Sjogren's Syndrome
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批准号:9979575
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项目类别:
-
资助金额:$24.56万
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财政年份:2020
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负责人:Erika Darrah
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依托单位:
海外基金