Mechanisms controlling ABC differentiation and function in SLE
SLE 中 ABC 分化和功能的控制机制
基本信息
- 批准号:10364120
- 负责人:
- 金额:$ 56.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAffectAfrican AmericanAgeAntiviral ResponseAutoantibodiesAutoimmuneAutoimmune DiseasesAutoimmunityB cell differentiationB-Lymphocyte SubsetsB-LymphocytesC57BL/6 MouseCOVID-19 pandemicCell LineageCell physiologyCellsCellular biologyCharacteristicsChildClinicalDataDevelopmentDiseaseEffector CellEpigenetic ProcessEstrogensExhibitsFamilyFamily memberFemaleGene Expression ProfileGenesGeneticGenetic studyGonadal Steroid HormonesHIVHomologous GeneHumanITGAX geneImmune responseImmunityInterferon Type IIInterferonsKnockout MiceLinkLupusLupus NephritisMolecularMolecular GeneticsMusMutationMyelogenousPathogenesisPatientsPeripheralPhenotypePlantsPlasma CellsPlasmablastPlayPopulationPredispositionProductionProteinsRegulationRisk FactorsRoleSex BiasSex DifferencesSignal TransductionStructure of germinal center of lymph nodeSusceptibility GeneSyndromeSystemSystemic Lupus ErythematosusT-bet proteinTLR7 geneTherapeuticTranslatingUp-RegulationVirusVirus DiseasesWomanX ChromosomeX Inactivationautoimmune pathogenesiscytokineearly onsetgenetic approachgenetic risk factorgenetic signaturegenome-wideimmunoregulationinterestmalemonocytenew therapeutic targetnovelresponsesexsexual dimorphismsystemic autoimmune diseasesystemic autoimmunityvaccination outcome
项目摘要
ABSTRACT
Abnormalities in B cell subsets play a key role in SLE, a disease that, in addition to AutoAb production and
multi-organ involvement, often includes upregulation of interferon stimulated genes (ISGs). One of the
hallmarks of SLE is that it preferentially affects women. Both sex hormones and the X chromosome (where
TLR7 is located) have been implicated in the heightened susceptibility of women to SLE and to other
autoimmune disorders. Understanding the molecular mechanisms that underlie the sex-bias that
accompanies SLE pathogenesis will thus provide critical information into the development of autoimmunity
and help uncover novel therapeutic targets. While expansion of germinal center (GC) B cells and
plasmablasts/plasma cells (PB/PC) has long been associated with SLE, recent studies have implicated a
novel B cell subset, termed Age/Autoimmune-associated B cells (ABCs), in lupus pathogenesis. In addition
to classical B cell markers, ABCs also express CD11c and the transcription factor T-bet. Formation of ABCs
is promoted by a combination of signals that includes TLR7 or TLR9 engagement and cytokines like IFN-g
and IL-21. Aberrant accumulation of ABCs is observed both in murine lupus and in SLE patients where
they are major producers of autoAbs and correlate with disease activity and clinical manifestations. Our lab
has had a long-standing interest in dissecting the regulation and function of IRF family members, which
have emerged as key controllers of B cell responses. While identifying IRF-interacting proteins, we isolated
a protein termed Def6. Def6 and its only other homologue, SWAP-70, play an important immunoregulatory
role in humans and mice. Def6 is a genetic risk factor for human SLE and biallelic mutations in Def6 result
in early-onset systemic autoimmunity. Furthermore, in C57BL/6 mice, the concomitant lack of Def6 and
SWAP-70 (Double-knockout mice=DKOs) leads to the spontaneous development of SLE, which, similarly
to humans, preferentially affects female mice. Lupus development in DKO mice is accompanied by a
marked accumulation of ABCs, which is controlled by IRF5. We have recently found that, as compared to
ABCs from DKO males, ABCs from DKO females expand to a greater extent, express an ISG signature,
and readily produce autoAbs upon TLR7 stimulation. Furthermore, in comparison with DKO males, DKO
females accumulate greater numbers of GC B cells and PB/PCs that contain CD11c+ subsets.
Dysregulating TLR7 expression in DKO males results in a marked expansion of ABCs and other B cell
effector lineages including CD11c-expressing B cell subsets and promotes autoAb production and disease
development in DKO males. Taken together these data suggest that sexual dimorphism underlies several
aspects of ABC biology in autoimmune settings. In this proposal we will investigate the hypothesis that sex-
specific mechanisms control the function and differentiation of ABCs as well as characterize the
developmental relationships between ABCs and other effector B cell lineages.
摘要
B细胞亚群中的抗体在SLE中起关键作用,SLE是一种除了自身抗体产生和
多器官参与,通常包括干扰素刺激基因(ISG)的上调。之一
SLE的特点是它优先影响女性。性激素和X染色体(其中
TLR 7位于)与女性对SLE和其他疾病的易感性增加有关。
自身免疫性疾病了解性别偏见的分子机制,
因此,伴随SLE发病机制的蛋白质将为自身免疫的发展提供关键信息
并帮助发现新的治疗靶点。当生殖中心(GC)B细胞和
浆母细胞/浆细胞(PB/PC)长期以来与SLE相关,最近的研究表明,
新的B细胞亚群,称为年龄/自身免疫相关B细胞(ABC),在狼疮发病机制。此外
与经典的B细胞标志物不同,ABC也表达CD 11 c和转录因子T-bet。ABC的形成
由包括TLR 7或TLR 9接合和细胞因子如IFN-g的信号组合促进
IL-21。在小鼠狼疮和SLE患者中均观察到ABC的异常积累,
它们是自身抗体的主要生产者,并与疾病活动和临床表现相关。我们实验室
长期以来,他一直对剖析IRF家族成员的调节和功能感兴趣,
已经成为B细胞反应的关键控制者。在鉴定IRF相互作用蛋白质的同时,我们分离了
一种叫做Def 6的蛋白质Def 6和它唯一的其他同源物SWAP-70在免疫调节中起着重要的作用。
在人类和小鼠中的作用。Def 6是人类SLE的遗传危险因素,Def 6中的双等位基因突变导致
早期全身性自身免疫此外,在C57 BL/6小鼠中,伴随的Def 6和
SWAP-70(双敲除小鼠= DKO)导致SLE的自发发展,类似地,
对人类来说,优先影响雌性小鼠。DKO小鼠的狼疮发展伴随着一种免疫抑制剂。
ABC的显著积累,这是由IRF 5控制的。我们最近发现,与
来自DKO雄性的ABC,来自DKO雌性的ABC扩增到更大程度,表达ISG标记,
并且在TLR 7刺激时容易产生自身抗体。此外,与DKO男性相比,
女性积累更多数量的GC B细胞和含有CD 11 c+亚群的PB/PC。
DKO雄性中TLR 7表达失调导致ABC和其他B细胞显著扩增
包括表达CD 11 c的B细胞亚群的效应子谱系,并促进自身抗体产生和疾病
DKO男性的发育。综合这些数据表明,两性异形是几个
自身免疫环境中ABC生物学的各个方面。在这个建议中,我们将调查性的假设-
特定的机制控制ABC的功能和分化,并表征
ABC和其他效应B细胞谱系之间的发育关系。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ALESSANDRA B PERNIS其他文献
ALESSANDRA B PERNIS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ALESSANDRA B PERNIS', 18)}}的其他基金
Mechanisms controlling ABC differentiation and function in SLE
SLE 中 ABC 分化和功能的控制机制
- 批准号:
10620619 - 财政年份:2022
- 资助金额:
$ 56.96万 - 项目类别:
Hospital for Special Surgery Research Institute Rheumatology Training
特殊外科研究所风湿科培训医院
- 批准号:
9921297 - 财政年份:2017
- 资助金额:
$ 56.96万 - 项目类别:
Regulatory Mechanisms Controlling TFH Responses in Lupus
控制狼疮 TFH 反应的调节机制
- 批准号:
9271861 - 财政年份:2016
- 资助金额:
$ 56.96万 - 项目类别:
Rho GTPase-mediated pathways in autoimmune arthritis
Rho GTPase 介导的自身免疫性关节炎通路
- 批准号:
8230157 - 财政年份:2011
- 资助金额:
$ 56.96万 - 项目类别:
Rho GTPase-mediated pathways in autoimmune arthritis
Rho GTPase 介导的自身免疫性关节炎通路
- 批准号:
8770006 - 财政年份:2011
- 资助金额:
$ 56.96万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 56.96万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 56.96万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 56.96万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 56.96万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 56.96万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 56.96万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 56.96万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 56.96万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 56.96万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 56.96万 - 项目类别:
Studentship