Cytokine-mediated B-cell development in lupus

细胞因子介导的狼疮 B 细胞发育

基本信息

  • 批准号:
    10584137
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-02-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

The overall goal of this project is to determine if the IKAROS transcription factor regulates a program that maintains IL-4 receptor (IL-4R)-mediated B-cell quiescence to ribonuclear protein (RNP) autoantigens (autoAgs). We propose that B cell activation through the type I interferon (IFN)/TLR7 activation pathway is inhibited by this B-cell quiescence program. We also propose that failure to maintain B cell quiescence is associated with the development of RNP autoantibody in systemic lupus erythematosus (SLE). Our preliminary data suggest that in both lupus mice and in human SLE, multiple immune disease phenotypes can be initiated by loss of quiescence at the earliest stage of B cell development; that is, the transitional B cell. The key forces that promote quiescence is an IKAROS (or IKZF1)-based program that is sustained through IL-4R signaling on IgD+CD23+ B cells. The major opposing program that promotes loss of quiescence is mediated through the type I interferon receptor (IFNAR) signaling, assembly and signaling competency of the TLR7 pathway, and development of B cells that can produce autoantibodies. We hypothesize that early-stage loss of quiescence leads to a series of B cell development defects after the transitional stage involving progression from a resting naïve to an activated naïve predominance and then to development of the pathogenic CD11c+Tbet+IgD−CD27− double negative 2 (DN2) or germinal center (GC) B cells that ultimately lead to the development of RNP autoantibody producing plasmablasts and plasma cells (PB/PC). In Aim 1, we will use several knockout and knock-in mouse strategies in lupus prone mice to determine if type I IFN and IL-4 act at the Tr B cells to regulate autoreactive B cell development and survival. The specific effects of Ikaros in modulating type I IFN and IL-4 signaling-mediated RNP-reactive B-cell quiescence at the Tr and naïve stage will also be analyzed. In Aim 2, we will determine if SLE patients exhibit a loss of IL-4R/IKZF1-mediated B cell quiescence program starting at the Tr stage of B-cell development. We will determine if the loss of this pathway disrupts B-cell tolerance to type I IFN and TLR7 stimulation, leading to the development of RNP- reactive DN2 B cells and PB/PC. The innovative scientific basis of this proposal will be its ability to interpret the broad spectrum of immune and disease characteristics of SLE by understanding the key initiating events of loss of B cell quiescence at the transitional stage. B cells from mouse models of lupus and from SLE subjects will be characterized by high dimension flow cytometry and transcriptomics analyses for well-established cell surface protein antigen markers that define B cell development at all major developmental stages. We have established a team of coordinators at the BVAMC to facilitate recruitment and have acquired numbers of SLE subjects necessary for definitive and statistically meaningful results. A state-of-the-art immunologic laboratory and BVAMC flow cytometry facility that includes the latest FACS analysis and sorting equipment, as well as a dedicated BVAMC 10X single-cell analysis facility, and analytical pipeline for bioinformatics analysis of the results are established. Significance: The successful conclusion of these experiments will be the development of new diagnostic and therapeutic approaches. From a diagnostic approach, the key defining phenotype of quiescent versus non-quiescent B cells can be economically and easily measured using standard clinical laboratory flow cytometry equipment with a relatively low number of cell surface (such as IL-4R or IFNAR1) or intracellular factors (such as intracellular IFNβ, TLR7, or IKAROS). This could be extended to analyze trajectories of abnormal B cell development that result from the loss of B cell quiescence at the earliest stages to understand therapeutics that may be beneficial in subjects who have acquired SLE in the past. At the very minimum, such approaches should enable the studies and types of treatments that will promote the maintenance of B cell quiescence and in effect, force SLE into a state of remission which can be maintained once the causes of the immune or environmental factors that disrupt such remission are defined.
这个项目的总体目标是确定IKAROS转录因子是否调节一个程序, 维持IL-4受体(IL-4 R)介导的B细胞对核糖核蛋白(RNP)自身抗原的静止 (autoAgs)。我们认为,通过I型干扰素(IFN)/TLR 7活化途径激活B细胞是一种有效的方法。 被这种B细胞静止程序所抑制我们还提出,不能维持B细胞的静止, 与系统性红斑狼疮(SLE)中RNP自身抗体的发生相关。我们 初步数据表明,在狼疮小鼠和人类SLE中,多种免疫疾病表型可 在B细胞发育的最早阶段,即过渡期B细胞,由静止期的丧失引发。的 促进静止的关键力量是基于IKAROS(或IKZF 1)的程序,该程序通过IL-4 R IgD+ CD 23 + B细胞上的信号传导。促进静止丧失的主要对立程序是介导的 通过TLR 7的I型干扰素受体(IFNAR)信号传导、组装和信号传导能力 途径,以及产生自身抗体的B细胞的发育。我们假设早期的丧失 静止期的过度表达导致一系列B细胞发育缺陷, 从静止的幼稚到激活的幼稚优势,然后发展为致病性 CD 11 c +Tbet+IgD− CD 27 −双阴性2(DN 2)或生发中心(GC)B细胞,最终导致 产生RNP自身抗体的浆母细胞和浆细胞(PB/PC)的发育。在目标1中,我们将使用 在狼疮易感小鼠中的几种敲除和敲入小鼠策略,以确定I型IFN和IL-4是否在 Tr B细胞调节自身反应性B细胞发育和存活。Ikaros的具体效果 在Tr和幼稚期调节I型IFN和IL-4信号传导介导的RNP反应性B细胞静止 也将进行分析。在目的2中,我们将确定SLE患者是否表现出IL-4 R/IKZF 1介导的B细胞 在B细胞发育的Tr阶段开始的静止程序。我们将决定是否失去这个 途径破坏B细胞对I型IFN和TLR 7刺激的耐受性,导致RNP-1的发展。 反应性DN 2 B细胞和PB/PC。这一提议的创新科学基础将是它解释 通过了解SLE的关键起始事件, 过渡期B细胞静止期丧失。来自狼疮小鼠模型和SLE受试者的B细胞 将通过高维度流式细胞术和转录组学分析来表征良好建立的细胞 在所有主要发育阶段定义B细胞发育的表面蛋白抗原标志物。我们有 在BVAMC建立了一个协调员团队,以促进招募,并获得了一些SLE 确定性和有统计学意义的结果所必需的受试者。最先进的免疫学实验室 和BVAMC流式细胞仪设施,包括最新的FACS分析和分选设备,以及 专用的BVAMC 10 X单细胞分析设施,以及用于生物信息学分析的分析管道。 结果已经确立。意义:这些实验的成功结束将是发展 新的诊断和治疗方法。从诊断方法来看, 静止与非静止的B细胞可以使用标准的临床 细胞表面数量相对较少的实验室流式细胞仪设备(如IL-4 R或IFNAR 1),或 细胞内因子(如细胞内IFNβ、TLR 7或IKAROS)。这可以扩展到分析 由于B细胞在最早阶段失去静止状态而导致的异常B细胞发育的轨迹 了解可能对过去患有系统性红斑狼疮的受试者有益的治疗方法。最 至少,这种方法应该能够促进研究和治疗类型, 维持B细胞静止,并有效地迫使SLE进入缓解状态, 一旦确定了干扰这种缓解的免疫或环境因素的原因。

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 }}

John D Mountz其他文献

John D Mountz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('John D Mountz', 18)}}的其他基金

B-cell innate and adaptive protective immunity to SARS-CoV-2
B 细胞对 SARS-CoV-2 的先天性和适应性保护性免疫
  • 批准号:
    10778521
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
B-cell innate and adaptive protective immunity to SARS-CoV-2
B 细胞对 SARS-CoV-2 的先天性和适应性保护性免疫
  • 批准号:
    10154041
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
B-cell innate and adaptive protective immunity to SARS-CoV-2
B 细胞对 SARS-CoV-2 的先天性和适应性保护性免疫
  • 批准号:
    10341174
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
B cell intrinsic interferon-beta regulates autoreactive B cell development
B 细胞内在干扰素-β 调节自身反应性 B 细胞发育
  • 批准号:
    10326335
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Interferon Beta Initiated Development of Immunogenic T1 B cells in Lupus
干扰素 Beta 启动狼疮中免疫原性 T1 B 细胞的发育
  • 批准号:
    10046270
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Interferon Beta Initiated Development of Immunogenic T1 B cells in Lupus
干扰素 Beta 启动狼疮中免疫原性 T1 B 细胞的发育
  • 批准号:
    10477180
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Training Program in Rheumatic and Musculoskeletal Diseases Research
风湿病和肌肉骨骼疾病研究培训计划
  • 批准号:
    10628089
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Role of ST6Gal I-Mediated Receptor Sialylation in Autoimmune Disease
ST6Gal I 介导的受体唾液酸化在自身免疫性疾病中的作用
  • 批准号:
    8309520
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Epigenetics of Lupus
狼疮的表观遗传学
  • 批准号:
    8309522
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
ROS Modulation of Innate and Adaptive Immunity in RA
ROS 对 RA 先天性和适应性免疫的调节
  • 批准号:
    8309519
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

相似海外基金

Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens
针对 1 型糖尿病自身抗原的工程化 TCR-Treg 细胞疗法
  • 批准号:
    10764143
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Study of identification for autoantigens in a mouse model of pituitary dysfunction induced by CTLA-4 or PD-1 blockade
CTLA-4或PD-1阻断诱导的垂体功能障碍小鼠模型中自身抗原的鉴定研究
  • 批准号:
    22K08648
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens
针对 1 型糖尿病自身抗原的工程化 TCR-Treg 细胞疗法
  • 批准号:
    10545634
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
identification of autoantigens of autoimmune pancreatitis
自身免疫性胰腺炎自身抗原的鉴定
  • 批准号:
    21H02901
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Genetic Basis of Variable Expression of Glycan Xeno-Autoantigens by Cattle
牛聚糖异种自身抗原变异表达的遗传基础
  • 批准号:
    DP200103734
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
    Discovery Projects
The study to identify novel pathogenesis and autoantigens in patients with membranous nephropathy
确定膜性肾病患者新发病机制和自身抗原的研究
  • 批准号:
    19K08694
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Project 3-Proteomic Analysis of Explanted Livers with characterization of Autoantigens
项目 3 - 外植肝脏的蛋白质组学分析及自身抗原的表征
  • 批准号:
    10356015
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Project 3-Proteomic Analysis of Explanted Livers with characterization of Autoantigens
项目 3 - 外植肝脏的蛋白质组学分析及自身抗原的表征
  • 批准号:
    10560561
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Project 3-Proteomic Analysis of Explanted Livers with characterization of Autoantigens
项目 3 - 外植肝脏的蛋白质组学分析及自身抗原的表征
  • 批准号:
    10093988
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Identification of autoantigens presented by specific HLA class I alleles in aplastic anemia
再生障碍性贫血中特定 HLA I 类等位基因呈现的自身抗原的鉴定
  • 批准号:
    19H03686
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了