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-4R)介导的B细胞对核蛋白自身抗原的沉默 (AutoAgs)。我们认为,通过I型干扰素/TLR7激活途径激活B细胞是 被这种B细胞静息程序抑制。我们还提出,维持B细胞静止状态的失败是 与系统性红斑狼疮(SLE)中RNP自身抗体的产生有关。我们的 初步数据表明,在狼疮小鼠和人类系统性红斑狼疮中,多种免疫疾病表型都可以 在B细胞发育的最早阶段,即过渡性B细胞,由静止期的丧失开始。这个 促进静止的关键力量是基于IKAROS(或IKZF1)的计划,该计划通过IL-4R维持 IGD+CD23+B细胞上的信号传导。促进静默丧失的主要对立程序被调解 通过I型干扰素受体(IFNAR)信号、组装和TLR7的信号能力 途径,以及能够产生自身抗体的B细胞的发展。我们假设早期的损失 在涉及进展的过渡期之后,静止期导致一系列B细胞发育缺陷 从静止的幼稚到激活的幼稚优势,然后发展到致病 CD11c+Tbet+IGD−CD27−双阴性2(Dn2)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)的研制在目标1中,我们将使用 在狼疮易感小鼠中采用几种敲除和敲入小鼠策略来确定I型干扰素和IL-4是否在 Tr B细胞调节自身反应性B细胞的发育和存活。伊卡洛斯在中国的特殊影响 调节I型干扰素和IL-4信号介导的RNP反应性B细胞在Tr和幼稚阶段的静止 也将被分析。在目标2中,我们将确定SLE患者是否表现出IL-4R/IKZF1介导的B细胞丢失 静息程序始于B细胞发育的Tr阶段。我们将确定这一损失是否 途径破坏B细胞对I型干扰素和TLR7刺激的耐受性,导致RNP- 反应性DN2B细胞和PB/PC。这一提议的创新科学基础将是它的解释能力 通过了解SLE的关键启动事件了解SLE的广泛免疫和疾病特征 B细胞在过渡期静止期消失。狼疮小鼠模型和SLE受试者的B细胞 将通过高维流式细胞术和成熟细胞的转录组学分析来表征 表面蛋白抗原标记物,定义所有主要发育阶段的B细胞发育。我们有 在BVAMC建立了一个协调员团队,以促进招聘,并获得了许多SLE 确定和统计上有意义的结果所必需的科目。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分析和分类设备,以及 专用的BVAMC 10X单细胞分析设备和用于生物信息学分析的分析管道 结果是成立的。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,定义表型的关键是 静止期和非静止期B细胞可以使用标准的临床方法经济且容易地进行测量 细胞表面相对较少的实验室流式细胞仪设备(如IL-4R或IFNAR1)或 细胞内因子(如细胞内干扰素β、TLR7或IKAROS)。这可以扩展到分析 早期B细胞静止丧失所致的异常B细胞发育轨迹 了解可能对过去患上系统性红斑狼疮的受试者有益的治疗方法。在最重要的时候 至少,这种方法应该使研究和治疗类型能够促进 维持B细胞的静止,实际上,迫使SLE进入可以维持的缓解状态 一旦确定了破坏这种缓解的免疫或环境因素的原因。

项目成果

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John D Mountz其他文献

John D Mountz的其他文献

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{{ 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:

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针对 1 型糖尿病自身抗原的工程化 TCR-Treg 细胞疗法
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自身免疫性胰腺炎自身抗原的鉴定
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