Age-Associated B cells in Autoimmune Lupus

自身免疫性狼疮中与年龄相关的 B 细胞

基本信息

  • 批准号:
    9882944
  • 负责人:
  • 金额:
    $ 23.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-03-01 至 2022-02-28
  • 项目状态:
    已结题

项目摘要

Abstract Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies directed against self- antigens including DNA- and RNA-associated cellular components. Recent work from our lab and several other groups has shown that the nucleic acid sensing endosomal TLRs, TLR9 and TLR7, are required to break B cell self tolerance to these antigens and produce anti-DNA or anti-RNA autoantibodies. Despite these important insights, a great deal remains unknown about the origin of autoantibodies in lupus including the precise cellular differentiation routes that give rise to autoantibody-forming cells (AFCs). In particular, it remains unknown to what extent autoantibodies arise directly from the activation and differentiation of naive autoreactive B cells; whether an autoimmune B cell response can generate a pool of resting autoreactive memory B cells that can be reactivated over time; or whether both processes occur simultaneously. Recently a novel population of "age-associated B cells" (ABCs) was defined in mice and humans that are expanded in human SLE patients and in several murine models of lupus, including MRL/lpr. ABCs have been implicated as a candidate autoimmune memory B cell population and could be an important source of AFCs in lupus. These cells lack expression of B subset markers for follicular, marginal zone, transitional or B-1 lineages; express CD11c and CD11b; and express the transcription factor T-bet. ABCs have been postulated to contain TLR- dependent autoreactive and antiviral memory B cells, based on the presence of somatic mutations, expression of memory markers, and other properties. In this proposal, we will use genetic tools available in the MRL/lpr mouse model of lupus to investigate key questions about ABCs in vivo and to test the hypothesis that these cells are autoimmune memory and plasmablast precursors that promote lupus disease. In Aim 1, we will determine the lineage relationships of ABCs relative to naive B cells and plasmablasts, and determine the kinetics of their formation and activation. In Aim 2, we will test the hypothesis that ABCs are (or include) stable autoreactive memory B cells, and determine how the gene signature of MRL/lpr ABCs is similar to or different from that of conventional memory B cells or ABCs generated in normal aging. Finally in Aim 3, using genetic systems in which ABCs can be specifically targeted for constitutive or inducible depletion, we will test the hypothesis that ABCs are necessary for the initiation and propagation of lupus disease and evaluate their potential as a novel target for therapeutic intervention.
摘要 系统性红斑狼疮(SLE)的特征在于产生针对自身免疫缺陷的自身抗体。 抗原,包括DNA和RNA相关的细胞成分。我们实验室最近的工作和几个 其他研究小组已经表明,核酸感应内体TLRs,TLR 9和TLR 7, B细胞自身耐受这些抗原并产生抗DNA或抗RNA自身抗体。尽管有这些 重要的见解,很多仍然未知的起源,自身抗体在狼疮,包括 精确的细胞分化途径,产生自身抗体形成细胞(AFC)。特别是 自身抗体在多大程度上直接由幼稚细胞的激活和分化引起, 自身反应性B细胞;自身免疫性B细胞应答是否可产生静息自身反应性 记忆B细胞可以随着时间的推移而重新激活;或者这两个过程是否同时发生。最近 在小鼠和人中定义了一种新的“年龄相关B细胞”(ABC)群体, 在人SLE患者和几种狼疮鼠模型中,包括MRL/lpr。ABC被认为是 一种候选的自身免疫记忆B细胞群,可能是狼疮中AFC的重要来源。这些 细胞缺乏滤泡、边缘区、过渡或B-1谱系的B亚群标志物的表达;表达 CD 11 c和CD 11b;表达转录因子T-bet。假设ABC含有TLR- 依赖自身反应性和抗病毒记忆B细胞,基于体细胞突变的存在,表达 记忆标记和其他属性。在本提案中,我们将使用MRL/lpr中可用的遗传工具 狼疮小鼠模型,以研究体内ABC的关键问题,并检验这些假设, 细胞是促进狼疮疾病的自身免疫记忆和浆母细胞前体。在目标1中,我们 确定ABC相对于幼稚B细胞和浆母细胞的谱系关系,并确定 其形成和活化的动力学。在目标2中,我们将检验ABC是(或包括)稳定的假设 自身反应性记忆B细胞,并确定MRL/lpr ABC的基因特征如何相似或不同 与在正常老化中产生的常规存储器B单元或ABC不同。最后,在目标3中,使用遗传 系统中,ABC可以特异性靶向组成型或诱导型耗竭,我们将测试 假设ABC是狼疮疾病的启动和传播所必需的,并评估其 作为治疗干预的新靶点的潜力。

项目成果

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Kevin Nickerson其他文献

Kevin Nickerson的其他文献

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{{ truncateString('Kevin Nickerson', 18)}}的其他基金

Opposing Roles of TLR7 and TLR9 Signaling in Systemic Lupus Erythematosus
TLR7 和 TLR9 信号传导在系统性红斑狼疮中的相反作用
  • 批准号:
    7333866
  • 财政年份:
    2007
  • 资助金额:
    $ 23.01万
  • 项目类别:

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