"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"

“狼疮易感位点对外周 B 细胞耐受性的干扰”

基本信息

  • 批准号:
    8564791
  • 负责人:
  • 金额:
    $ 36.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-08-15 至 2015-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Autoimmune diseases are associated with a loss of immunological tolerance, a failure of an organism's adaptive immune cells to distinguish between 'self' and 'non-self'. While the existence of B cell central tolerance is now well-established, our knowledge about the cellular and molecular mechanisms of peripheral tolerance and how they may be altered in autoimmunity are limited. Understanding peripheral B cell tolerance is important as perturbed regulation of these tolerance mechanisms may allow for the development of autoreactive B cells and pathogenic IgG autoantibodies that contribute to autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we have used a targeted B cell antigen receptor (BCR) knock-in mouse model (HKIR) that yields dual-reactive {Arsonate (Ars) and DNA-chromatin-reactive} B cells. HKIR dual- reactive B cells escape central tolerance and develop into mature follicular B cells. These B cells can be recruited into the antibody forming cell (AFC) and germinal center (GC) pathways with Ars-conjugated foreign Ag. In contrast to other autoreactive transgenic mouse models in which B cells are excluded from the peripheral lymphoid follicles, the HKIR model is ideal to study peripheral B cell tolerance mechanisms operative in the AFC and GC-memory pathways or checkpoints that regulate autoantibody production. Our published data show that due to their autoreactivity, HKIR dual-reactive B cells differentiate into primary AFCs but are prevented from expanding in the GC response and do not efficiently become memory B cells. Our published and preliminary data indicate that peripheral B cell tolerance checkpoints operative at antibody forming cell (AFC) and germinal center (GC) pathways can be altered in the presence of lupus susceptibility locu Sle1. However, the influence of Sle1 on the AFC and GC-memory checkpoints appeared to be incompletely penetrant indicating the possible requirement of defects in T and/or myeloid compartments for such loss of peripheral B cell tolerance leading to production of IgG ANAs and development of lupus. Here, we propose to identify the susceptibility gene(s) within the Sle1 locus that confer a B cell autonomous break in the AFC and GC tolerance checkpoints (Aim-1). In Aim-2, we will determine the cell type (T and/or DCs) that provides B cell help and thus promotes a break in GC tolerance. Data generated from these studies will reveal how these two mechanisms permit autoantibody production in lupus and thus have both diagnostic and therapeutic implications.
描述(由申请人提供):自身免疫性疾病与免疫耐受性丧失有关,生物体的适应性免疫细胞无法区分“自我”和“非自我”。虽然B细胞中枢耐受性的存在现已得到证实,但我们对外周耐受性的细胞和分子机制以及它们如何在自身免疫中改变的知识有限。理解外周B细胞耐受性是重要的,因为这些耐受性机制的干扰调节可能允许自身反应性B细胞和致病性IgG自身抗体的发展,其有助于自身免疫性疾病,如系统性红斑狼疮(SLE)。在这里,我们使用了靶向B细胞抗原受体(BCR)基因敲入小鼠模型(HKIR),该模型产生双重反应性{胂酸盐(Ars)和DNA染色质反应性} B细胞。HKIR双反应性B细胞逃避中枢耐受并发育成成熟的滤泡B细胞。这些B细胞可以被招募到抗体形成细胞(AFC)和生殖中心(GC)途径与Ars-缀合的外来Ag。与其他自身反应性转基因小鼠模型相比,其中B细胞被排除在外周淋巴滤泡之外,HKIR模型是研究AFC和GC记忆通路或调节自身抗体产生的检查点中的外周B细胞耐受机制的理想模型。我们发表的数据表明,由于其自身反应性,HKIR双反应性B细胞分化为原代AFC,但在GC反应中被阻止扩增,并且不能有效地成为记忆B细胞。我们发表的和初步的数据表明,外周B细胞耐受性检查点在抗体形成细胞(AFC)和生发中心(GC)的途径,可以改变狼疮易感基因座Sle 1的存在。然而,Sle 1对AFC和GC记忆检查点的影响似乎是不完全渗透的,这表明T和/或髓样区室的缺陷可能需要外周B细胞耐受性的丧失,从而导致IgG ANA的产生和狼疮的发展。在这里,我们建议确定的易感基因(S)内的Sle 1基因座赋予B细胞自主突破AFC和GC耐受性检查点(Aim-1)。在Aim-2中,我们将确定提供B细胞帮助并因此促进GC耐受性破坏的细胞类型(T和/或DC)。这些研究产生的数据将揭示这两种机制如何允许狼疮中自身抗体的产生,从而具有诊断和治疗意义。

项目成果

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Ziaur Rahman其他文献

Ziaur Rahman的其他文献

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{{ truncateString('Ziaur Rahman', 18)}}的其他基金

miR-21 regulation of autoreactive B cell and lupus nephritis development
miR-21对自身反应性B细胞和狼疮性肾炎发展的调节
  • 批准号:
    10888833
  • 财政年份:
    2022
  • 资助金额:
    $ 36.9万
  • 项目类别:
IRF7-mediated development of autoreactive B cells and SLE
IRF7 介导的自身反应性 B 细胞和 SLE 的发育
  • 批准号:
    10888832
  • 财政年份:
    2021
  • 资助金额:
    $ 36.9万
  • 项目类别:
IRF7-mediated development of autoreactive B cells and SLE
IRF7 介导的自身反应性 B 细胞和 SLE 的发育
  • 批准号:
    10277067
  • 财政年份:
    2021
  • 资助金额:
    $ 36.9万
  • 项目类别:
IRF7-mediated development of autoreactive B cells and SLE
IRF7 介导的自身反应性 B 细胞和 SLE 的发育
  • 批准号:
    10437008
  • 财政年份:
    2021
  • 资助金额:
    $ 36.9万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8507140
  • 财政年份:
    2011
  • 资助金额:
    $ 36.9万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8704864
  • 财政年份:
    2011
  • 资助金额:
    $ 36.9万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8183980
  • 财政年份:
    2011
  • 资助金额:
    $ 36.9万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8318614
  • 财政年份:
    2011
  • 资助金额:
    $ 36.9万
  • 项目类别:
Impact of lupus susceptibility loci on peripheral tolerance and onset of disease
狼疮易感位点对外周耐受性和疾病发作的影响
  • 批准号:
    7846768
  • 财政年份:
    2008
  • 资助金额:
    $ 36.9万
  • 项目类别:
Impact of lupus susceptibility loci on peripheral tolerance and onset of disease
狼疮易感位点对外周耐受性和疾病发作的影响
  • 批准号:
    7669145
  • 财政年份:
    2008
  • 资助金额:
    $ 36.9万
  • 项目类别:

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  • 资助金额:
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肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
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肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
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