Activation of B Cells by Host Toll-Like Receptor Ligands

宿主 Toll 样受体配体激活 B 细胞

基本信息

项目摘要

B cells isolated from the B cell receptor (BCR) transgenic model AM 14 recognize a prototypic autoantigen, lgG2a, with relatively low affinity, and are relatively unresponsive to most lgG2a-containing immune complexes (IC). However, these rheumatoid factor producing B cells proliferate vigorously in response to IC consisting of lgG2a bound to DNA- or RNA-associated autoantigens via a mechanism that involves sequential engagement of the BCR located on the plasma membrane and Toll-like receptor 9 (TLR9) or TLR7, located in a cytoplasmic compartment. This experimental system has clearly implicated TLR7 and TLR9 in the activation of autoreactive B cells and shown that these receptors are specific for CG-rich dsDNA - potent endogenous DNA ligands include CpG islands. Importantly, we have shown that the functions elicited by physiologically relevant ICs cannot be reproduced with artificial ligands. However the exact role played by TLR7 and TLR9 in disease onset and progression is still unclear, and very little is known about the distinct functions elicited by TLR9 compared to TLR7 triggered pathways. The overall goal of the current application is to gain a better understanding of exactly how TLR9 and TLR7-expressing cell types contribute to SLE pathogenesis. Specific questions that will be addressed in this project include: (1) what are the natural sources of endogenous TLR ligands and when do they become available to the immune system; (2) what structural features of RNA determine TLR7 reactivity; (3) can TLR7 and TLR9 form functional heterodimers that detect DNA/RNA autoantigens; (4) which cellular compartments are involved in the detection of TLR7 and TLR9 ligands and how does the specific compartment regulate function; (5) how do type 1 interferons modulate the autoantibody repertoire and autoreactive B cell function; and (6) what functional outcomes distinguish BCR/TLR9 from BCR/TLR7 activation. The results of the studies will provide important information regarding the development of novel therapies for the treatment of systemic diseases such as SLE. RELEVANCE (See instructions): SLE is a chronic life threatening autoimmune disorder that afflicts up to 2 million individuals within the United States. Current therapeutic options can moderate disease severity but often have deleterious side effects that limit their extended use. Insights gained from this proposal should facilitate the development of drugs that specifically target the relevant immune effector mechanisms without the debilitating side effects of now associated with standard treatments
从B细胞受体(BCR)转基因模型AM 14分离的B细胞识别原型自身抗原, LgG2a,亲和力相对较低,对大多数含有lgG2a的免疫反应相对无效 复合体(IC)。然而,这些产生类风湿因子的B细胞在IC的响应下强烈增殖 由lgG2a通过一种机制与DNA或RNA相关的自身抗原结合组成,该机制包括 位于质膜上的BCR与Toll样受体9(TLR9)或 TLR7,位于细胞质隔间。这个实验系统清楚地牵涉到TLR7和 TLR9在激活自身反应性B细胞中的作用,并表明这些受体是富含CG的dsDNA的特异性受体 -强大的内源性DNA配体包括CpG岛。重要的是,我们已经证明了这些函数 由生理上相关的ICs激发的DNA不能用人工配体复制。然而,确切的角色是 TLR7和TLR9在疾病的发生和发展中所起的作用仍然不清楚,对TLR7和TLR9在疾病的发生和发展中所起的作用也知之甚少 与TLR7触发通路相比,TLR9触发的功能不同。当前的总体目标是 应用是为了更好地了解TLR9和TLR7表达的细胞类型到底是如何贡献的 对SLE发病机制的影响。本项目将解决的具体问题包括:(1)什么是 内源性TLR配体的自然来源及其何时可用于免疫系统;(2) TLR7的结构特征决定了TLR7的反应性;(3)TLR7和TLR9能否形成功能性 检测DNA/RNA自身抗原的异源二聚体;(4)哪些细胞室参与了 TLR7和TLR9配体的检测以及特定的隔室如何调节功能;(5)如何 1型干扰素调节自身抗体谱和自身反应B细胞功能;和(6)什么 功能结果区分bcr/TLR9和bcr/TLR7激活。研究结果将提供 关于开发治疗系统性疾病的新疗法的重要信息 如系统性红斑狼疮。 相关性(请参阅说明): 系统性红斑狼疮是一种威胁生命的慢性自身免疫性疾病,在美国有多达200万人患有此病。 各州。目前的治疗方案可以减轻疾病的严重程度,但往往会产生有害的副作用 这限制了它们的广泛使用。从这项提案中获得的见解应该会促进药物的开发 它专门针对相关的免疫效应器机制,而不会产生现在令人衰弱的副作用 与标准治疗相关

项目成果

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Ann Marshak-Rothstein其他文献

Ann Marshak-Rothstein的其他文献

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{{ truncateString('Ann Marshak-Rothstein', 18)}}的其他基金

The role of TLRs, Type II IFN and Type III IFN in a Murine Model of Autoinflammation
TLR、II 型 IFN 和 III 型 IFN 在小鼠自身炎症模型中的作用
  • 批准号:
    10576930
  • 财政年份:
    2021
  • 资助金额:
    $ 0.79万
  • 项目类别:
The role of TLRs, Type II IFN and Type III IFN in a Murine Model of Autoinflammation
TLR、II 型 IFN 和 III 型 IFN 在小鼠自身炎症模型中的作用
  • 批准号:
    10375346
  • 财政年份:
    2021
  • 资助金额:
    $ 0.79万
  • 项目类别:
Mechanisms by which TLR9-deficiency and FasL Promote Cutaneous Lupus
TLR9 缺陷和 FasL 促进皮肤狼疮的机制
  • 批准号:
    9752064
  • 财政年份:
    2019
  • 资助金额:
    $ 0.79万
  • 项目类别:
Mechanisms by which TLR9-deficiency and FasL Promote Cutaneous Lupus
TLR9 缺陷和 FasL 促进皮肤狼疮的机制
  • 批准号:
    9884735
  • 财政年份:
    2019
  • 资助金额:
    $ 0.79万
  • 项目类别:
Distinct Functional Outcomes of BCR/TLR7 and BCR/TLR9 Co-engagement
BCR/TLR7 和 BCR/TLR9 共同参与的不同功能结果
  • 批准号:
    9228925
  • 财政年份:
    2015
  • 资助金额:
    $ 0.79万
  • 项目类别:
Distinct Functional Outcomes of BCR/TLR7 and BCR/TLR9 Co-engagement
BCR/TLR7 和 BCR/TLR9 共同参与的不同功能结果
  • 批准号:
    9033830
  • 财政年份:
    2015
  • 资助金额:
    $ 0.79万
  • 项目类别:
CO-FUNDING-NIAID
联合资助-NIAID
  • 批准号:
    8504901
  • 财政年份:
    2013
  • 资助金额:
    $ 0.79万
  • 项目类别:
Activation of B Cells by Host Toll-Like Receptor Ligands
宿主 Toll 样受体配体激活 B 细胞
  • 批准号:
    8504902
  • 财政年份:
    2013
  • 资助金额:
    $ 0.79万
  • 项目类别:
CO-FUNDING-NIAID
联合资助-NIAID
  • 批准号:
    8378436
  • 财政年份:
    2012
  • 资助金额:
    $ 0.79万
  • 项目类别:
Activation of B Cells by Host Toll-Like Receptor Ligands
宿主 Toll 样受体配体激活 B 细胞
  • 批准号:
    8290052
  • 财政年份:
    2011
  • 资助金额:
    $ 0.79万
  • 项目类别:

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使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
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