Activation of Innate Immunity by Small Ribonucleoprotein

小核糖核蛋白激活先天免疫

基本信息

  • 批准号:
    6839619
  • 负责人:
  • 金额:
    $ 29.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-09-16 至 2008-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Many patients with chronic autoimmune diseases such as systemic lupus erythematosus (SLE) develop autoantibodies to ubiquitous host cellular molecules, such as Sm small ribonucleoproteins (snRNPs) containing the small RNAs U1, U2, U4-6, and U5 RNAs. These small RNAs are highly structured molecules containing extensive regions of duplex (double-stranded, ds) RNA. High concentrations of dsRNA produced by replicating RNA viruses activate innate immunity by binding to dsRNA binding proteins such as TLR3 and/or the dsRNA dependent protein kinase (PKR), causing increased production of type I interferon (IFN) leading to an antiviral response. The purpose of this project is to elucidate the mechanism by which snRNP activates innate immunity in systemic lupus erythematosus (SLE). Mononuclear cells from SLE patients with increased anti-snRNPs autoantibodies express higher levels of genes usually induced by type-I IFN, an innate cytokine that plays a key role in SLE. Additional preliminary data show that double-stranded (ds) U1 RNA from snRNP stimulates mononuclear cells to activate dsRNA-induced protein kinase (PKR), a hallmark of the IFN response. It is hypothesized that snRNP triggers IFN production by engaging Toll-like receptor 3 (TLR3) in innate immune cells via U1 RNA. Preliminary studies indicated that peripheral blood mononuclear cells from a subset of patients with autoantibodies against the small ribonucleoproteins nRNP/Sm and Ro/La express higher levels of IFN inducible genes than healthy controls or the subset of lupus patients who are negative for these autoantibodies. Moreover, it was found that purified authentic U1 RNA and synthetic stem-loop II of U1 are potent stimulators of IFN-inducible gene expression and PKR autophosphorylation. Interestingly, type I IFNs also have been implicated in the pathogenesis of SLE. We hypothesize that the small RNAs associated with U1 snRNPs promote autoimmune responses to the protein components of UI snRNPs by stimulating signaling via TLR3 and/or PKR. By stimulating type I IFN production, highly structured small RNAs of cellular origin may promote dendritic cell maturation and activation of autoreactive T cells and/or the activation and maturation of autoreactive B cells specific for snRNPs. Three Specific Aims are proposed. Aim I is to examine how U1 RNA stimulates an antiviral (IFN) response by investigating whether the IFN response is mediated by TLR3 signaling, internalization of the U1 RNA followed by binding and activation of PKR, or some other pathway. The portion(s) of U1 RNA responsible for the immunostimulatory effect will be identified and the possibility that immunoinhibitory dsRNAs also exist will be examined. Aim 2 is to determine what normally prevents endogenous U1 RNA from activating the IFN system. It is hypothesized that proteins bound to structured regions of the RNA prevent it from engaging TLR3 or PKR. The ability of series of partially disrupted U1 snRNP fractions to stimulate IFN responses or PKR activation will be examined. Aim 3 is to identify the cell type that becomes activated in response to U1 RNA. The effects of U1 RNA on dendritic cell maturation, macrophage activation, and B cell development will be determined. These studies may lead to a better understanding of why autoimmune responses in SLE selectively target the Sm (U series) and other snRNPs. By triggering innate immunity, the highly structured, RNAs contained in these molecules could promote autoimmunity by promoting dendritic cell maturation and/or the activation of autoreactive B or T lymphocytes.
描述(由申请人提供): 许多慢性自身免疫性疾病的患者,如系统性红斑狼疮(SLE),都会产生针对普遍存在的宿主细胞分子的自身抗体,如含有U1、U2、U4-6和U5小RNA的Sm小核糖核蛋白(SnRNPs)。这些小RNA是高度结构化的分子,含有广泛的双链(双链,DS)RNA区域。由复制的RNA病毒产生的高浓度dsRNA通过与dsRNA结合蛋白如TLR3和/或dsRNA依赖蛋白激酶(PKR)结合来激活先天免疫,导致I型干扰素(IFN)的产生增加,从而导致抗病毒反应。本项目的目的是阐明SnRNP激活系统性红斑狼疮(SLE)天然免疫的机制。抗SNRNPs自身抗体升高的SLE患者的单个核细胞表达更高水平的基因,通常是由I型干扰素诱导的,I型干扰素是一种在SLE中发挥关键作用的天生细胞因子。其他初步数据显示,来自SnRNP的双链(Ds)U1 RNA刺激单个核细胞激活dsRNA诱导的蛋白激酶(PKR),这是干扰素反应的标志。据推测,SnRNP通过U1 RNA与天然免疫细胞中的Toll样受体3(TLR3)结合,从而触发干扰素的产生。初步研究表明,抗小核糖核蛋白nRNP/Sm和Ro/La自身抗体阳性患者的外周血单核细胞比健康对照组或自身抗体阴性的狼疮患者外周血单核细胞表达更高水平的干扰素诱导基因。此外,纯化的U1真核RNA和合成的U1茎环II是干扰素诱导的基因表达和PKR自动磷酸化的有效刺激因子。有趣的是,I型IFN也与SLE的发病机制有关。我们假设,与U1SnRNPs相关的小RNA通过刺激TLR3和/或PKR信号来促进对U1SnRNPs蛋白质组分的自身免疫反应。通过刺激I型干扰素的产生,细胞来源的高度结构的小RNA可能促进树突状细胞的成熟和自身反应性T细胞的激活和/或针对SNRNPs的自身反应性B细胞的激活和成熟。提出了三个具体目标。目的研究U1 RNA是否通过TLR3信号转导途径、U1 RNA内化及PKR结合和激活途径或其他途径来刺激抗病毒(IFN)反应。U1RNA中负责免疫刺激作用的部分(S)将被确定,并将检查是否也存在免疫抑制dsRNAs。目的2是确定正常情况下是什么阻止内源性U1 RNA激活干扰素系统。它被假设是与RNA结构区域结合的蛋白质阻止它与TLR3或PKR接触。将检测一系列部分中断的U1SnRNP组分刺激干扰素反应或PKR激活的能力。目标3是确定对U1 RNA做出反应而被激活的细胞类型。U1 RNA对树突状细胞成熟、巨噬细胞激活和B细胞发育的影响将被确定。这些研究可能有助于更好地理解为什么系统性红斑狼疮的自身免疫反应选择性地针对Sm(U系列)和其他SNRNP。通过触发天然免疫,这些分子中包含的高度结构化的RNA可以通过促进树突状细胞成熟和/或自身反应性B或T淋巴细胞的激活来促进自身免疫。

项目成果

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WESTLEY H REEVES其他文献

WESTLEY H REEVES的其他文献

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{{ truncateString('WESTLEY H REEVES', 18)}}的其他基金

AUTOIMMUNE DISEASE DATABASE AND REPOSITORY
自身免疫性疾病数据库和存储库
  • 批准号:
    7950700
  • 财政年份:
    2008
  • 资助金额:
    $ 29.52万
  • 项目类别:
AUTOIMMUNE DISEASE DATABASE AND REPOSITORY
自身免疫性疾病数据库和存储库
  • 批准号:
    7717070
  • 财政年份:
    2007
  • 资助金额:
    $ 29.52万
  • 项目类别:
MECHANISMS OF AUTOANTIBODY PRODUCTION IN SLE
SLE 自身抗体产生机制
  • 批准号:
    7605436
  • 财政年份:
    2006
  • 资助金额:
    $ 29.52万
  • 项目类别:
MECHANISMS OF AUTOANTIBODY PRODUCTION IN SLE
SLE 自身抗体产生机制
  • 批准号:
    7374626
  • 财政年份:
    2005
  • 资助金额:
    $ 29.52万
  • 项目类别:
Activation of Innate Immunity by Small Ribonucleoprotein
小核糖核蛋白激活先天免疫
  • 批准号:
    7121670
  • 财政年份:
    2004
  • 资助金额:
    $ 29.52万
  • 项目类别:
Activation of Innate Immunity by Small Ribonucleoprotein
小核糖核蛋白激活先天免疫
  • 批准号:
    7278714
  • 财政年份:
    2004
  • 资助金额:
    $ 29.52万
  • 项目类别:
Activation of Innate Immunity by Small Ribonucleoprotein
小核糖核蛋白激活先天免疫
  • 批准号:
    6950446
  • 财政年份:
    2004
  • 资助金额:
    $ 29.52万
  • 项目类别:
MECHANISMS OF AUTOANTIBODY PRODUCTION IN SLE
SLE 自身抗体产生机制
  • 批准号:
    7202921
  • 财政年份:
    2004
  • 资助金额:
    $ 29.52万
  • 项目类别:
Mechanisms of autoantibody production in SLE
SLE 自身抗体产生机制
  • 批准号:
    7041153
  • 财政年份:
    2003
  • 资助金额:
    $ 29.52万
  • 项目类别:
IMMUNE MECHANISMS IN PRISTANE INDUCED LUPUS NEPHRITIS
降植烷诱发的狼疮性肾炎的免疫机制
  • 批准号:
    2731810
  • 财政年份:
    1999
  • 资助金额:
    $ 29.52万
  • 项目类别:

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