Investigating the Role of Fc Receptors in the Pathogenesis of Osteoarthritis

研究 Fc 受体在骨关节炎发病机制中的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): Current therapies for OA simply alleviate symptoms of advanced disease rather than inhibit the processes that drive the disease. A better understanding of the mechanisms underlying the pathogenesis of OA would undoubtedly yield new therapeutic approaches. Although OA was long considered a purely mechanical disorder, it is becoming clear that it also involves inflammation and activation of immune cells. Synovial tissues of individuals with OA contain inflammatory cytokines and are infiltrated with both innate and adaptive immune cells, and the presence of synovial inflammation predicts more rapid cartilage destruction. These infiltrating immune cells express Fc receptors (FcRs), which normally serve to protect against infection by binding to antibodies and thereby triggering the release of inflammatory and cytotoxic mediators. However, aberrant activation or regulation of FcR-mediated signaling can lead to inflammatory and autoimmune diseases. We have garnered evidence that FcRs also play a central role in the pathogenesis of OA. We found that mice lacking the common ?-chain, through which several of the activating FcRs signal, are resistant to cartilage degeneration in a mouse model of OA. Mice deficient specifically in Fc?RIII, which does not signal through the ¿-chain but has been shown to mediate autoantibody-induced tissue damage and inflammation, were also resistant. We hypothesize that one or more activating FcR contributes to the pathogenesis of OA by inducing FcR-expressing immune cells in OA synovial tissue to release inflammatory, vasoactive, cytotoxic, and degradative molecules that in turn contribute to the synovitis, cell death, and cartilage erosion characteristic of OA. Antigen-bound antibodies activate FcRs, and antibodies directed against joint components are present in OA synovial fluid, synovial tissue, and cartilage. Findings in mice indicate that antibodies to various joint components can elicit inflammatory joint destruction. It is possible that such antibodies develop following exposure of cartilage components to the immune system- owing to mechanical cartilage breakdown-and contribute to inflammatory joint destruction in OA by activating FcRs. We propose to use genetically deficient mice, an established mouse model of OA, and samples from patients with OA to (i) determine whether activating FcRs promote mouse OA, and whether they do so by activating mast cells, macrophages, or other immune cells; (ii) determine how early in the development of human OA FcR-expressing immune cells infiltrate the synovial joints; (iii) determine whether levels of FcR expression or levels of immune-cell activation correlate with levels of OA-associated inflammation or with disease severity in human OA; and (iv) determine whether debris from human OA cartilage can activate innate immune cells in an FcR-dependent manner. Several approaches to targeting FcRs are being developed for the treatment of inflammatory disorders. Targeting FcRs, which could prevent the triggering of a cascade of different inflammatory mediators, may prove more therapeutically efficacious than targeting a single inflammatory mediator (the latter being an approach that has so far proven unsuccessful in OA). Thus, by shedding light on the role of FcRs in OA, success of the proposed studies could open up new avenues for the treatment of OA, for which disease- modifying treatments are urgently needed.
描述(由申请人提供): 目前的OA治疗只是缓解晚期疾病的症状,而不是抑制驱动疾病的过程。更好地了解OA发病机制的基础上,无疑会产生新的治疗方法。虽然OA长期以来被认为是一种纯粹的机械性疾病,但越来越清楚的是,它也涉及炎症和免疫细胞的激活。患有OA的个体的滑膜组织含有炎性细胞因子,并且被先天性和适应性免疫细胞浸润,并且滑膜炎症的存在预示着更快速的软骨破坏。这些浸润性免疫细胞表达Fc受体(FcR),其通常用于通过与抗体结合来保护免受感染,从而触发炎症和细胞毒性介质的释放。然而,FcR介导的信号传导的异常激活或调节可导致炎性和自身免疫性疾病。我们已经收集到的证据表明,FcRs在OA的发病机制中也发挥着重要作用。我们发现老鼠缺乏共同的?-链,通过它的几个激活FcRs信号,是抵抗软骨退化的小鼠模型中的OA。特异性Fc缺陷小鼠?RIII不通过ω链发出信号,但已被证明介导自身抗体诱导的组织损伤和炎症,也具有耐药性。我们假设一种或多种激活性FcR通过诱导OA滑膜组织中表达FcR的免疫细胞释放炎症、血管活性、细胞毒性和降解分子,进而导致OA的滑膜炎、细胞死亡和软骨侵蚀特征,从而促进OA的发病机制。抗原结合抗体激活FcR,并且针对关节成分的抗体存在于OA滑液、滑液组织和软骨中。在小鼠中的发现表明,各种关节成分的抗体可引起炎症性关节破坏。这类抗体可能是在软骨成分暴露于免疫系统后产生的-由于机械性软骨分解-并通过激活FcRs导致OA中的炎性关节破坏。我们建议使用遗传缺陷小鼠(一种已建立的OA小鼠模型)和来自OA患者的样本来(i)确定激活FcR是否促进小鼠OA,以及它们是否通过激活肥大细胞、巨噬细胞或其他免疫细胞来促进;(ii)确定在人类OA发展的早期,表达FcR的免疫细胞浸润滑膜关节;(iii)确定FcR表达水平或免疫细胞活化水平是否与OA相关炎症水平或与人OA的疾病严重程度相关;和(iv)确定来自人OA软骨的碎片是否可以以FcR依赖性方式活化先天免疫细胞。正在开发几种靶向FcR的方法用于治疗炎性病症。靶向FcR可以防止触发不同炎症介质的级联反应,可能证明比靶向单一炎症介质更有效(后者是迄今为止在OA中证明不成功的方法)。因此,通过阐明FcR在OA中的作用,所提出的研究的成功可以为OA的治疗开辟新的途径,对于OA,迫切需要改善疾病的治疗。

项目成果

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William H Robinson其他文献

Immune tolerance of citrullinated peptides.
瓜氨酸肽的免疫耐受。
  • DOI:
    10.1038/s41584-024-01081-0
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    R. Thomas;William H Robinson
  • 通讯作者:
    William H Robinson
Imatinib for the treatment of rheumatic diseases
伊马替尼用于治疗风湿性疾病
  • DOI:
    10.1038/ncprheum0465
  • 发表时间:
    2007-04-01
  • 期刊:
  • 影响因子:
    32.700
  • 作者:
    Ricardo T Paniagua;William H Robinson
  • 通讯作者:
    William H Robinson
Human peptidome display
人类肽组展示
  • DOI:
    10.1038/nbt.1888
  • 发表时间:
    2011-06-07
  • 期刊:
  • 影响因子:
    41.700
  • 作者:
    William H Robinson;Lawrence Steinman
  • 通讯作者:
    Lawrence Steinman

William H Robinson的其他文献

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{{ truncateString('William H Robinson', 18)}}的其他基金

BCCMA: Targeting Osteoarthritis Pain and Progression: Proteomics, RNASeq & Immunostaining to elucidate the immune pathotypes of OA
BCCMA:针对骨关节炎疼痛和进展:蛋白质组学、RNASeq
  • 批准号:
    10590409
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Investigating the IL-4/13 Axis in Osteoarthritis
研究骨关节炎中的 IL-4/13 轴
  • 批准号:
    9891690
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Investigating the IL-4/13 Axis in Osteoarthritis
研究骨关节炎中的 IL-4/13 轴
  • 批准号:
    10092814
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Investigating the IL-4/13 Axis in Osteoarthritis
研究骨关节炎中的 IL-4/13 轴
  • 批准号:
    10438519
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Investigating the IL-4/13 Axis in Osteoarthritis
研究骨关节炎中的 IL-4/13 轴
  • 批准号:
    10553629
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
ShEEP Request for BioPlex 3D System
ShEEP 请求 BioPlex 3D 系统
  • 批准号:
    9796566
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Targeting Mast Cells in Post-Traumatic Joint Rehabilitation and Osteoarthritis
在创伤后关节康复和骨关节炎中靶向肥大细胞
  • 批准号:
    10025268
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Targeting Mast Cells in Post-Traumatic Joint Rehabilitation and Osteoarthritis
在创伤后关节康复和骨关节炎中靶向肥大细胞
  • 批准号:
    10672163
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Targeting Mast Cells in Post-Traumatic Joint Rehabilitation and Osteoarthritis
在创伤后关节康复和骨关节炎中靶向肥大细胞
  • 批准号:
    10284924
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Large-Scale Characterization of Anti-Cancer Antibody Responses in Lung Adenocarci
肺腺癌抗癌抗体反应的大规模表征
  • 批准号:
    8664101
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:

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阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
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