Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
基本信息
- 批准号:8968799
- 负责人:
- 金额:$ 41.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-07-01 至 2016-11-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): A role for B cells in autoimmune diseases is now clearly established both with mouse models as well as in humans by successful treatment of rheumatoid arthritis (RA) and other autoimmune diseases with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells may promote the development of autoimmune diseases remain poorly understood. We previously demonstrated that untreated active RA patients, patients with systemic lupus erythematosus, and patients with type 1 diabetes display abnormal early B cell tolerance checkpoints resulting in the accumulation of large numbers of autoreactive naove B cells in their blood. We recently established that these early B cell tolerance defects were primary to these autoimmune diseases and can be induced in asymptomatic donors by risk alleles such as PTPN22, which interfere with B cell receptor (BCR) signaling and the establishment of central B cell tolerance. In addition, anergy, one of the central B cell tolerance mechanisms, seems to be favored in some RA patients as illustrated by the increased frequency of peripheral unresponsive autoreactive B cells, which do not express the complement receptor 2/CD21 and are refractory to BCR and CD40 triggering. Hence, increased numbers of naove autoreactive B cells in patients with RA may favor disease development but it remains to be determined what pathways and mechanisms break B cell tolerance. The long range goal of the proposed research is to continue to characterize the mechanisms that regulate B cell tolerance in healthy humans but are defective in RA patients. The working hypothesis is that RA B cells suffer from intrinsic defects caused by associated risk alleles, which impinge on sensing self-antigens and result in an altered induction/regulation of central B cell tolerance mechanisms. Hence, receptor editing and deletion fail to be properly regulated in RA patients whereas anergy also contributes to the increased numbers of autoreactive B cells reaching the periphery where inflammatory conditions such as in the synovium may lead the activation of these autoreactive B cells and promote disease development. In addition, understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease and design more specific and sustained therapies.
描述(由申请人提供):通过成功治疗类风湿关节炎(RA)和其他自身免疫性疾病,使用抗CD20单克隆抗体,可以通过小鼠模型以及人类中的人体清楚地确定B细胞在自身免疫性疾病中的作用。但是,B细胞可能促进自身免疫性疾病的发展的基本机制仍然知之甚少。我们先前证明,未经治疗的活性RA患者,全身性红斑狼疮患者以及1型糖尿病患者表现出异常的早期B细胞耐受性检查点,导致大量自动反应性NAOVE B细胞积累。我们最近确定,这些早期的B细胞耐受性缺陷主要是这些自身免疫性疾病,可以通过诸如PTPN22等风险等位基因(例如PTPN22)在无症状的供体中诱导,这些风险会干扰B细胞受体(BCR)信号传导和中央B细胞耐受性的建立。此外,Anergy是中央B细胞耐受性机制之一,在某些RA患者中似乎受到青睐,如周围无反应性自动反应性B细胞的增加所示,这些频率不表达补体受体2/CD21,并且是对BCR和CCR和CD40触发的反应。因此,RA患者的NAOVE自动反应性B细胞数量增加可能有利于疾病发展,但仍有待确定哪些途径和机制破坏B细胞的耐受性。拟议的研究的远距离目标是继续表征调节健康人类B细胞耐受性但在RA患者中有缺陷的机制。工作假设是RA B细胞遭受由相关风险等位基因引起的固有缺陷,这会影响自我抗原,并导致中央B细胞耐受机制的诱导/调节改变。因此,在RA患者中无法适当调节受体编辑和缺失,而厌食也有助于增加到达周围的自动反应性B细胞的数量,在这种情况下,诸如Synovium的炎症状况可能会导致这些自动反应性B细胞的激活并促进疾病的发展。此外,了解预防或解释自动反应性B细胞产生的机制可能提出了控制疾病和设计更具体和持续疗法的新方法。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition.
- DOI:10.1084/jem.20121486
- 发表时间:2013-03-11
- 期刊:
- 影响因子:0
- 作者:Amara K;Steen J;Murray F;Morbach H;Fernandez-Rodriguez BM;Joshua V;Engström M;Snir O;Israelsson L;Catrina AI;Wardemann H;Corti D;Meffre E;Klareskog L;Malmström V
- 通讯作者:Malmström V
共 1 条
- 1
Eric Meffre的其他基金
Elucidating the immunology of autoantibody formation and function in COVID-19
阐明 COVID-19 中自身抗体形成和功能的免疫学
- 批准号:1063970710639707
- 财政年份:2023
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
SYK and ZAP70 kinases in lymphocyte selection
SYK 和 ZAP70 激酶在淋巴细胞选择中的作用
- 批准号:1046721510467215
- 财政年份:2022
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
SYK and ZAP70 kinases in lymphocyte selection
SYK 和 ZAP70 激酶在淋巴细胞选择中的作用
- 批准号:1055788210557882
- 财政年份:2022
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Impact of regulatory T cells on human peripheral B cell tolerance
调节性 T 细胞对人外周 B 细胞耐受的影响
- 批准号:84242168424216
- 财政年份:2012
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Impact of regulatory T cells on human peripheral B cell tolerance
调节性 T 细胞对人外周 B 细胞耐受的影响
- 批准号:83025788302578
- 财政年份:2012
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Loss of B cell tolerance in rheumatoid arthritis
类风湿性关节炎 B 细胞耐受性丧失
- 批准号:80917618091761
- 财政年份:2010
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Autoreactive B Cell Development in Autoimmune Disease
自身免疫性疾病中自身反应性 B 细胞的发育
- 批准号:76876827687682
- 财政年份:2009
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
- 批准号:88110798811079
- 财政年份:2006
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
- 批准号:85864598586459
- 财政年份:2006
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Loss of B cell tolerance in rheumatoid arthritis
类风湿性关节炎 B 细胞耐受性丧失
- 批准号:74468087446808
- 财政年份:2006
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
相似国自然基金
伪旋毛虫乙酰胆碱酯酶破坏肠道ILC2s的ChAT-ACh通路实现免疫逃逸的机制研究
- 批准号:32302960
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
元宝枫种子中抑制乙酰胆碱酯酶活性成分的高效发现及其作用机理研究
- 批准号:32100323
- 批准年份:2021
- 资助金额:24.00 万元
- 项目类别:青年科学基金项目
元宝枫种子中抑制乙酰胆碱酯酶活性成分的高效发现及其作用机理研究
- 批准号:
- 批准年份:2021
- 资助金额:30 万元
- 项目类别:青年科学基金项目
肠神经元芳香烃受体/乙酰胆碱酯酶信号通路介导的青黛肠道不良反应研究
- 批准号:
- 批准年份:2020
- 资助金额:55 万元
- 项目类别:面上项目
具有乙酰胆碱酯酶抑制活性间苯三酚衍生物的发现及其作用机制研究
- 批准号:
- 批准年份:2019
- 资助金额:58 万元
- 项目类别:面上项目
相似海外基金
Paternal preconception alcohol on epigenetics and offspring drinking
父亲孕前饮酒对表观遗传学和后代饮酒的影响
- 批准号:85943978594397
- 财政年份:2013
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Paternal preconception alcohol on epigenetics and offspring drinking
父亲孕前饮酒对表观遗传学和后代饮酒的影响
- 批准号:87586558758655
- 财政年份:2013
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
- 批准号:88110798811079
- 财政年份:2006
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
- 批准号:85864598586459
- 财政年份:2006
- 资助金额:$ 41.63万$ 41.63万
- 项目类别:
Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
- 批准号:82375518237551
- 财政年份:2006
- 资助金额:$ 41.63万$ 41.63万
- 项目类别: