"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:8507140
- 负责人:
- 金额:$ 35.96万
- 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
- 来源:
- 关键词:AntibodiesAntigensAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmune ProcessAutoimmunityB-LymphocytesCD4 Positive T LymphocytesCell physiologyCellsChromatinDNADataDefectDendritic CellsDevelopmentDiagnosticFailureFamilyGenesGeneticHyperactive behaviorImmuneImmunoglobulin GIn VitroKeyhole Limpet HemocyaninKnock-in MouseKnowledgeLeadLupusLymphoid FollicleMapsMediatingMemoryMemory B-LymphocyteModelingMolecularMusMyelogenousOrganismPathway interactionsPeripheralPhenotypePredispositionProductionProliferatingProtein IsoformsPublishingReceptors, Antigen, B-CellRecruitment ActivityRegulationRegulatory T-LymphocyteRoleSLEB1 geneSLEB3 geneStructure of germinal center of lymph nodeSusceptibility GeneSystemic Lupus ErythematosusT-LymphocyteTestingTherapeuticTransgenic Miceagedarsonateautoreactive B cellautoreactivitybasecell typecentral tolerancedifferentiated B cellinsightlupus prone micemouse modelperipheral tolerancepreventresponsesle1/sle3 gene
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已经得到证实,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发生改变的了解仍然有限。了解外周B细胞耐受性很重要,因为这些耐受性机制的失调调节可能导致自身反应性B细胞和致病性IgG自身抗体的发展,从而导致系统性红斑狼疮(SLE)等自身免疫性疾病。在这里,我们使用了靶向B细胞抗原受体(BCR)敲入小鼠模型(HKIR),产生双反应性{Arsonate (Ars)和dna -染色质反应性}B细胞。HKIR双反应性B细胞逃避中央耐受,发育为成熟的滤泡B细胞。这些B细胞可以被ars偶联的外源Ag招募到抗体形成细胞(AFC)和生发中心(GC)途径中。与其他将B细胞排除在外的自身反应性转基因小鼠模型相比,HKIR模型是研究在AFC和gc -记忆途径或调节自身抗体产生的检查点中运行的外周B细胞耐受机制的理想选择。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,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,在抗体形成细胞(AFC)和生发中心(GC)途径上工作的外周B细胞耐受检查点可以在狼疮易感位点Sle1的存在下被改变。然而,Sle1对AFC和gc -记忆检查点的影响似乎不是完全渗透的,这表明T细胞和/或髓细胞室的缺陷可能导致外周B细胞耐受性的丧失,从而导致IgG抗体的产生和狼疮的发展。在这里,我们建议鉴定Sle1位点内的易感基因,该基因在AFC和GC耐受检查点(Aim-1)中赋予B细胞自主断裂。在Aim-2中,我们将确定提供B细胞帮助的细胞类型(T和/或dc),从而促进GC耐受性的中断。从这些研究中产生的数据将揭示这两种机制如何允许狼疮产生自身抗体,从而具有诊断和治疗意义。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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
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"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:
$ 35.96万 - 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:
8564791 - 财政年份:2011
- 资助金额:
$ 35.96万 - 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:
$ 35.96万 - 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”
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8318614 - 财政年份:2011
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