"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(申请人提供):自身免疫性疾病与免疫耐受性的丧失有关,即生物体的适应性免疫细胞无法区分“自我”和“非自我”。虽然B细胞中枢耐受的存在已被证实,但我们对外周耐受的细胞和分子机制以及它们在自身免疫中如何改变的了解有限。了解外周B细胞耐受性很重要,因为对这些耐受机制的干扰调节可能会导致自身反应性B细胞和致病性免疫球蛋白自身抗体的发展,从而导致自身免疫性疾病,如系统性红斑狼疮(SLE)。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),该模型产生双重反应的B细胞。HKIR双反应性B细胞逃避中枢耐受,发育成成熟的滤泡B细胞。这些B细胞可以与Ars结合的外源抗原一起被招募到抗体形成细胞(AFC)和生发中心(GC)途径。与其他自身反应性转基因小鼠模型不同,在这些模型中,B细胞被排除在外周淋巴滤泡之外,HKIR模型是研究AFC和GC记忆通路或调节自身抗体产生的检查点中外周B细胞耐受机制的理想模型。我们发表的数据表明,由于HKIR双反应B细胞的自身反应性,它们可以分化为原代AFCs,但在GC反应中被阻止扩张,并且不能有效地成为记忆B细胞。我们已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基因Sle1的存在下改变。然而,Sle1对AFC和GC记忆检查点的影响似乎是不完全穿透的,这表明T和/或髓系缺陷可能是导致外周B细胞耐受性丧失导致产生Ig G-Ana和发展成狼疮的原因。在这里,我们建议在Sle1基因座上鉴定易感基因(S),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细胞帮助从而促进GC耐受性打破的细胞类型(T和/或DC)。这些研究产生的数据将揭示这两种机制如何允许狼疮中产生自身抗体,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)
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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"
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8318614 - 财政年份:2011
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