"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: 8507140
• 负责人: Ziaur Rahman
• 金额: $ 35.96万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8507140
• 关键词: Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chromatin; DNA; Data; Defect; Dendritic Cells; Development; Diagnostic; Failure; Family; Genes; Genetic; Hyperactive behavior; Immune; Immunoglobulin G; In Vitro; Keyhole Limpet Hemocyanin; Knock-in Mouse; Knowledge; Lead; Lupus; Lymphoid Follicle; Maps; Mediating; Memory; Memory B-Lymphocyte; Modeling; Molecular; Mus; Myelogenous; Organism; Pathway interactions; Peripheral; Phenotype; Predisposition; Production; Proliferating; Protein Isoforms; Publishing; Receptors, Antigen, B-Cell; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Role; SLEB1 gene; SLEB3 gene; Structure of germinal center of lymph node; Susceptibility Gene; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; aged; arsonate; autoreactive B cell; autoreactivity; base; cell type; central tolerance; differentiated B cell; insight; lupus prone mice; mouse model; peripheral tolerance; prevent; response; sle1/sle3 gene

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、生物体适应性免疫细胞无法区分“自身”和“非自身”有关。虽然 B 细胞中枢耐受性的存在现已得到充分证实，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有限。了解外周 B 细胞耐受性非常重要，因为这些耐受机制的扰动调节可能会导致自身反应性 B 细胞和致病性 IgG 自身抗体的产生，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)，该模型产生双反应性 {Arsonate (Ars) 和 DNA 染色质反应性} B 细胞。 HKIR 双反应性 B 细胞逃避中枢耐受并发育成成熟的滤泡 B 细胞。这些 B 细胞可以通过 Ars 缀合的外源 Ag 被募集到抗体形成细胞 (AFC) 和生发中心 (GC) 通路中。与其他 B 细胞被排除在外周淋巴滤泡之外的自身反应性转基因小鼠模型相比，HKIR 模型非常适合研究在 AFC 和 GC 记忆通路或调节自身抗体产生的检查点中起作用的外周 B 细胞耐受机制。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 反应中被阻止扩展，并且不能有效地成为记忆 B 细胞。我们发表的初步数据表明，在狼疮易感基因座 Sle1 存在的情况下，在抗体形成细胞 (AFC) 和生发中心 (GC) 通路上起作用的外周 B 细胞耐受检查点可能会发生改变。然而，Sle1 对 AFC 和 GC 记忆检查点的影响似乎不完全渗透，表明 T 和/或骨髓区室的缺陷可能需要外周 B 细胞耐受性的丧失，从而导致 IgG ANA 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，这些基因赋予 B 细胞在 AFC 和 GC 耐受检查点 (Aim-1) 中的自主断裂。在 Aim-2 中，我们将确定提供 B 细胞帮助并从而促进 GC 耐受性破坏的细胞类型（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。