"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: 8318614
• 负责人: Ziaur Rahman
• 金额: $ 1.37万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318614
• 关键词: Adoptive Transfer; Affect; Anti-DNA Antibodies; Antibodies; Antibody Formation; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Development; B-Lymphocytes; Bone Marrow; Cells; Chromatin; DNA; Data; Defect; Dendritic Cells; Development; Enhancing Antibodies; Failure; Family; Genes; Hyperactive behavior; IFNAR1 gene; Immune; Immunization; Immunoglobulin G; Interferon Type I; Interferon-alpha; Interferons; Keyhole Limpet Hemocyanin; Knock-in Mouse; Knowledge; Lead; Lupus; Lupus Nephritis; Lymphoid; Lymphoid Follicle; Mediating; Mediator of activation protein; Memory; Memory B-Lymphocyte; Modeling; Molecular; Mus; Myelogenous; Nuclear; Organ; Organism; Pathway interactions; Peripheral; Play; Predisposition; Process; Production; Protein Isoforms; Protocols documentation; Publishing; Receptors, Antigen, B-Cell; Regulation; Research Design; Role; SLEB1 gene; SLEB3 gene; Self Tolerance; Structure of germinal center of lymph node; Susceptibility Gene; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Transgenic Mice; Work; anti-IgG; arsonate; autoreactive B cell; autoreactivity; base; cell type; central tolerance; differentiated B cell; improved; insight; lupus prone mice; lupus-like; man; mouse model; peripheral tolerance; prevent; response; sle1/sle3 gene; type I interferon receptor

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 (in the bone marrow) is now well-established, our knowledge about the cellular and molecular mechanisms of peripheral tolerance (in peripheral lymphoid organs) and their perturbation in autoimmune diseases such as 'lupus' is 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 B cell antigen receptor (BCR) knock-in mouse model (HKIR) that yields dual-reactive {Arsonate (Ars) and DNA-chromatin-self-antigen- reactive} B cells. We previously showed that dual-reactive HKIR B cells can develop into follicular B cells and differentiate into antibody forming cells (AFCs) upon immunization with Ars-conjugated foreign antigen. These dual-reactive cells also can enter germinal centers (GCs), but due to their autoreactivity are negatively regulated or prevented from expanding in GCs by a GC tolerance mechanism and do not efficiently become memory B cells. Therefore, in contrast to other autoreactive transgenic mouse models in which B cells are excluded from the peripheral lymphoid follicles including AFC and GC pathways, the HKIR model is well suited to study AFC and GC-mediated B cell tolerance pathways of nuclear-Ag-specific HKIR B cells that regulate autoantibody production. Our published and preliminary data indicate that peripheral B cell tolerance operative in the AFC and GC pathways can be altered in the presence of lupus susceptibility locus Sle1. However, the influence of Sle1 on the AFC and GC-memory tolerance 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 drive B cell development into AFC and GC pathways leading to loss of peripheral B cell tolerance (Aim-1). In Aim-2, we will determine the cell type (T and/or DCs) affected by the susceptibility gene(s) within the Sle3 interval that provides B cell help and thus promotes a break in GC tolerance. In Aim-3, we will study how type I IFNs (IFN-1) may accelerate the process of a break in GC-memory tolerance and permits robust autoantibody production in lupus-prone mice.

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（在骨髓中）的存在现已得到充分证实，但我们对外周耐受性（在外周淋巴器官中）的细胞和分子机制及其在“狼疮”等自身免疫性疾病中的干扰的了解仍然有限。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 B 细胞抗原受体 (BCR) 敲入小鼠模型 (HKIR)，该模型产生双反应性 {砷酸盐 (Ars) 和 DNA 染色质自身抗原反应性} B 细胞。我们之前表明，双反应性 HKIR B 细胞在用 Ars 缀合的外源抗原免疫后可以发育为滤泡 B 细胞并分化为抗体形成细胞 (AFC)。这些双反应细胞也可以进入生发中心 (GC)，但由于它们的自身反应性受到 GC 耐受机制的负调控或阻止在 GC 中扩增，并且不能有效地变成记忆 B 细胞。因此，与其他自身反应性转基因小鼠模型（其中B细胞被排除在外周淋巴滤泡（包括AFC和GC途径）之外）相比，HKIR模型非常适合研究AFC和GC介导的核抗原特异性B细胞耐受途径HKIR B 细胞调节自身抗体的产生。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 AFC 和 GC 途径中起作用的外周 B 细胞耐受性可能会发生改变。然而，Sle1 对 AFC 和 GC 记忆耐受性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，这些基因驱动 B 细胞发育为 AFC 和 GC 途径，导致外周 B 细胞耐受性丧失 (Aim-1)。在 Aim-2 中，我们将确定 Sle3 间隔内受易感基因影响的细胞类型（T 和/或 DC），该基因为 B 细胞提供帮助，从而促进 GC 耐受性的破坏。在 Aim-3 中，我们将研究 I 型干扰素 (IFN-1) 如何加速 GC 记忆耐受性的破坏过程，并允许狼疮易感小鼠产生强大的自身抗体。