"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（在骨髓中）的存在现在已经很好地建立，但我们对外周耐受（在外周淋巴器官中）的细胞和分子机制及其在自身免疫性疾病如“狼疮”中的扰动的认识是有限的。理解外周B细胞耐受性是重要的，因为这些耐受性机制的干扰调节可能允许自身反应性B细胞和致病性IgG自身抗体的发展，其有助于自身免疫性疾病，如系统性红斑狼疮（SLE）。在这里，我们使用了B细胞抗原受体（BCR）敲入小鼠模型（HKIR），其产生双重反应性{胂酸盐（Ars）和DNA-染色质-自身抗原反应性} B细胞。我们以前的研究表明，双反应HKIR B细胞可以发展成滤泡B细胞和分化成抗体形成细胞（AFC）免疫后，与Ars结合的外来抗原。这些双反应性细胞也可以进入生发中心（GC），但由于它们的自身反应性被GC耐受机制负调节或阻止在GC中扩增，并且不能有效地成为记忆B细胞。因此，与将B细胞排除在外周淋巴滤泡（包括AFC和GC途径）之外的其他自身反应性转基因小鼠模型相比，HKIR模型非常适合研究调节自身抗体产生的核抗原特异性HKIR B细胞的AFC和GC介导的B细胞耐受途径。我们发表的和初步的数据表明，外周B细胞耐受性AFC和GC途径中的工作可以改变狼疮易感基因座Sle 1的存在。然而，Sle 1对AFC和GC记忆耐受性的影响似乎是不完全渗透的，表明T和/或髓样区室的缺陷可能需要外周B细胞耐受性的丧失，导致IgG ANA的产生和狼疮的发展。在这里，我们建议确定的Sle 1基因座内的易感基因，驱动B细胞发展到AFC和GC途径，导致外周B细胞耐受性的损失（Aim-1）。在Aim-2中，我们将确定Sle 3间隔内受易感基因影响的细胞类型（T和/或DC），该基因提供B细胞帮助，从而促进GC耐受性的打破。在目的-3中，我们将研究I型干扰素（IFN-1）如何加速GC记忆耐受性破坏的过程，并允许狼疮易感小鼠产生强大的自身抗体。