"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
• 负责人: Ziaur Rahman
• 金额: $ 38.75万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183980
• 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. PUBLIC HEALTH RELEVANCE: Completion of the proposed studies will provide important new insights into the role of peripheral self-tolerance operative during the AFC and GC-memory pathways in silencing autoantibody production. These studies will also facilitate our understanding of how perturbations in these pathways due to the presence of lupus susceptibility loci lead to the development of autoantibody production and autoimmune disease lupus.

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（在骨髓中）的存在现已得到证实，但我们对外周耐受性（在外周淋巴器官）的细胞和分子机制及其在自身免疫性疾病（如狼疮）中的扰动的了解有限。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 -染色质自身抗原反应}B细胞。我们之前的研究表明，双反应性HKIR B细胞在与ars结合的外源抗原免疫后可以发育为滤泡性B细胞并分化为抗体形成细胞（AFCs）。这些双反应细胞也可以进入生发中心（GCs），但由于其自身反应性受到GC耐受机制的负调控或阻止其在GCs中扩张，因此不能有效地成为记忆B细胞。因此，与其他将B细胞排除在外周淋巴滤泡（包括AFC和GC途径）的自身反应性转基因小鼠模型相比，HKIR模型非常适合研究AFC和GC介导的核ag特异性HKIR B细胞调节自身抗体产生的B细胞耐受途径。我们已发表的和初步的数据表明，在狼疮易感位点Sle1的存在下，在AFC和GC途径中工作的外周B细胞耐受性可以改变。然而，Sle1对AFC和gc -记忆耐受性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，我们提出在Sle1基因座中确定驱动B细胞发育进入AFC和GC途径导致外周B细胞耐受性丧失的易感基因（Aim-1）。在Aim-2中，我们将确定在Sle3区间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耐受性的中断。在Aim-3中，我们将研究I型ifn （IFN-1）如何加速gc -记忆耐受的中断过程，并允许狼疮易感小鼠产生强大的自身抗体。