"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"

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。

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.