The Role of Dendritic Cells and Macrophages in Systemic Lupus Erythematosus

描述(申请人提供)：先天性免疫反应调节缺陷与自身免疫性疾病有关，包括系统性红斑狼疮(SLE)。在先天免疫反应中，B细胞通过Toll样受体(TLRs)的刺激促进多克隆免疫球蛋白的分泌，同时维持自身反应性B细胞的耐受性。在有自身免疫倾向的个体中，先天免疫反应的激活无法维持B细胞的耐受性。最近，我们描述了树突状细胞(DC)和巨噬细胞(M&S)分泌的IL-6和sCD40L在先天免疫应答中调节自身反应性B细胞。DC/M介导的耐受是选择性的，因为只有自身反应而不是NAVE的B细胞受到IL-6和sCD40L的抑制。在这一应用中，我们建议定义DC和M&S选择性抑制Ig分泌的分子基础，并检验DC/M介导的耐受缺陷导致狼疮易感小鼠自身免疫表型的假设。 IL-6R结扎选择性抑制内毒素诱导的自身反应性B细胞Ig分泌的研究表明，慢性BCR刺激使IL-6R重新编程，从而调节先天免疫反应。在目标1中，我们建议定义IL-6在自身反应中对内毒素诱导的Ig分泌的不同调节机制(S)，与NAOVE B细胞相比。 多个抑制因子调节Ig分泌的研究结果表明，IL-6和sCD40L可能表现出多余的或可能不重叠的功能。在亚目标2a中，我们将确定树突状细胞(IL-6)和M&S(IL-6+sCD40L)抑制的B细胞亚群(S)，并确定DC/M介导的耐受失调是否促进自身免疫小鼠中特定B细胞亚群的自身抗体分泌。 凋亡细胞参与了SLE的发病，并可能激活自身反应性B细胞。在次目标2b中，我们建议评估凋亡细胞是否减少DC和M&IL-6分泌IL-6和sCD40L，从而间接激活自身反应性B细胞。此外，我们将确定凋亡细胞是否扰乱B细胞中IL-6R的重新编程，从而使自身反应细胞被激活。 来自狼疮易感小鼠的DC和M&S在体外抑制自身抗体产生方面存在缺陷，尽管目前尚不清楚这些缺陷是否导致体内的自身免疫表型。在子目标3a中，我们建议产生混合骨髓嵌合体，以解决野生型DC和M&S重建mrl/lpr小鼠是否阻止自身免疫的发生或恢复耐受。为了研究IL-6和CD40L的缺失是否会诱导非自身免疫小鼠的自身免疫，我们在AIM 3b中建议监测DC和MS缺乏CD40L和/或IL-6的小鼠的自身抗体产生。 了解调节自身抗体分泌的机制对于预防自身免疫和自身免疫相关疾病，如系统性红斑狼疮(SLE)至关重要。这项应用描述了一种新的耐受机制的分子和细胞方面的特征，在这种机制中，树突状细胞和巨噬细胞调节细菌和病毒感染期间自身抗体的分泌。我们还建议解决干细胞治疗作为SLE治疗的潜力。

DESCRIPTION (provided by applicant): Defects in the regulation of innate immune responses are implicated in autoimmune diseases, including Systemic Lupus Erythematosus (SLE). During innate immune responses, the stimulation of B cells through Toll Like Receptors (TLRs) promotes polyclonal immunoglobulin secretion while simultaneously maintaining tolerance of autoreactive B cells. In autoimmune-prone individuals activation of innate immune responses fails to maintain B cell tolerance. Recently, we described that IL-6 and sCD40L secreted by dendritic cells (DCs) and macrophages (M&s) regulates autoreactive B cells during innate immune responses. DC/M&-mediated tolerance is selective in that only autoreactive, and not naove, B cells are repressed by IL-6 and sCD40L. In this application we propose to define the molecular basis for the selective repression of Ig secretion by DCs and M&s, and to test the hypothesis that defects in DC/M&-mediated tolerance contribute to the autoimmune phenotype of lupus-prone mice. The finding that IL-6R ligation selectively represses LPS-induced Ig secretion by autoreactive B cells suggests that chronic BCR stimulation reprograms the IL-6R, thereby regulating innate immune responses. In aim 1, we propose to define the mechanism(s) whereby IL-6 differentially regulates LPS-induced Ig secretion in autoreactive, compared to naove B cells. The findings that multiple repressive factors regulate Ig secretion suggested that IL-6 and sCD40L could exhibit redundant, or possibly non-overlapping functions. In subaim 2a, we will identify the B cell subset(s) repressed by DCs (IL-6) and M&s (IL-6+sCD40L), and determine whether dyregulation of DC/M&-mediated tolerance facilitates autoantibody secretion by select B cell subsets within autoimmune mice. Apoptotic cells are implicated in SLE and may activate autoreactive B cells. In subaim 2b, we propose to assess whether apoptotic cells diminish secretion of IL-6 and sCD40L by DC and M&-IL-6, thereby indirectly activating autoreactive B cells. In addition, we will determine whether apoptotic cells disrupt IL-6R reprogramming in B cells allowing autoreactive cells to become activated. DCs and M&s from lupus-prone mice are defective in repressing autoantibody production in vitro, although it remains unclear whether these defects cause the autoimmune phenotype in vivo. In subaim 3a, we propose to generate mixed bone marrow chimeras to address if reconstitution of MRL/lpr mice by wildtype DCs and M&s prevents the onset of autoimmunity or restores tolerance. To investigate if the loss of IL-6 and CD40L induce autoimmunity in non-autoimmune mice, we propose in aim 3b to monitor autoantibody production in mice where DCs and Ms are deficient in CD40L and/or IL-6.NARRATIVE Understanding the mechanisms that regulate autoantibody secretion is central to preventing autoimmunity and autoimmune-associated diseases such as systemic lupus erythematosus (SLE). This application characterizes molecular and cellular aspects of a novel tolerance mechanism wherein dendritic cells and macrophages regulate autoantibody secretion during bacterial and viral infections. We also propose to address the therapeutic potential of stem cell therapy as a treatment for SLE.