The Role of Dendritic Cells and Macrophages in Systemic Lupus Erythematosus

描述（由申请人提供）：先天免疫应答调节缺陷与自身免疫性疾病有关，包括系统性红斑狼疮（SLE）。在先天免疫应答期间，通过Toll样受体（TLR）刺激B细胞促进多克隆免疫球蛋白分泌，同时维持自身反应性B细胞的耐受性。在自身免疫易感个体中，先天免疫应答的激活不能维持B细胞耐受性。最近，我们描述了由树突状细胞（DCs）和巨噬细胞（M&s）分泌的IL-6和sCD 40 L在天然免疫应答期间调节自身反应性B细胞。DC/M β介导的耐受性是选择性的，因为只有自身反应性的而不是幼稚的B细胞被IL-6和sCD 40 L抑制。在这个应用程序中，我们建议定义的选择性抑制IG分泌的DC和M&S的分子基础，并测试的假设，在DC/M&介导的耐受性的缺陷，有助于狼疮易感小鼠的自身免疫表型。 IL-6 R连接选择性抑制自身反应性B细胞的LPS诱导的IG分泌的发现表明，慢性BCR刺激重新编程IL-6 R，从而调节先天性免疫应答。在目的1中，我们提出定义IL-6与天然B细胞相比差异调节LPS诱导的自身反应性IG分泌的机制。 多种抑制因子调节IG分泌的发现表明，IL-6和sCD 40 L可能表现出冗余或可能不重叠的功能。在子目标2a中，我们将鉴定由DC（IL-6）和M&s（IL-6+ sCD 40 L）抑制的B细胞亚群，并通过选择自身免疫小鼠内的B细胞亚群来确定DC/M& s介导的耐受性的失调是否促进自身抗体分泌。 凋亡细胞与SLE有关，并可激活自身反应性B细胞。在子目标2B中，我们提出评估凋亡细胞是否减少DC和M β-IL-6分泌IL-6和sCD 40 L，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破坏B细胞中的IL-6 R重编程，从而使自身反应性细胞被激活。 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，尽管尚不清楚这些缺陷是否导致体内自身免疫表型。在子目标3a中，我们提出产生混合骨髓嵌合体以解决通过野生型DC和M&s重建MRL/lpr小鼠是否防止自身免疫的发作或恢复耐受。为了研究IL-6和CD 40 L的缺失是否在非自身免疫小鼠中诱导自身免疫，我们在目的3b中提出监测DC和Ms缺乏CD 40 L和/或IL-6的小鼠中的自身抗体产生。 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。本申请表征了新耐受机制的分子和细胞方面，其中树突状细胞和巨噬细胞在细菌和病毒感染期间调节自身抗体分泌。我们还建议解决干细胞疗法作为SLE治疗的治疗潜力。

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.