The Role of Dendritic Cells and Macrophages in Systemic Lupus Erythematosus

先天性免疫反应的缺陷与自身免疫性疾病有关，包括系统性狼疮 红斑狼疮（SLE）。在先天免疫应答的激活过程中，免疫耐受性被破坏。 维持，而多克隆B细胞活化促进对入侵病原体的免疫。但在 病毒感染诱导的自身免疫易感个体多克隆激活剂克服了B细胞耐受性。 最近，我们描述了树突状细胞（DCs）和巨噬细胞（MOs）分泌的可溶性介质， 在先天免疫系统激活期间维持耐受性。IL-6和sCD 40 L选择性抑制 自身反应性B细胞的免疫球蛋白（IG）分泌对幼稚B细胞没有抑制作用。在这 应用中，我们建议确定DC选择性抑制IG分泌的分子基础， MOD，并检验DC/Mo介导的耐受性缺陷导致自身免疫性 狼疮易感小鼠的表型。 IL-6 R连接选择性抑制自身反应性B细胞分泌LPS诱导的IG的发现 表明慢性BCR刺激重新编程IL-6 R，从而调节先天免疫应答。 在目的1中，我们提出确定IL-6差异调节LPS诱导的IG的机制 与幼稚B细胞相比，在自身反应性分泌中。 多种抑制因子调节IG的分泌，提示IL-6和sCD 40 L可能参与调节免疫球蛋白的分泌。 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B细胞亚群。 受DC（IL-6）和MO（IL-6+ sCD 40 L）抑制，并确定DC/MO介导的调节异常是否 耐受性通过选择自身免疫小鼠内的B细胞亚群促进自身抗体分泌。 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，我们建议 评估凋亡细胞是否减少DC和MO-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IL-6 R 在B细胞中重编程，允许自身反应性B细胞被激活。 来自狼疮易感小鼠的DC和MO在体外抑制自身抗体产生方面存在缺陷，尽管 这些缺陷是否在体内引起自身免疫表型仍不清楚。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MRL/lpr小鼠的重建问题 DC和MO可防止自身免疫的发生或恢复耐受性。为了研究IL-6的缺失是否 和CD 40 L在非自身免疫小鼠中诱导自身免疫，我们在目的3b中提出监测自身抗体 在IL-6 + × CD 40+小鼠中产生。

Defects in the innate immune response are implicated in autoimmune diseases, including Systemic Lupus Erythematosus (SLE). During activation of the innate immune response, immunological tolerance is maintained while polyclonal B cell activation promotes immunity to the invading pathogen. However, in autoimmune-prone individuals polyclonal activators induced by viral infection overcome B cell tolerance. Recently, we described that soluble mediators secreted by dendritic cells (DCs) and macrophages (MOs) maintain tolerance during activation of the innate immune system. IL-6 and sCD40L selectively repress immunoglobulin (Ig) secretion by autoreactive B cells yet had no repressive effect on naive B cells. In this application we propose to define the molecular basis for the selective repression of Ig secretion by DCs and MOD, and to test the hypothesis that defects in DC/Mo-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 naive B cells. The findings that multiple repressive factors regulated 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 MOs (IL-6+sCD40L), and determine whether dyregulation of DC/MO-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 MO-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 B cells to become activated. DCs and MO 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 MOs 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 IL-6"'" x CD40L"'" mice.