The Role of Dendritic Cells and Macrophages in Systemic Lupus Erythematosus

树突状细胞和巨噬细胞在系统性红斑狼疮中的作用

• 批准号: 7497254
• 负责人: BARBARA J VILEN
• 金额: $ 35.84万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497254
• 关键词: Address; Affect; Affinity; Antigens; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow; Cells; Chimera organism; Chronic; Defect; Dendritic Cells; Exhibits; Exposure to; Genetic; Hen Egg Lysozyme; Immune response; Immune system; Immunity; Immunoglobulins; Immunosuppression; In Vitro; Inbred MRL lpr Mice; Individual; Interleukin-6; Invaded; Knock-out; Ligation; Lupus; Lupus Erythematosus; Mediating; Mediator of activation protein; Molecular; Monitor; Mus; Phenotype; Production; Repression; Role; Signal Transduction; Systemic Lupus Erythematosus; TNFSF5 gene; Testing; Therapeutic immunosuppression; Virus Diseases; autoreactive B cell; base; experience; immune function; in vivo; in vivo Model; macrophage; novel; pathogen; prevent; reconstitution

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.

先天免疫反应的缺陷与自身免疫性疾病有关，包括全身性狼疮 红斑（SLE）。在激活先天免疫反应期间，免疫耐受性是 在多克隆B细胞活化时保持维持可促进对入侵病原体的免疫力。但是，在 由病毒感染诱导的自身免疫性个体多克隆活化剂克服了B细胞耐受性。 最近，我们描述了树突状细胞（DC）和巨噬细胞（MOS）分泌的可溶性介体（MOS） 在激活先天免疫系统期间保持耐受性。 IL-6和SCD40L有选择地压抑 自动反应性B细胞的免疫球蛋白（IG）分泌，但对幼稚B细胞没有抑制作用。在这个 我们建议的应用程序来定义DC和DC选择Ig分泌的分子基础 mod，并测试DC/MO介导的公差缺陷的假设有助于自身免疫性 狼疮易发的表型。 IL-6R连接选择性抑制LPS诱导的Ig分泌的发现 表明慢性BCR刺激重编程IL-6R，从而调节先天免疫反应。 在AIM 1中，我们建议定义IL-6差异调节LPS诱导的Ig的机制 与幼稚的B细胞相比，自动反应性的分泌。 调节IG分泌多种抑制性因素的发现表明IL-6和SCD40L可以 表现出冗余或可能的非重叠功能。在Subaim 2a中，我们将确定B细胞子集 受到DC（IL-6）和MOS（IL-6+SCD40L）的抑制 耐受性促进了自身免疫小鼠中选择的B细胞子集的自身抗体分泌。 凋亡细胞与SLE有关，并可能激活自动反应性B细胞。在Subaim 2b中，我们建议 评估凋亡细胞是否通过DC和MO-IL-6减少IL-6和SCD40L的分泌，从而间接地分泌 激活自动反应性B细胞。此外，我们将确定凋亡细胞是否破坏IL-6R 在B细胞中重新编程，允许自动反应性B细胞被激活。 来自狼疮的小鼠的DC和MO在体外抑制自身抗体的产生方面有缺陷，尽管 尚不清楚这些缺陷是否引起体内自身免疫表型。在Subaim 3a中，我们 建议生成混合的骨髓嵌合体，以解决WildType是否重构MRL/LPR小鼠 DC和MOS可防止自身免疫的发作或恢复公差。调查IL-6的损失是否 CD40L在非自动免疫小鼠中诱导自身免疫性，我们在AIM 3B中提议监测自身抗体 IL-6“'” X CD40L“'”小鼠的产生。