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: 8045442
• 负责人: BARBARA J VILEN
• 金额: $ 36.06万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045442
• 关键词: Address; Affect; Affinity; Antigens; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Infections; Bone Marrow; Cells; Chimera organism; Chronic; Defect; Dendritic Cells; Disease; Exhibits; Exposure to; Genetic; Immune response; Immunoglobulins; Immunosuppression; In Vitro; Inbred MRL lpr Mice; Individual; Interleukin-6; Knock-out; Ligation; Mediating; Mediator of activation protein; Molecular; Monitor; Mus; Phenotype; Production; Regulation; Repression; Role; Signal Transduction; Systemic Lupus Erythematosus; TNFSF5 gene; Testing; Therapeutic; Toll-like receptors; Virus Diseases; autoreactive B cell; base; experience; immune function; in vivo; in vivo Model; lupus prone mice; macrophage; novel; prevent; reconstitution; stem cell therapy

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.

描述（由申请人提供）：对先天免疫反应的调节缺陷与自身免疫性疾病有关，包括全身性红斑狼疮（SLE）。在先天免疫反应期间，通过像受体（TLR）TOLL（TLR）刺激B细胞可促进多克隆免疫球蛋白分泌，同时维持自动反应性B细胞的耐受性。在自身免疫性的个体中，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在先天免疫反应期间调节自动反应性B细胞。 DC/M＆介导的耐受性是选择性的，因为它仅自动反应，而不是NAOVE，B细胞被IL-6和SCD40L抑制。在此应用中，我们建议定义DCS和M＆S选择性抑制Ig分泌的分子基础，并检验以DC/M＆介导的耐受性缺陷的假设有助于狼疮p-蛋白小鼠的自身免疫表型。 IL-6R连接有选择地抑制LPS诱导的自动反应性B细胞的Ig分泌的发现表明，慢性BCR刺激对IL-6R进行了重编程，从而调节了先天免疫反应。在AIM 1中，我们建议定义与NAOVE B细胞相比，IL-6通过差异调节自动反应性Ig的Ig分泌的机制。 多种抑制因素调节Ig分泌的发现表明IL-6和SCD40L可能表现出冗余或可能是非重叠的功能。在Subaim 2a中，我们将确定由DCS（IL-6）和M＆S（IL-6+SCD40L）抑制的B细胞子集，并确定DC/M＆M介导的耐受性的染色器是否有助于自动免疫小鼠中的某些B细胞子集对自动抗体分泌。 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M＆-IL-6减少IL-6和SCD40L的分泌，从而间接激活自动反应性B细胞。此外，我们将确定凋亡细胞是否破坏了B细胞中的IL-6R重编程，从而使自动反应性细胞被激活。 来自狼疮的小鼠的DC和M＆S在体外抑制自身抗体产生方面有缺陷，尽管尚不清楚这些缺陷是否引起体内自身免疫性表型。在Subaim 3a中，我们建议生成混合的骨髓嵌合体，以解决Wildtype DCS和M＆S对MRL/LPR小鼠的重建，而M＆S可以防止自身免疫的发作或恢复耐受性。为了调查IL-6和CD40L的损失是否诱导非自动免疫小鼠的自身免疫性，我们建议在AIM 3B中监测DC和MS在CD40L和/或IL-6中缺陷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性和自身免疫相关疾病（例如全身性红斑狼疮）（SLE）至关重要。这种应用是一种新型耐受机制的分子和细胞方面的特征，其中树突状细胞和巨噬细胞调节细菌和病毒感染过程中自身抗体的分泌。我们还建议解决干细胞疗法作为SLE治疗的治疗潜力。

项目成果

Staphylococcus aureus Protein A Disrupts Immunity Mediated by Long-Lived Plasma Cells.

• DOI: 10.4049/jimmunol.1600093
• 发表时间: 2017-02-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Keener AB;Thurlow LT;Kang S;Spidale NA;Clarke SH;Cunnion KM;Tisch R;Richardson AR;Vilen BJ
• 通讯作者: Vilen BJ

BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis.

• DOI: 10.4049/jimmunol.1600281
• 发表时间: 2017-04-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kang S;Fedoriw Y;Brenneman EK;Truong YK;Kikly K;Vilen BJ
• 通讯作者: Vilen BJ

IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF.

• DOI: 10.4049/jimmunol.1402527
• 发表时间: 2016-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kang S;Keener AB;Jones SZ;Benschop RJ;Caro-Maldonado A;Rathmell JC;Clarke SH;Matsushima GK;Whitmire JK;Vilen BJ
• 通讯作者: Vilen BJ