Follicular Exclusion of Self Antigens Prevents Development of Autoantibodies

滤泡排除自身抗原可防止自身抗体的产生

• 批准号: 8795154
• 负责人: John D Mountz
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795154
• 关键词: Actins; Acute Megakaryocytic Leukemias; Adoptive Transfer; Affect; Antigen-Antibody Complex; Antigens; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Behavior; Cell Communication; Cell Death; Cell Surface Receptors; Cell Survival; Cell membrane; Cell physiology; Cells; Characteristics; Chronic; Collaborations; Data; Defect; Dendritic Cells; Development; Disease; Event; Exclusion; Exposure to; F-Actin; Factor X; Failure; Fc Receptor; Follicular Dendritic Cells; Freezing; Frozen Sections; Genes; Health; Human; Image; Immunologics; In Vitro; Interferon Type I; Interferons; Intracellular Membranes; Knockout Mice; Life; Ligands; Lupus; Maintenance; Mechanics; Membrane; Microscopic; Modeling; Molecular; Mus; Nuclear; Pathway interactions; Patients; Phagocytosis; Phenotype; Play; Process; Production; Proteins; Receptor Signaling; Regulation; Role; Serum Response Factor; Signal Transduction; Spleen; Systemic Lupus Erythematosus; Testing; Tumor Necrosis Factor-Beta; antigen processing; base; cellular imaging; clinically relevant; functional disability; functional loss; in vivo; lupus prone mice; macrophage; mouse model; novel; nucleocytoplasmic transport; polymerization; prevent; receptor; response; systemic autoimmune disease; therapeutic target; transcription factor; uptake

DESCRIPTION (provided by applicant): Accumulating evidence suggests that dysregulation of marginal zone macrophages (MZMs) of the spleen plays a role in the development of systemic autoimmune disease include systemic lupus erythematosus (SLE). The MZMs play an important role in trapping, processing, and inducing tolerance to apoptotic cell (AC) antigens. The molecular mechanisms underlying dysregulation of tolerogenic MZM responses in lupus and the signals that trigger this dysregulation have not been elucidated. The proposed studies test the hypotheses that: (1) A common mechanism underlying dysregulation of tolerogenic MZM responses in lupus is an alteration in the expression of a mechanosensing protein megakaryocytic leukemia-1 (MKL1) and associated filamentous actin assembly in MZMs that affects the ability of the MZMs to take up and maintain tolerance to apoptotic cell antigens (AC-Ags); (2) Alterations in expression of MKL1 and disruption of F-actin assembly can be induced by events that are characteristic of SLE. They can be induced by loss of signaling through the lymphotoxin- ¿ receptor (LT¿R) on the MZMs resulting from type I interferon (IFN) induced "mislocalization" of MZ B cells, which express membrane lymphotoxin (mLT), from the MZ to the follicle. Notably, the "interferon signature" is a hallmark of SLE in humans and deficiency of Type 1 IFN signals in BXD2- Ifn¿r-/- mice abrogates many of the abnormal immunologic MZM phenotypes as well as the production of autoantibodies and symptomatic lupus in these mice. The alterations in MKL1 and actin assembly also can be induced by chronic exposure to AC debris and immune complexes (ICs) through mechanosensing. These hypotheses will be tested using multiple mouse models with targeted disruption of pertinent pathways made available through extensive collaborations, pharmacological disruption, and state-of-the-art confocal microscopic analysis. Aim 1 will determine if IFN¿- induced follicular translocation of mLT+ MZ B cells leads to loss of MZM tolerance of ACs and ICs. In addition, BXD2 and B6.TC autoimmune mice will be used to determine if an MZM defect is a primary, early defect in lupus. Aim 2 will focus on the LT ¿R downstream signaling of MKL1 pathway and test in vivo and in vitro if the LT¿R/MLK1/actin polymerization pathways play a role in maintenance of the survival of tolerogenic MZMs. Frozen sections from SLE and normal human spleen will be used to determine if loss of MARCO+ MZMs in the SLE spleen is associated with high numbers of type 1-IFN producing pDCs, follicular translocation of LT+ B cells, and dysregulation of MKL1/actin polymerization. Clinical Relevance. The studies will provide a unified model of lupus, indicate a critical novel pathogenic mechanism of type I IFNs, and identify a new molecular pathway underlying regulation of tolerogenic macrophages in SLE thereby suggesting novel candidate therapeutic targets.

描述（由申请方提供）：越来越多的证据表明，脾脏边缘区巨噬细胞（MZM）调节异常在系统性自身免疫性疾病（包括系统性红斑狼疮（SLE））的发生中起作用。MZM在捕获、加工和诱导对凋亡细胞（AC）抗原的耐受性中起重要作用。狼疮中致耐受性MZM反应失调的分子机制和触发这种失调的信号尚未阐明。（1）狼疮中致耐受性MZM应答失调的一个共同机制是MZM中机械敏感蛋白巨核细胞白血病-1（MKL 1）和相关丝状肌动蛋白组装的表达改变，其影响MZM摄取和维持对凋亡细胞抗原（AC-Ag）的耐受性的能力;（2）MKL 1表达的改变和F-actin组装的破坏可由SLE特征性事件诱导。它们可以通过MZM上的光敏素受体（LT R）的信号传导损失来诱导，所述信号传导损失是由I型干扰素（IFN）诱导的MZ B细胞（其表达膜光敏素（mLT））从MZ到卵泡的“错误定位”引起的。值得注意的是，“干扰素特征”是人类SLE的标志，BXD 2- Ifn r-/-小鼠中1型IFN信号的缺乏消除了这些小鼠中许多异常的免疫学MZM表型以及自身抗体和症状性狼疮的产生。MKL 1和肌动蛋白组装的改变也可以通过机械传感通过长期暴露于AC碎片和免疫复合物（IC）来诱导。这些假设将使用多个小鼠模型进行测试，通过广泛的合作、药理学破坏和最先进的共聚焦显微镜分析，靶向破坏相关通路。目的1将确定IFN γ诱导的mLT+ MZ B细胞的卵泡易位是否导致AC和IC的MZM耐受性丧失。此外，BXD 2和B6.TC自身免疫小鼠将用于确定MZM缺陷是否是狼疮中的原发性早期缺陷。目的2将集中于MKL 1通路的LT <$R下游信号传导，并在体内和体外测试LT <$R/MLK 1/肌动蛋白聚合通路是否在维持耐受原性MZM的存活中发挥作用。来自SLE和正常人脾脏的冷冻切片将用于确定SLE脾脏中MARCO+ MZM的损失是否与大量1型-IFN产生pDC、LT+ B细胞的滤泡易位和MKL 1/肌动蛋白聚合的失调相关。临床相关性。这些研究将提供一个统一的狼疮模型，指出一个关键的新的致病机制的I型干扰素，并确定一个新的分子途径的调节致耐受性巨噬细胞在SLE，从而提出新的候选治疗目标。