The Role of Recycling Immune Complexes in the Breakdown of Tolerance

回收免疫复合物在耐受性破坏中的作用

• 批准号: 8489788
• 负责人: BARBARA J VILEN
• 金额: $ 26.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8489788
• 关键词: Amyloid; Antigen-Antibody Complex; Antinuclear Antibodies; Apoptotic; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Blood Circulation; Bone Marrow; Bulla; Cell Death; Cell surface; Cells; Chronic; Clinical Trials; Complement 1q; Coupled; Cytokine Signaling; Data; Defect; Degradation Pathway; Dendritic Cells; Deoxyribonucleases; Deposition; Diffusion; Disease; EGF gene; Electron Microscopy; Endocytosis; Endosomes; Event; Failure; Fatty acid glycerol esters; Flow Cytometry; Fluorescence Microscopy; Genetic; Genetic Predisposition to Disease; Globulins; Goals; Hour; Human; Hydrolase; Immune system; Immunoglobulin G; Immunoglobulins; In Vitro; Inbred MRL lpr Mice; Inflammation; Kidney; Kidney Diseases; Ligands; Link; Location; Lupus; Lysosomes; Milk; Modeling; Molecular; Mucins; Mus; Pathology; Pathway interactions; Phagocytosis; Process; Production; Receptor Signaling; Recycling; Relative (related person); Role; Serum; Signal Transduction; Surface; Systemic Lupus Erythematosus; T-Lymphocyte; TLR3 gene; TLR7 gene; Testing; Time; Tissues; Toll-like receptors; base; cell motility; chemokine; cytokine; in vivo; late endosome; lupus prone mice; lupus-like; macrophage; prevent; public health relevance; receptor; residence; therapeutic target

DESCRIPTION (provided by applicant): The defective clearance of apoptotic cells and the increase in circulating immune complexes (ICs) have repeatedly been implicated in heightened cytokine secretion in systemic lupus erythematosus (SLE). Despite evidence of clearance defects, and presumably diminished access of TLR ligands to the endosome, cytokine secretion has been found to result from activated endosomal TLRs. This paradox raised the possibility that a more complicated model involving TLR-dependent and TLR-independent mechanisms regulates cytokine secretion. Our preliminary data show that IgG-ICs (IgG-apop ICs) bound in part via Fc?Rs are elevated 30-fold on the surface of DCs and MFs from autoimmune prone MRL/lpr mice. We show that this accumulation results from a degradation defect that promotes the recycling of internalized Fc?Rs bound IgG-ICs. In vivo and in vitro, the accumulation of ICs heightens BAFF secretion. In this application we will test the central hypothesis that IgG-apop ICs accumulate on DCs and MFs due to defects in targeting or degrading ICs within the endocytic/phagocytic pathway. This leads to pathogenic cytokine production as a consequence of genetic predisposition and chronic TLR and/or Fc?Rs signaling. We propose in aim 1 to identify where in the degradative pathway the progression of ICs is attenuated. In aim 2, we postulate that chronic Fc?Rs signaling results when ICs bound to Fc?Rs remain aggregated during the recycling process, and that chronic TLR signaling results when the IC-loaded Fc?Rs spend prolonged time within these pathways. Lastly, we propose that although genetic predisposition might underlie the defects leading to the recycling of ICs, genetic events might also be required for heightened cytokine secretion. We will separate these putative genetic events by pharmacologically inducing IC recycling in non-autoimmune mice and assessing whether this leads to heightened cytokine production. Overall, this proposal is significant because it identifies that ICs accumulate on DCs and MFs and defines a more intricate mechanism for how TLR-dependent and TLR- independent mechanisms might contribute to elevated levels of lupus-related cytokines.

描述（由申请人提供）：凋亡细胞的有缺陷清除率和循环免疫复合物（IC）的增加与全身性红斑狼疮（SLE）的细胞因子分泌增加有关。尽管有清除缺陷的证据，并且可能会减少TLR配体进入内体的访问，但已经发现细胞因子分泌是由活化的内体TLR引起的。这种悖论提出了一种可能性，即涉及涉及TLR依赖性和TLR独立的机制的更复杂的模型可以调节细胞因子分泌。我们的初步数据表明，IgG-ICS（IgG-apop ICS）部分通过FC？RS绑定在DC的表面上升高30倍，而自身免疫性易免疫性MRL/LPR小鼠的MFS和MFS升高。我们表明，这种积累是由于降解缺陷促进了内部化FC的回收IgG-IG-Ig-IC的回收。在体内和体外，IC的积累增强了BAFF的分泌。在此应用程序中，我们将测试中心假设，即由于内吞/吞噬途径中的靶向或降解IC的缺陷，IgG-apop IC积累在DC和MFS上。由于遗传易感性和慢性TLR和/或Fc？RS信号传导，这导致致病性细胞因子的产生。我们在目标1中提出，以确定在降解途径中的何处IC的进展减弱。在AIM 2中，我们假设当与FC绑定的ICS在回收过程中保持汇总时，慢性FC信号传导结果，并且当IC负载的FC rs在这些途径中延长时间时，会产生慢性TLR信号传导。最后，我们建议，尽管遗传易感性可能是导致IC回收的缺陷的基础，但增加的细胞因子分泌也可能需要遗传事件。我们将通过药理学诱导非自动免疫小鼠的IC回收来分开这些推定的遗传事件，并评估这是否导致细胞因子的产生增强。总体而言，该提案很重要，因为它可以确定IC在DC和MFS上积累，并为TLR依赖性和TLR-独立机制如何有助于狼疮相关的细胞因子水平升高，从而定义了更复杂的机制。