Investigating the molecular mechanisms underlying lupus susceptibility conferred

研究狼疮易感性的分子机制

基本信息

批准号：
8646077
负责人：
Lucrezia Colonna
金额：
$ 5.51万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646077
关键词：
Adjuvant Affect Alleles Amino Acid Substitution Apoptotic Arginine Autoimmune Diseases Autoimmunity Biochemical Bypass C3bi CD14 gene Cell Adhesion Cell Maintenance Cells Chronic Co-Immunoprecipitations Collaborations Complement Complement 1q Complex DNA Binding Defect Dendritic Cells Development Erythrocytes Event Extravasation Freezing Gene Expression Profiling Histidine Human ITGAM gene ITGB2 gene Immune Immunoblotting Immunosuppression Immunosuppressive Agents Individual Inflammation Inflammation Mediators Inflammatory Integrins Interferons Ligands Ligation Lupus Macrophage Colony-Stimulating Factor Macrophage-1 Antigen Mannose Binding Lectin Mannose-Binding Lectins Mediating Modeling Molecular Monitor Mus Mutate Myeloid Cells Necrosis Nuclear Translocation Pathogenesis Patients Pb clearance Peripheral Blood Mononuclear Cell Phagocytes Phagocytosis Phosphorylation Phosphotransferases Physiological Predisposition Prevention Production Property Research Institute STAT1 gene Sampling Serum Signal Transduction Signaling Molecule Stimulus Surface Systemic Lupus Erythematosus Testing Toll-like receptors Variant base cellular transduction complement pathway complement system cytokine design genetic variant high risk inhibitor/antagonist macrophage migration neutrophil novel novel therapeutic intervention novel therapeutics public health relevance receptor response risk variant transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): The human ITGAM gene variant rs1143679 has been recently identified as one of the strongest susceptibility factors for human systemic lupus erythematosus, or SLE. The ITGAM gene encodes for the CD11b subunit of complement receptor 3 (CR3). CR3 is highly expressed on immune myeloid cells and has important functions in cell adhesion, spreading, and migration. Furthermore, CR3 mediates complement-dependent phagocytosis of apoptotic cells (AC), and transmits immunosuppresive signaling following engagement by its ligands, such as the complement component C3bi. In this way, the complement system participates in the physiological clearance of AC and the maintenance of tolerance to self. Importantly, deficiencies in different complement components predispose to SLE. The current model envisions that defective AC clearance predisposes to post- apoptotic necrosis and spillage of intracellular inflammatory molecules, thus predisposing to inflammation and autoimmunity. However, results in mice deficient in receptors and molecules devoted to AC clearance have suggested that AC accumulation is not sufficient to cause lupus autoimmunity. We propose a novel, more comprehensive, model for SLE development, whereby defective AC uptake in combination with aberrant CR3- mediated immunosuppressive signaling synergize to promote a loss of tolerance and SLE development. The ITGAM gene variant rs1143679 causes an arginine to histidine (R77H) amino acid substitution in CR3, and has been associated with defective CR3-mediated phagocytosis of red blood cells and defective suppression of proinflammatory cytokine production by human macrophages. Despite the central importance of complement-dependent AC phagocytosis in the pathogenesis of SLE, to this date, AC phagocytosis and AC- mediated immunosuppressive signaling has never been investigated in R77H-bearing individuals. We aim to investigate whether the R77H substitution in CD11b/CR3 confers a potential defect in AC phagocytosis as well as defective suppression of proinflammatory cytokines production following CR3-mediated AC uptake. Furthermore, we are planning to dissect the molecular mechanisms underlying CR3-mediated suppression of cellular activation with the aid of biochemical studies, and to analyze whether the R77H substitution causes the disruption of CD11b/CR3-mediated suppressive signaling events leading to aberrant phagocyte activation. The identification of the molecular defects underlying the lupus susceptibility of individuals carrying the rs1143679 ITGAM variant will aid the design of novel therapeutic strategies aimed to bypass such defect via the specific targeting of the signaling molecules involved. Enhancing CD11b/CR3-mediated AC phagocytosis and suppressive signaling would promote the swift and immunologically silent clearance of apoptotic cells for the treatment and, possibly, prevention of autoimmunity in high-risk individuals carrying the mutated allele.

描述（由申请人提供）：人类ITGAM基因变体rs1143679最近已被鉴定为人类系统性红斑狼疮（SLE）最强的易感因素之一。 ITGAM 基因编码补体受体 3 (CR3) 的 CD11b 亚基。 CR3在免疫骨髓细胞上高表达，在细胞粘附、扩散和迁移中具有重要功能。此外，CR3 介导凋亡细胞 (AC) 的补体依赖性吞噬作用，并在与其配体（例如补体成分 C3bi）结合后传递免疫抑制信号。这样，补体系统参与AC的生理清除和自身耐受性的维持。重要的是，不同补体成分的缺乏容易导致系统性红斑狼疮。目前的模型设想，有缺陷的AC清除容易导致细胞凋亡后坏死和细胞内炎症分子的溢出，从而容易发生炎症和自身免疫。然而，在缺乏专门用于 AC 清除的受体和分子的小鼠中的结果表明，AC 积累不足以引起狼疮自身免疫。我们提出了一种新的、更全面的 SLE 发展模型，其中有缺陷的 AC 摄取与异常 CR3 介导的免疫抑制信号相结合，协同促进耐受性丧失和 SLE 发展。 ITGAM 基因变体 rs1143679 导致 CR3 中精氨酸替换为组氨酸 (R77H)，并且与 CR3 介导的红细胞吞噬作用缺陷和人类巨噬细胞促炎细胞因子产生缺陷抑制相关。尽管补体依赖性 AC 吞噬作用在 SLE 发病机制中具有核心重要性，但迄今为止，AC 吞噬作用和 AC 介导的免疫抑制信号传导从未在 R77H 携带个体中进行过研究。我们的目的是研究 CD11b/CR3 中的 R77H 取代是否会导致 AC 吞噬作用的潜在缺陷以及 CR3 介导的 AC 摄取后促炎细胞因子产生的抑制缺陷。此外，我们计划借助生化研究剖析CR3介导的细胞激活抑制的分子机制，并分析R77H取代是否会导致CD11b/CR3介导的抑制信号传导事件的破坏，从而导致吞噬细胞的异常激活。识别携带 rs1143679 ITGAM 变体的个体狼疮易感性的分子缺陷将有助于设计新的治疗策略，旨在通过特异性靶向所涉及的信号分子来绕过这种缺陷。增强 CD11b/CR3 介导的 AC 吞噬作用和抑制信号传导将促进凋亡细胞的快速、免疫沉默清除，从而治疗携带突变等位基因的高危个体，并可能预防自身免疫。