The Impact of Fc gamma Receptor Signaling on Lupus-Induced Atherosclerosis

Fc γ 受体信号传导对狼疮引起的动脉粥样硬化的影响

基本信息

批准号：
9005318
负责人：
SHANMUGAM NAGARAJAN
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2017-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9005318
关键词：
Accounting Address Animal Model Antibodies Antibody Formation Antigen-Antibody Complex Antigens Apolipoprotein E Area Atherosclerosis Attenuated Autoantibodies Autoantigens Autoimmune Diseases B-Lymphocytes Binding Blocking Antibodies Blood Vessels Cardiovascular Diseases Carotid Atherosclerotic Disease Cause of Death Cell Line Cells Cholesterol Chronic Clinical Clinical Research Collaborations Comorbidity Complex Coronary Arteriosclerosis Coronary artery Data Dendritic Cells Development Diet Effector Cell Generations Genes Genetic Polymorphism Health Care Costs Hematopoietic Human Hyperlipidemia Immune Immunoglobulin G In Vitro Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Interferon Type I Interferons Intervention Investigation Link Lupus Lymphocyte Activation Mediating Molecular Morbidity - disease rate Mus Nephritis Pathogenesis Pathology Patients Pericarditis Play Premature Mortality Process Production Receptor Signaling Recruitment Activity Reporting Risk Factors Role SLEB1 gene Serum Signal Pathway Signal Transduction Site Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Intervention Transgenic Mice beta 2-glycoprotein I body system chronic autoimmune disease clinically significant ds-DNA early onset feeding immune function in vivo macrophage mortality mouse model new therapeutic target novel oxidized low density lipoprotein potential biomarker premature premature atherosclerosis public health relevance receptor response rheumatologist therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by the production of autoantibodies recognizing self-antigens. Clinical manifestation of lupus includes nephritis, pericarditis. Recent studies have implicated that lupus accelerates atherosclerosis, and accounts for premature mortality. Autoantibodies contribute to the pathology of lupus by recruiting and activating innate-immune effector cells. Interaction between Fcγ receptors (FcγR) expressed on inflammatory cells and B-lymphocytes to autoantibody-autoantigen immune complexes (IC) promote inflammatory responses associated with lupus and atherosclerosis. FcγRs are classified into activating and inhibitory receptors. Activating FcγRs are involved in innate immune cellular functions and inflammatory responses. The inhibitory FcγRIIb regulates the inflammatory response initiated by the activating FcγRs and control antibody production by regulating B lymphocyte activation. Autoantibodies in lupus and oxidized low-density lipoprotein immune complexes (oxLDL-IC) generated during hyperlipidemia could bind to the activating and/or inhibitory FcγRs and contribute to the inflammatory processes. Interestingly, FcγRIIb polymorphisms have been implicated as a risk factor for lupus and coronary artery disease. Furthermore, FcγRIIb deficiency has been shown to regulate type I interferon response, implicated in the pathogenesis of lupus and atherosclerosis. These studies suggest that crosstalk between inhibitory FcγRIIb and type I interferon response could contribute to the pathogenesis of lupus-induced atherosclerosis. Although the presence of autoantibodies has been reported in lupus patients and animal models, the contribution of FcγRs to the initiation and/or progression of lupus-induced atherosclerosis has not been studied. The central hypothesis of this proposal is that FcγRs play an important role in the progression of lupus-induced premature atherosclerosis. To test this hypothesis, we will complete the following aims: Aim 1. To determine molecular mechanism(s) by which FcγRIIb signaling modulate lupus-induced atherosclerosis, Aim 2. To determine crosstalk between inhibitory FcγRIIb and type I IFN signaling contributing to lupus-induced atherosclerosis, and Aim 3. Investigate the role of human FcγR in promoting inflammatory responses associated with lupus-induced atherosclerosis. The proposed studies will be significant because they will provide novel information supporting the contention that FcγR signaling pathways may represent a novel therapeutic target for interventions aimed at ameliorating the vascular complications of autoimmune diseases, an area that is in dire need for development.

描述（由适用提供）：全身性红斑狼疮（SLE）是一种典型的自身免疫性疾病，其特征是产生识别自我抗原的自身抗体。狼疮的临床表现包括肾炎，心心炎。最近的研究实施了狼疮加速了动脉粥样硬化，并说明了早亡率的过早死亡率。自身抗体通过募集和激活先天免疫效应子细胞来促进狼疮的病理。在炎症细胞和B淋巴细胞上表达的Fcγ受体（FCγR）与自身抗体 - 自动抗体免疫复合物（IC）的相互作用促进与狼疮和动脉粥样硬化有关的炎症反应。 FcγR被分类为激活和抑制受体。激活的FcγR参与先天免疫细胞功能和炎症反应。抑制性FCγRIIB调节激活FcγRS引发的炎症反应和通过调节B淋巴细胞激活来控制抗体的产生。高脂血症期间产生的狼疮和氧化的低密度脂蛋白免疫复合物（OXLDL-IC）的自身抗体可能与激活和/或抑制性FCγR结合，并有助于炎症过程。有趣的是，FcγRIIB多态性已被暗示为狼疮和冠状动脉疾病的危险因素。此外，已显示FcγRIIB缺乏症可以调节I型干扰素反应，这在狼疮和动脉粥样硬化的发病机理中暗示。这些研究表明，抑制性FcγRIIB和I型干扰素反应之间的串扰可能有助于狼疮引起的动脉粥样硬化的发病机理。尽管狼疮患者和动物模型已经报道了自身抗体的存在，但尚未研究FcγRS对狼疮引起的动脉粥样硬化的主动性和/或进展的贡献。该提议的中心假设是FcγRS在狼疮引起的早产性动脉粥样硬化的进展中起重要作用。为了检验该假设，我们将完成以下目的：目的1。确定FcγRIIB信号传导调节狼疮引起的动脉粥样硬化的分子机制，目的2。确定抑制性FcγRIIIB和I型IFN信号在与Lupus诱导的Athersosclerisis Remiented themersclimis Remients conment form from和Aim from from from form form from contrim form form form form form from and aim from form from form from and a form form form a form and form form from form form from form form from forms 3。狼疮引起的动脉粥样硬化。拟议的研究将是重要的，因为它们将提供新的信息，以支持FcγR信号通路可能代表旨在改善自身免疫性疾病的血管并发症的干预措施的新型热目标，该区域是直接需要发育的领域。