Natural IgM Sensing of DAMPS

DAMPS 的天然 IgM 传感

基本信息

批准号：
8874108
负责人：
Michael Craig Carroll
金额：
$ 22.08万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2014-06-17 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874108
关键词：
Acute Address Animal Model Annexin A4 Antibodies Antigen Targeting Antigens Apoptotic Arthritis Autoantigens Autoimmune Diseases B-Lymphocyte Subsets B-Lymphocytes Binding Biology Blocking Antibodies Brain Cell Death Cells Cellular Stress Complement Development Disease Endothelium Event Evolution Exhibits Exposure to Figs - dietary Future Goals Growth Health Heart Hypoxia Immune response Immunoglobulin M Immunoglobulin Somatic Hypermutation Infection Inflammation Inflammatory Inflammatory Response Injury Intestines Ischemia Knock-in Mouse Knowledge Lectin Ligands Lymphocyte Macular degeneration Mediating Modeling Molecular Monoclonal Antibodies Mus Myosin Heavy Chains Myosin Type II Natural Killer Cells Nuclear Pathway interactions Pattern Peptides Proteins Reagent Reperfusion Injury Reperfusion Therapy Resources Retina Role Shapes Site Skeletal Muscle Source Specificity Staging Sterility Stress Synovial Membrane T-Lymphocyte Testing Tissues Trauma Ursidae Family antigen binding beta 2-glycoprotein I biological adaptation to stress cell injury complement system extracellular human disease immunoglobulin receptor improved insight lupus-like mast cell microbial mouse model non-muscle myosin novel progenitor receptor response self-renewal sensor trafficking

项目摘要

DESCRIPTION (provided by applicant): Natural IgM Sensing of DAMPS The concept of DAMPS (damage associated molecular patterns) which are self-antigens that induce acute inflammation is well established. The general principle is that trauma, infection or other forms of stress such as hypoxia leads to exposure of highly conserved nuclear or cytoplasmic antigens that trigger an innate response. Both intracellular and extracellular sensors of DAMPS have been identified. Of the latter, natural antibodies, produced by B-1 cells, represent a major set of recognition proteins. Although produced by B lymphocytes, natural antibodies act as innate receptors as they have evolved to bind highly conserved self-antigens or neoepitopes. Binding of self-antigen by natural antibodies following hypoxic stress, i.e. reperfusion, induces a complement-dependent inflammatory response leading to severe and often fatal disease as observed in multiple tissues such as intestinal, skeletal muscle, heart and brain. A broader role in inflammation is suggested by their enhancement of injury in sites of inflammation such as the synovium in arthritis and retina in macular degeneration. Despite the potential importance of natural antibodies in human disease, fundamental unanswered questions remain. To address this barrier, we propose to construct a murine model in which the B cells express an immunoglobulin receptor specific for a known reperfusion injury neoepitope, i.e. non-muscle myosin heavy chain II and relevant clonotypic monoclonal antibodies. In addition, we will test the hypothesis that B-1 cells specific for IR antigen migrate into inflamed tissues where they modify the response. The availability of the new animal model and anti-clonotypic reagents can be used as proof of concept for support of more in depth studies in the future to move this important field forward.

描述（由申请人提供）：潮湿的自然IgM传感湿（损伤相关的分子模式）是诱导急性炎症的自我抗原。一般原则是创伤，感染或其他形式缺氧之类的压力会导致触发先天反应的高度保守的核或细胞质抗原。已经确定了潮湿的细胞内和细胞外传感器。 B-1细胞产生的后一种天然抗体代表了一组主要集合识别蛋白。尽管由B淋巴细胞产生，但天然抗体作为先天受体，因为它们已经演变为结合高度保守的自我抗原或新皮上。在低氧应激之后，自然抗体（即再灌注）结合自我抗原，会诱导补体依赖性炎症反应，从而导致严重且常常致命的疾病，如肠道，骨骼肌，心脏和脑中所观察到的。在炎症中，在炎症中提高了更广泛的作用，这表明了它们在炎症部位的损伤增强，例如关节炎和黄斑变性中的视网膜滑膜。尽管天然抗体在人类疾病中具有潜在的重要性，但仍有根本的未解决问题。为了解决这一障碍，我们建议构建一种鼠模型，其中B细胞表达针对已知再灌注损伤新EPITOPE的免疫球蛋白受体，即非肌肉肌球蛋白重链II和相关的clonotypic单克隆抗体。此外，我们将检验以下假设：IR抗原特有的B-1细胞迁移到发炎的组织中，它们会改变反应。新的动物模型和抗粘液型试剂的可用性可以用作概念证明，以支持将来更多的深度研究，以向前发展这一重要领域。