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Autoantibody mediated pathogenesis in chronic rhinosinusitis with nasal polyps: mechanisms and consequences

自身抗体介导的慢性鼻窦炎伴鼻息肉的发病机制：机制和后果

基本信息

批准号：
10388102
负责人：
Bruce K Tan
金额：
$ 39.5万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388102
关键词：
Adaptive Immune System Adrenal Cortex Hormones Affinity Airway Disease Antibodies Antigens Autoantibodies Autoantigens Autoimmunity B-Cell Activation B-Lymphocytes Basement membrane Binding Biological Markers Case-Control Studies Cells Chronic Clinical Collaborations Complement Complement 2 Complement Activation Complement component C1r DNA Deposition Diagnostic tests Disease Dropout Environment Epithelial Frequencies Future Goals Health Heavy-Chain Immunoglobulins Human IgG autoantibodies Immune Immunoglobulin-Secreting Cells Impairment In Vitro Inflammation Inflammatory Investigation Laboratories Mediating Medical Mentored Patient-Oriented Research Career Development Award Modeling Molecular Target Monoclonal Antibodies Mucosal Immunity Mucous Membrane Mus Nasal Polyps Nuclear Nuclear Antigens Operative Surgical Procedures Pathogenesis Pathogenicity Patients Phenotype Plasmablast Play Positioning Attribute Postoperative Period Principal Investigator Property Proteins Quality of life Recurrence Research Role Sampling Scientist Sinus Structure of mucous membrane of nose Surface Surgeon Surgical Management Survival Analysis Symptoms Testing Time Tissues Tonsil Translational Research Work antimicrobial autoreactive B cell autoreactivity base chronic rhinosinusitis clinical phenotype cohort complement C4d cross reactivity ds-DNA enzyme linked immunospot assay eosinophilic inflammation experience experimental study human disease immunoglobulin structure immunopathology improved interest lymphoid organ matrigel microbial microorganism antigen mouse model mucosal site natural antibodies novel novel diagnostics novel marker prevent prognostic prognostic value prospective receptor reduce symptoms response transcriptome sequencing translational impact

项目摘要

Project Summary B-cells and antibodies are a critical interface between the innate and adaptive immune systems since they have both natural and acquired recognition of microbial antigens. However, the antibodies that naturally bind microbial antigens frequently also react with self-antigens and, in health, these autoreactive B-cells have to be stringently regulated to prevent autoimmunity. Recent evidence from our laboratory has previously demonstrated that B-cells, plasmablasts and self-reactive autoantibodies against DNA and the basement membrane are strikingly elevated in nasal polyp tissue especially in patients with severe disease. Furthermore, we find that highly specific markers for antibody-mediated complement activation like C4d and C1rs-inh are found at high levels within nasal polyp tissue suggesting these antibodies are activating potent pro- inflammatory immune cascades. Our central hypotheses for the proposed work are: 1) that the these autoantibodies are cross-reactive with natural antibodies that bind microbial antigens, 2) that the levels of autoreactive antibodies may predict nasal polyp recurrence and 3) that the autoreactive B-cells in nasal polyps may represent a pathogenic manifestation of a subtype of B-cells called B-1 cells that have been well characterized in mice but remain enigmatic in humans. In the highly translational research proposed, we will leverage the Principal Investigator’s expertise as a surgeon-scientist whose clinical interests focus on CRS patients with his research interests in mucosal immunity. Specific aims in the experiments will: (1) identify the specific tissue antigens that are recognized by nasal polyp derived antibodies and evaluate their potential to cross-react with microbial proteins and activate complement; (2) comprehensively analyze samples collected from a prospective observational trial of nasal polyp recurrence after sinus surgery for autoantibodies and complement. Survival analysis will then be used to evaluate the biomarkers that provide significant prognostic information; and (3) isolate the cells producing autoantibodies to identify lineage markers, conduct analysis of antibody structural diversity and generate monoclonal autoantibodies from these cells for future studies. If successful, these studies will firmly establish a novel pathogenic mechanism in a debilitating upper airway disease, validate novel biomarkers of prognostic value, and discover fundamental features of human mucosal B-cells.

项目摘要 B细胞和抗体是先天免疫系统和适应性免疫系统之间的关键界面，因为它们具有对微生物抗原的天然和后天识别。然而，天然结合的抗体微生物抗原也经常与自身抗原发生反应，在健康情况下，这些自身反应性B细胞必须被严格控制以防止自身免疫我们实验室最近的证据表明，表明B细胞，浆母细胞和自身反应性自身抗体对DNA和基底膜在鼻息肉组织中显著升高，特别是在病情严重的患者中。此外，委员会认为，我们发现抗体介导的补体激活的高度特异性标志物，如C4 d和C1 rs-inh，在鼻息肉组织中发现了高水平的抗体，这表明这些抗体激活了有效的促甲状腺激素释放激素，炎症性免疫级联反应。我们的中心假设为拟议的工作是：1）这些自身抗体与结合微生物抗原的天然抗体交叉反应，2）自身抗体的水平自身反应性抗体可预测鼻息肉复发; 3）鼻息肉中的自身反应性B细胞可能代表一种称为B-1细胞的B细胞亚型的致病表现，但在人类中仍然是个谜。在所提出的高度转化研究中，我们将利用主要研究者作为外科医生-科学家的专业知识，其临床兴趣集中于CRS 他对粘膜免疫的研究兴趣。实验的具体目标是：（1）确定鼻息肉衍生抗体识别的特异性组织抗原，并评估其与微生物蛋白质发生交叉反应并激活补体;（2）对采集的样本进行全面分析从一项关于鼻窦手术后鼻息肉复发的自身抗体的前瞻性观察试验中，补体然后将使用生存分析来评估提供显著预后的生物标志物。（3）分离产生自身抗体的细胞以鉴定谱系标志物，抗体结构多样性，并从这些细胞中产生单克隆自身抗体用于未来的研究。如果如果成功，这些研究将牢固地建立一个新的致病机制，在衰弱的上呼吸道疾病，验证新的生物标志物的预后价值，并发现人类粘膜的基本特征， B细胞