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

• 批准号: 9903228
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-25 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903228
• 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; Epithelium; Frequencies; Future; Goals; Health; Heavy-Chain Immunoglobulins; Human; Immune; Immunoglobulin G; 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; 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

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细胞和抗体是先天和适应性免疫系统之间的关键接口 对微生物抗原具有自然和获得的认可。但是，自然结合的抗体 微生物抗原经常与自我抗原反应，在健康方面，这些自动反应性B细胞必须是 严格调节以防止自身免疫性。我们实验室的最新证据以前有 证明了B细胞，血浆和自身反应性自身抗体针对DNA和地下室 鼻息肉组织中的膜显着升高，尤其是在严重疾病的患者中。此外， 我们发现抗体介导的完成激活（如C4D和C1RS-INH）的高度特异性标记是 在鼻息肉组织中发现的高水平表明这些抗体正在激活有效的促进症 炎症免疫级联反应。我们提出的工作的中心假设是：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） 自动反应性抗体可以预测鼻息音复发，3）鼻息肉中的自动反应性B细胞 可能代表B-Cells亚型的致病表现，称为B-1细胞，已很好 在小鼠中的特征是，但在人类中仍然是神秘的。在提出的高度翻译的研究中，我们将 利用主要研究者作为外科医生科学家的专业知识，其临床利益集中在CRS上 他对粘膜免疫的研究兴趣的患者。实验中的具体目的将：（1）确定 特定的组织抗原被鼻息质抗体识别，并评估其潜力 与微生物蛋白交叉反应并激活完成； （2）全面分析收集的样品 从鼻窦手术后的自身抗体和 完全的。然后，将使用生存分析来评估提供明显预后的生物标志物 信息; （3）隔离产生自身抗体以识别谱系标记的细胞，进行分析 抗体结构多样性并从这些细胞中产生单克隆自身抗体，以供将来研究。如果 成功的研究将首先在令人衰弱的上呼吸道中建立一种新型的致病机制 疾病，验证预后价值的新型生物标志物，并发现人粘膜的基本特征 B细胞。