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细胞和抗体是先天免疫系统和获得性免疫系统之间的关键接口，因为它们 对微生物抗原既有自然识别又有后天识别。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，这些自身反应的B细胞必须 严格监管以防止自身免疫。我们实验室的最新证据表明， 证明了B细胞、浆母细胞和针对DNA和基底的自身反应性抗体 鼻息肉组织中的细胞膜明显升高，特别是在病情严重的患者。此外， 我们发现，抗体介导的补体激活的高度特异性标志物，如C4D和C1Rs-inh是 在鼻息肉组织中发现高水平的抗体，表明这些抗体正在激活有效的亲 炎症免疫级联反应。我们对拟议工作的中心假设是：1)这些 自身抗体与结合微生物抗原的天然抗体发生交叉反应，2) 自身反应性抗体可预测鼻息肉复发；3)鼻息肉中自身反应性B细胞 可能代表一种称为B-1细胞的B细胞亚型的病理性表现，这种细胞一直很好 在老鼠身上具有这种特征，但在人类身上仍然是谜。在提出的高度翻译的研究中，我们将 利用首席研究员作为外科科学家的专业知识，其临床兴趣集中在CRS上 与他对粘膜免疫有研究兴趣的患者。实验的具体目标将：(1)确定 鼻息肉衍生抗体识别的特定组织抗原并评估其潜在的 与微生物蛋白质发生交叉反应，激活补体；(2)全面分析采集的样本 来自鼻窦手术后鼻息肉复发的前瞻性观察试验 互补性。然后将使用生存分析来评估提供重要预后的生物标记物。 信息；以及(3)分离产生自身抗体的细胞以识别谱系标志，进行分析 抗体结构多样性，并从这些细胞产生单克隆性自身抗体，用于未来的研究。如果 这些研究的成功将在衰弱的上呼吸道中确立一种新的致病机制。 疾病，验证具有预后价值的新生物标记物，并发现人类粘膜的基本特征 B细胞。