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

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C4d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 与微生物蛋白交叉反应，激活补体;（2）对采集的样品进行综合分析 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

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.