呼吸道粘膜免疫在诱导A型流感病毒广谱中和抗体中的作用和机制

The high antigenic variability of influenza virus (IAV) and lack of cross-protective immunity are the biggest challenge to IAV vaccine research. Mucosal IgA is able to provide cross protection and last a long time in mucosal sites, which are beneficial for IAV immunity. However, the current injective IAV vaccination only induced serum IgG. We first found that mucosal administration of b2m significantly enhanced FcRn- dependent DC antigen uptake and secretory IgA (SIgA) responses. Thus, we hypothesize that enhancement of FcRn function and expression would promote diversity and longevity of antibody responses to IAV. The hypothesis will be tested by following two specific aims: 1) study the role of FcRn-mediated B cell activation in HA antibody responses by antigen design and immunization strategy and by increasing FcRn function and expression; 2) determine the role of FcRn-mediated mucosal immune responses in promoting cross and diverse B cell responses to HA and in generation of long-lived plasma cells and B memory cells by analyzing antibody reaction to different types of HA, diversity of B cell repertoire, and longevity of plasma and memory cells. Accomplishment of the proposal will open up new avenues for development of universal IAV vaccine in both basic research and application.

流感病毒的高变异性和缺少交叉免疫保护是疫苗研究的最大挑战。粘膜IgA具有交叉抗原反应和持久存在的特点，在抗IAV感染中有重要作用。我们首次发现粘膜给予b2m显著增强FcRn依赖的DC细胞对抗原的摄取和分泌性IgA抗体反应。由此假设促进FcRn的功能和表达增强对IAV表面抗原HA的抗体反应多样性和持久性。设以下两个课题：课题一研究FcRn介导的抗体反应在促进诱导广谱HA抗体中的作用，通过HA抗原和免疫方案的设计和促进FcRn的功能和表达以及检测HA特异性抗体水平，证实FcRn在粘膜HA抗体反应中的作用。课题二研究是否FcRn促进B细胞反应的多样性和长寿浆细胞/记忆B细胞的生成？通过分析抗体对不同HA的交叉反应、B细胞免疫组库多样性比对和长寿浆细胞/记忆细胞检测确定FcRn-介导的粘膜抗体反应在IAV交叉保护和长效免疫力中的作用。此课题的完成将为通用IAV粘膜疫苗研发在理论和应用上开辟新途径。

流感病毒（IAV）的高变异性和缺少交叉免疫保护是疫苗研究的最大挑战。粘膜IgA具有交叉抗原反应和持久存在的特点，在抗IAV感染中有重要作用。我们首次发现粘膜给予2m显著增强FcRn-依赖的DC细胞对抗原的摄取和分泌性IgA抗体（SIgA）反应。由此我们假设促进FcRn的功能和表达增强对IAV表面抗原HA的抗体反应多样性和持久性。将设以下两个课题：课题一研究FcRn介导的抗体反应在促进诱导广谱HA抗体中的作用，通过HA抗原和免疫方案的设计和促进FcRn的功能和表达以及检测HA特异性抗体水平，证实FcRn在粘膜HA抗体反应中的作用。课题二研究是否FcRn促进B细胞反应的多样性和长寿浆细胞/记忆B细胞的生成？通过分析抗体对不同HA的交叉反应、B细胞免疫组库多样性的比对和长寿浆细胞/记忆细胞的检测确定FcRn-介导的粘膜抗体反应在IAV交叉保护和长效免疫力中的作用。此课题的完成将为通用IAV粘膜疫苗的研发在理论和应用上开辟新途径。