Protective humoral immunity to influenza infection

项目总结 卵泡外(EF)B细胞反应在气道腔内产生病毒特异性的IgM、IgG和IgA 和局部淋巴结，最早在流感病毒感染后72小时，与病毒存在时间相关性 通行证。EF反应在动力学、功能和信号要求上与较慢者不同 生发中心反应。EF B细胞反应在很大程度上被认为在病原体- 诱导免疫，因为它们只产生短暂的浆细胞和低亲和力抗体。 然而，与最近关于BCR和BCR之间高亲和力相互作用的要求的研究一致 诱导EF反应的抗原，我们的研究表明，流感病毒HA的EF反应原型 A/波多黎各/8/34在流感感染后长期产生高亲和力保护性抗体。因此， 将这一反应确定为初级流感感染诱导的抗病毒免疫的关键组成部分。 然而，佐剂中灭活病毒免疫未能诱导EF应答，但确实诱导了 强大的生发中心，从而确定疫苗诱导的体液免疫的特定缺陷， 可能会降低其疗效。因为诱导EF反应的信号是未知的，它们的保护作用 能力尚不清楚，它们不能用于治疗或预防用途。要克服这一点 我们提出的知识鸿沟是为了验证我们的假设，即先天B细胞直接信号驱动高亲和力 通过诱导强烈的EF反应产生长期保护性的抗病毒体液免疫。具体目标#1将 利用基因靶向的小鼠识别与EF发育有关的受体和信号通路 流感感染后与相应配体补充灭活流感疫苗 以生成EF响应。目标2将描绘这些信号通路的分子靶点 B细胞分化为EF浆母细胞，跟随流感HA特异性B细胞的命运。目标3将 评估EF和GC B细胞反应的质量和保护能力。这些活动的成功结果 研究将通过证明EF对感染的反应可以产生 高亲和力抗体反应并提供免疫保护。配体的鉴定、信号传递 驱动EF反应的途径和基因靶点将增加关于 B细胞分化机制及为开发EF增强应答打开大门 通过治疗和预防干预获得免疫力。

PROJECT SUMMARY The extrafollicular (EF) B cell response generates virus-specific IgM, IgG and IgA in the airway lumen and local lymph nodes as early as 72h after influenza virus infection, correlating temporally with virus clearance. EF responses are distinct in kinetics, function and signaling requirements from the slower germinal center responses. EF B cell responses habe been largely dismissed as significant in pathogen- induced immunity, as they are though to generate only short-lived plasma cells and low affinity antibodies. Yet, consistent with recent studies on a requirement for high-affinity interaction between BCR and antigen for induction of EF responses, our studies show that a prototypic EF response to HA of influenza A/Puerto Rico /8/34 generates high-affinity protective antibodies long-term after influenza infection. Thus, identifying this response as a crucial component of primary influenza-infection-induced antiviral immunity. However, immunization with inactivated virus in adjuvant failed to induce EF responses, yet did induce strong germinal centers, thereby identifying a specific deficit in vaccine-induced humoral immunity, that may reduce its efficacy. Because the signals inducing EF responses are unknown, and their protective capacity is unclear, they cannot be exploited for therapeutic or prophylactic uses. To overcome this knowledge gap we propose to test our hypothesis that innate B cell direct signaling drives high affinity long-term protective antiviral humoral immunity via induction of strong EF responses. Specific Aim #1 will use gene-targeted mice to identify the receptors and signaling pathways responsible for EF development after influenza infection and complement inactivated influenza vaccines with their corresponding ligands to generate EF responses. Aim 2 will delineate the molecular targets of these signaling pathways for the differentiation of B cells to EF plasma blasts, following the fate of influenza HA-specific B cells. Aim 3 will assess the quality and protective capacity of EF and GC B cell responses. Successful outcome of these studies will provide a conceptual advance by demonstrating that EF responses to infection can generate high-affinity antibody responses and provide immune protection. Identification of the ligands, signaling pathways and the gene targets that drive EF responses will increase fundamental knowledge on the mechanisms of B cell differentiation and open the door for the exploitation of EF responses to enhance immunity through therapeutic and prophylactic interventions.