Biology of the Eosinophilic Leukocyte

在本报告年度，我们继续探索嗜酸性粒细胞及其与呼吸道病毒病原体的相互作用。我们的第一项主要研究是与澳大利亚纽卡斯尔大学和新南威尔士大学的同事合作进行的，直接解决了这些问题。利用我们实验室建立的小鼠肺炎病毒(PVM)感染模型，我们研究了新生儿病毒感染和抗原暴露与嗜酸性粒细胞聚集和过敏性哮喘的其他标志症状之间的相互作用。在我们的发现中，我们观察到过敏性呼吸道炎症，包括嗜酸性粒细胞的募集，在过敏原攻击之前从新生儿PVM感染中恢复的小鼠中最为突出。此外，从新生儿感染中恢复并表现出明显的嗜酸性粒细胞增多的小鼠也表现出基于Th2的免疫反应增强，包括血清中抗卵清蛋白IgE和IgG1水平的升高，以及Th2相关细胞因子IL-4、IL-5和IL-13的相对表达增加。总体而言，我们得出结论，早期病毒感染和变应原敏化/挑战共同作用，促进儿童哮喘的特征特征，包括嗜酸性粒细胞招募和偏向Th2的免疫反应(Siegle JS等人，Respir res 2010)。 我们在这一主题上的第二个主要研究集中于分离的嗜酸性粒细胞与血小板激活因子(PAF)的相互作用，PAF是一种从激活的巨噬细胞、肥大细胞和嗜碱性粒细胞释放的磷脂介质，促进病理生理反应、全身炎症和过敏反应。嗜酸性粒细胞对PAF和严重全身反应的反应是复杂的，但仍不完全清楚。根据我们实验室开发的方法，同时使用野生型和PAF受体基因缺失的从骨髓培养的小鼠嗜酸性粒细胞(如Dyer等人所述。J.免疫。2008)，我们发现PAF、溶解PAF和相关的磷脂激活小鼠嗜酸性粒细胞，但它们通过令人惊讶地独立于表征的PAF受体的机制来实现这一作用。新的受体和信号通路的性质有待进一步的表征(Dyer等人，J.免疫2010)。

During this reporting year, we have continued our exploration of eosinophils and their interactions with respiratory virus pathogens. Our first major study, performed in collaboration with colleagues at The University of Newcastle and The University of New South Wales, Australia, addresses these questions directly. Using the pneumonia virus of mice (PVM) infection model developed by our laboratory, we examine the interplay of neonatal virus infection and antigen exposure in relation to eosinophil recruitment and other hallmark signs of allergic asthma. Among our findings, we observed that allergic airway inflammation, including recruitment of eosinophils, was most prominent in mice that had recovered from neonatal infection with PVM prior to allergen challenge. Furthermore, the mice that recovered from neonatal infection and displayed significant eosinophilia also exhibited an augmented Th2-biased immune response, including elevated serum levels of anti-ovalbumin IgE and IgG1 as well as increased relative expression of Th2-associated cytokines IL-4, IL-5 and IL-13. Overall, we concluded that early-life viral infection and allergen sensitization/challenge together function to promote characteristic features of childhood asthma, including eosinophil recruitment and a Th2-biased immune response (Siegle JS et al., Respir Res 2010) Our second major study on this topic focused the interactions of isolated eosinophils with platelet-activating factor (PAF), a phospholipid mediator released from activated macrophages, mast cells, and basophils that promotes pathophysiologic responses, systemic inflammation and anaphylaxis. Eosinophil responses to PAF and to severe systemic responses are complex but remain incompletely elucidated. Using both wild-type and PAF receptor gene-deleted mouse eosinophils cultured from bone marrow as per the methods developed by our laboratory (as described in Dyer et al. J. Immunol. 2008) we found that PAF, lysoPAF and related phospholipids activate mouse eosinophils, but they do so via mechanisms that are surprisingly independent of the characterized PAF receptor. The nature of the novel receptor and signaling pathway awaits further characterization (Dyer et al., J. Immunol 2010).