Genetic and hormonal mechanisms of sex differences in immune responses and influenza vaccine efficacy in young and aged mice

SADII研究项目3：免疫反应中性别差异的遗传和激素机制 和流感疫苗在幼鼠和老年鼠中的效力 摘要 使用C57BL/6小鼠和灭活的2009年H1N1疫苗启动和增强策略，我们已经证明 年轻成年女性中较大的抗体足以预防流感。追随流感病毒 年轻成年雌性小鼠接种疫苗后，具有更强的抗体反应和对攻击的保护作用 一种流感漂移变异病毒比男性。来自接种疫苗女性的抗体具有更好的保护作用 天真的男性和女性都比男性产生的抗体更多，这种保护与 提高了对流感病毒的抗体特异性和亲和力。我们已经确定了两个因素来减少 流感疫苗接种后女性偏向的抗体反应和保护--老龄化和缺失 控制体细胞超突变(激活诱导胞苷脱氨酶[Aicda])和抗体类别的基因 B细胞中的开关重组(Toll样受体7[TLR7])。因为性类固醇的分泌减少到 年龄较大的女性比男性年龄更大，与年龄相关的女性偏向免疫力下降 暗示了性激素的作用。相反，因为TLR7位于X染色体上并逃脱了X的失活 在B细胞中，女性偏向的流感免疫也可能反映了性染色体的直接影响。这个 SADII研究项目3的首要目标是分析和操纵调节 通过完成三个目标实现对流感免疫的性别和年龄差异：目标1将系统地 评估性染色体如何直接通过X和Y基因的不平衡表达来补充，或者 通过性激素浓度间接导致性别在免疫力和对流感的保护方面的差异， 使用转基因小鼠(即四个核心基因型)；Aim 2将梳理出按时间顺序年龄与 生殖衰老对体液免疫和流感防护作用的性别差异 与年轻成年小鼠相比；Aim 3将描述转录活性的性别差异。 以及接种后的B细胞流感特异性受体谱系，最初侧重于激活 我们已经证明在小鼠中存在性别差异调控的通路(例如，TLR7信号)， 以及在对项目1和2的细胞进行分析时发现的新途径。 研究项目3中的研究将提供可用于检验假设的翻译机制洞察力 来自研究项目1和2的人类数据。

SADII RESEARCH PROJECT 3: Genetic and hormonal mechanisms of sex differences in immune responses and influenza vaccine efficacy in young and aged mice SUMMARY Using C57BL/6 mice and an inactivated 2009 H1N1 vaccine prime and boost strategy, we have shown that greater antibody in young adult females is sufficient for protection against influenza. Following influenza virus vaccination, young adult female mice have greater antibody responses and protection against challenge with an influenza drift variant virus than males. Antibody derived from vaccinated females is better at protecting both naïve males and females than antibody derived from males, and this protection is associated with increased antibody specificity and avidity to the influenza virus. We have identified two factors that reduce female-biased antibody responses and protection following influenza vaccination—old age and deletion of genes that control somatic hypermutation (activation-induced cytidine deaminase [Aicda]) and antibody class switching recombination in B cells (toll like receptor 7 [Tlr7]). Because secretion of sex steroids is reduced to a greater extent in females than males with older age, the age-associated reduction in female-biased immunity suggests a role for sex steroids. In contrast, because Tlr7 is on the X chromosome and escapes X inactivation in B cells, female-biased immunity to influenza may also reflect direct effects sex chromosomes. The overarching goal of SADII Research Project 3 is to analyze and manipulate the biological factors mediating the sex and age differences in immunity to influenza, through completion of three aims: Aim 1 will systematically evaluate how sex chromosome complement either directly through imbalanced expression of X and Y genes or indirectly via sex hormone concentrations cause sex differences in immunity and protection from influenza, using transgenic mice (i.e., Four Core Genotype); Aim 2 will tease apart the impact of chronological age versus reproductive senescence on reduced sex differences in humoral immunity and protection from influenza in aged as compared with young adult mice; and Aim 3 will characterize sex differences in transcriptional activity and B-cell influenza-specific receptor repertoire following vaccination, focusing initially on activation of pathways that we have shown to be differentially regulated between the sexes (e.g., TLR7 signaling) in mice, as well as novel pathways that are uncovered in the analyses of cells from Projects 1 and 2. Together, the studies in Research Project 3 will provide translational mechanistic insights that can be used test hypotheses derived from the human data from Research Projects 1 and 2.