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

年轻和老年小鼠免疫反应和流感疫苗功效性别差异的遗传和激素机制

• 批准号: 10213173
• 负责人: SABRA L. KLEIN
• 金额: $ 46.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213173
• 关键词: Affect; Age; Aging; Antibodies; Antibody Avidity; Antibody Response; Antibody Specificity; Antibody-mediated protection; Antigens; Autoantigens; B-Cell Antigen Receptor; B-Lymphocytes; Biological Factors; C57BL/6 Mouse; Cells; Chronology; Elderly; Female; Four Core Genotypes; Gene Deletion; Genes; Genetic; Genetic Transcription; Goals; Gonadal Steroid Hormones; H1N1 vaccine; Hormonal; Human; Humoral Immunities; Immune Response Genes; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunologic Memory; Immunology; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Length; Life; Mediating; Memory B-Lymphocyte; Mus; Outcome; Ovary; Pathway interactions; Phenotype; Ploidies; Predisposition; Principal Investigator; Puberty; Research Project Grants; Role; Sex Chromosomes; Sex Differences; Signal Transduction; Specificity; TLR7 gene; Testing; Testis; Transgenic Mice; Vaccinated; Vaccination; Vaccines; Variant; Virus; X Chromosome; X Inactivation; activation-induced cytidine deaminase; age difference; aged; autosome; base; biological sex; cell growth regulation; genotypic sex; human data; human old age (65+); improved; influenza infection; influenza virus vaccine; influenzavirus; insight; male; next generation; novel; programs; receptor; reproductive senescence; response; sex; transcriptome sequencing; vaccine efficacy; vaccine response; vaccine-induced antibodies; vaccine-induced immunity; young adult

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.

SADII研究项目3：免疫反应性别差异的遗传和激素机制 和流感疫苗在年轻和老年小鼠中的效力 总结 使用C57 BL/6小鼠和灭活的2009年H1N1疫苗初免和加强策略，我们已经表明， 年轻的成年女性中较高的抗体足以保护免受流感。流感病毒之后 接种疫苗后，年轻成年雌性小鼠具有更大的抗体应答和针对用 比男性更容易感染流感漂移变异病毒。来自接种疫苗的女性的抗体更好地保护 与来自男性的抗体相比，这种保护作用与以下因素有关： 增加抗体对流感病毒的特异性和亲合力。我们已经确定了两个因素， 流感疫苗接种后女性偏向的抗体应答和保护-老年和 控制体细胞超突变的基因（激活诱导的胞苷脱氨酶[Aicda]）和抗体类别 在B细胞中转换重组（Toll样受体7 [Tlr 7]）。因为性类固醇的分泌减少到 年龄较大的女性比男性的程度更大，女性偏见免疫力的年龄相关性降低 表明性类固醇的作用相反，由于Tlr 7位于X染色体上并逃避X失活， 在B细胞中，对流感的女性偏好免疫也可能反映了性染色体的直接影响。的 SADII研究项目3的总体目标是分析和操纵介导生物学因素 性别和年龄差异的免疫力对流感，通过完成三个目标：目标1将系统地 评估性染色体如何通过X和Y基因的不平衡表达直接互补， 间接地通过性激素浓度导致免疫力和对流感的保护的性别差异， 使用转基因小鼠（即，四个核心基因型）;目标2将梳理出实际年龄与 生殖衰老对减少体液免疫和流感保护的性别差异的影响 与年轻的成年小鼠相比，老年小鼠; Aim 3将表征转录活性的性别差异 和B细胞流感特异性受体库，最初集中在激活 我们已经证明在性别之间差异调节的途径（例如，TLR 7信号传导）， 以及在项目1和项目2的细胞分析中发现的新途径。统称 研究项目3中的研究将提供可用于检验假设的转化机制见解 来自研究项目1和2的人类数据。