Impact of immune sex differences in the first 1000 days of life and in childhood and adolescence

出生前1000天免疫性别差异的影响 在童年和青春期 项目摘要：男性和男性的免疫反应存在很大差异 对健康和生存有严重影响的女性。免疫性别差异在几周内开始 并在一生中保持不变。然而，我们继续实施预防和 没有考虑免疫性别差异的治疗，主要是由于缺乏对 他们的机制。了解这些免疫性别差异的机制是至关重要的，因为它将 为量身定做疫苗和治疗以及改善健康结果提供理论依据。 我们在这里试图定义早期生命中免疫性别差异的基本机制 通过专注于特定免疫和感染的三个目标一直持续到青春期： 在目标1中，我们评估了免疫性别差异在卡介苗免疫应答中的作用机制 出生后6个月接种麻疹疫苗。我们将不仅关注保护的具体应对措施 而且对这些疫苗的非特异性免疫效果也有影响，这些疫苗减少了 儿童因结核病和麻疹以外的疾病死亡50%。既有特定的也有非特定的 女性的反应更强烈。我们将研究南非的性不和谐双胞胎，以解决目标1-2。 在目标2中，我们调查了免疫性别差异对艾滋病病毒暴露结果的影响 子宫。以前的研究表明，出生在日本的未感染艾滋病毒的儿童对免疫功能有很大影响 感染艾滋病毒的母亲。除了未感染艾滋病毒的双胞胎队列外，我们还将在夸祖鲁-纳塔尔进行研究 自2015年以来，我们一直跟踪调查了230对感染艾滋病毒的母婴。我们最近做了 表明女性胎儿更容易通过抵抗I型干扰素而在宫内感染 病毒，特别是当母亲在怀孕期间进行血清转换时。 在目标3中，我们将在一项观察性研究中评估免疫性别差异对SARS-CoV-2的反应 在英国12-17岁的青少年队列中接种疫苗。免疫性别差异一直是 观察所有获得许可的疫苗，从出生到老年，女性产生更强的抗体反应 但遭受更大的不良事件，如上所述。中和抗体水平高出76% 与16-25YO相比，12-15YO观察到的辉瑞-生物技术新冠肺炎疫苗的反应是惊人的 在展示年龄对免疫力的特定影响方面，即使是在青少年与年轻人之间。 在这项研究中，我们解决了TLR7-干扰素-I的性别差异的最重要的假设 在非常规T细胞(如MAIT细胞和Vd2+Gd T细胞)激活过程中的信号转导途径 DNA甲基化在性激素水平和胎盘中对特定免疫基因的调节 母体抗体的转移-所有这些因素都驱动并影响着性别之间的结局差异 在生命早期及以后预防疫苗和感染。

IMPACT OF IMMUNE SEX DIFFERENCES IN THE FIRST 1000 DAYS OF LIFE AND IN CHILDHOOD AND ADOLESCENCE PROJECT SUMMARY: Substantial differences exist between the immune responses made by males and females that critically impact on health and survival. Immune sex differences start within weeks of conception and are maintained throughout life. However, we continue to administer preventions and treatments without taking immune sex differences into account, largely through a lack of understanding of their mechanism. Understanding mechanisms of these immune sex differences is essential because it will provide the rationale to tailor vaccines and treatments and improve health outcomes. We seek here to define the fundamental mechanisms underlying immune sex differences in early life through to adolescence via three aims that focus on specific immunizations and infections: In Aim 1, we evaluate mechanisms of immune sex differences in response to BCG immunization at birth and measles vaccination at 6 months. We will focus not only on the specific responses protecting against tuberculosis and measles but also on the non-specific immune effects of these vaccines that reduce childhood mortality from diseases other than TB and measles by 50%. Both specific and non-specific responses are stronger in females. We will study sex-discordant twins in South Africa to address Aims 1-2. In Aim 2, we investigate the impact of immune sex differences on outcome from HIV exposure in utero. Previous studies have shown strong effects on immune function in HIV-uninfected children born to mothers living with HIV. In addition to the HIV-uninfected twin cohort we will also study in KwaZulu-Natal a cohort of >230 HIV-infected mother-child pairs we have followed from birth since 2015. We have recently demonstrated that female fetuses are more susceptible to in utero infection via type I interferon-resistant viruses, especially when the mothers have themselves seroconverted during the pregnancy. In Aim 3, we will evaluate in an observational study immune sex differences in response to SARS-CoV-2 vaccination in an adolescent cohort aged 12-17 years in UK. Immune sex differences have been observed to all licensed vaccines, from birth to old age, with females making stronger antibody responses but suffering greater adverse events, as described above. The 76% higher levels of neutralising antibodies observed in 12-15yo compared to 16-25yo in response to the Pfizer-BioNTech COVID-19 vaccine is striking in demonstrating the age-specific effects on immunity even among adolescents versus young adults. In this study, we address the over-arching hypotheses that sex differences in the TLR7-IFN-I signalling pathway, in the activation of nonconventional T-cells such as MAIT cells and Vd2+ gd T-cells, in the regulation of specific immune genes by DNA methylation, in sex steroid levels, and in the transplacental transfer of maternal antibody - all of these factors drive and have an impact on sex differences in outcome from vaccines and infections in early life and beyond.