The impact of sex and gender on disease progression, from developmental origins

摘要 母胎界面是荷尔蒙和免疫丰富的环境，对正常很重要。 妊娠前三个月的胎盘。这也是成人疾病发展的原因 起源。在怀孕的这个阶段，荷尔蒙和免疫环境都已经是性二态的。 我们在全球范围内以及在怀孕早期的各个细胞类型中确定了性别二态基因的表达。 胎盘受到母胎界面信号的影响，其中包括转化生长因子-β超家族的成员， 尤其是转化生长因子β-1和骨形态发生蛋白在男性。在单个细胞类型中，来自CCL家族的配体最多 IL1RN和MMP9在女性中高度表达，而在男性中高度表达，其 母体表面存在相应的受体。双氢睾丸素，它只由 除了转化生长因子β1和雌二醇外，男性胎儿在个体细胞中也被认为是重要的上游调节因子 妊娠早期胎盘的类型。然而，荷尔蒙环境可能并不是唯一的生物性行为 影响免疫系统的不同因素，因为我们在早期也发现了关键的转录调节因子 妊娠可能解释了免疫性疾病的发育起源。 在人的一生中，荷尔蒙被认为在免疫功能障碍和 疾病的发展，因为总体来说，女性自身免疫性疾病的患病率较高，例如 系统性红斑狼疮、类风湿性关节炎和多发性硬化症。然而，男性更有可能发展为 强直性脊柱炎。此外，在#年，男性的哮喘患病率比女性更高。 儿童时期，但性二态的患病率在青春期后发生变化，这表明睾酮可能是 防护性的。潜在的性别差异也会影响免疫系统。然而，POST 青春期，荷尔蒙调节再次变得性二态，很难将 从性别影响看生物性激素对免疫系统的影响 这是由于外部因素的影响。 因此，为了更好地了解生物性别在胚胎发育起源过程中的影响。 免疫功能，包括荷尔蒙环境的影响，我们打算识别性别特异性转录 妊娠前三个月胎盘的监管签名。此外，由于性激素在体内不是二态的 儿童早期，在青春期之前，我们打算更好地了解性别对发育的影响 在荷尔蒙影响之前，免疫系统的差异，以确定性行为的关键驱动因素 免疫功能的二形性。我们的目标是确定免疫功能障碍的性行为独特调节者 最终被用作治疗免疫性疾病的更个性化的方法。

Abstract The maternal fetal interface is hormonal and immunologically rich environment that is important for normal placentation during the first trimester of pregnancy. This is also where adult diseases have developmental origins. Both the hormonal and immunologic milieus at this stage of gestation are already sexually dimorphic. We identified sexually dimorphic gene expression globally and among individual cell types of the first trimester placenta impacted by signaling at the maternal fetal interface, which includes members of the TGF-β superfamily, specifically TGFβ-1 and BMPs in males. Among individual cell types, ligands from the CCL family were most highly representative in females whereas IL1RN and MMP9 were highly expressed in males, with their corresponding receptors present on the maternal surface. Dihydrotestosterone, which is only produced by the male fetus, in addition to TGFβ1 and estradiol were identified as significant upstream regulators in individual cell types of the first trimester placenta. However, the hormonal environment may not be the only biologically sex different factor influencing the immune system, as we have also identified key transcription regulators in early gestation that may account for developmental origins of immune disease. Throughout the lifespan, hormones have been implicated to play a significant role in immune dysfunction and development of disease, as overall there is a higher prevalence of autoimmune diseases in females, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Yet men are more likely to develop ankylosing spondylitis. Furthermore, males have increased prevalence of asthma compared to females in childhood, but the sexually dimorphic prevalence changes post-puberty, suggesting testosterone may be protective. There are also potential gender differences that influence the immune system. However, post puberty, hormonal regulation becomes sexually dimorphic again and it becomes difficult to separate the influence of hormones which is a function of biologic sex on the immune system from the influence of gender which is due to external influences. Therefore, in order to better understand the influence of biological sex during developmental origins of immune function, including the effect of the hormonal milieu, we intend to identify sex specific transcriptional regulatory signatures in the first trimester placenta. Furthermore, since sex hormones ar e not dimorphic in early childhood, prior to puberty, we intend to better understand the influence of gender on developmental differences of the immune system, prior to hormonal influences, to identify the critical drivers of sexual dimorphism in immune function. Our goal is to identify sex unique regulators of immune dysfunction that can ultimately be used as a more personalized approach to treating immunologic diseases.