Microbiome and sex chromosome complement interact in sexually dimorphic immunity

项目概要/摘要： 免疫反应的性别差异是众所周知的，女性对感染的敏感性较低，但 患自身免疫性疾病的可能性是男性的10倍。个体性别特异性因素的参与， 包括：性激素、性染色体补体和微生物组。但 是我们对这些因素介导性别特异性反应的机制的理解中的一个关键空白。 此外，尚不清楚这些因素是否或如何相互作用，以调节男性与女性的整体反应性。 女性免疫系统 目前的提案将测试肠道微生物组代谢物，特别是短链脂肪酸（SCFA）， 通过促进X连锁免疫相关基因的双等位基因表达诱导性别特异性反应， 女性大多数以前的微生物组研究都集中在确定性别特异性微生物组群体 具有独特的代谢能力来解释两性异形反应。然而，我们的初步数据显示， 表明类似水平的SCFA可以不同的方式调节体液免疫应答， XX依赖。我们假设SCFAs通过利用 表观遗传调控机制，以差异影响免疫相关基因表达在XX与XY- 依赖的方式。这些假设将在两个具体目标中得到解决。具体目标1将确定是否 SCFA介导的HDAC抑制通过促进X连锁的双等位基因表达增加B细胞活化 免疫相关基因具体目标2将评估SCFA增强体液免疫的潜力 对热灭活肺炎链球菌（HKSP）的反应-以XX依赖性方式免疫。 通过定义有助于性别特异性反应的潜在机制，拟议的研究将 有助于开发更好的治疗策略，以对抗性别偏见的自身免疫性和炎症性疾病。 提高疫苗的效力。这些研究也是相关的，因为肠道微生物组代谢物是 由于它们的免疫调节活性而作为潜在的免疫治疗剂销售。益生元， 益生菌和SCFA补充剂是容易获得的非处方药，最近，SCFA已被 被提议作为几种免疫相关疾病的治疗。然而，很少有研究调查 这些化合物发挥性别特异性免疫作用的潜力，据我们所知， 已经解决了这种效应可能以性染色体补体依赖性方式发生的可能性。

Project Summary/Abstract: Sex differences in immune responses are well-recognized, with females being less susceptible to infection, but 10X more likely to develop autoimmune disease than males. The involvement of individual sex-specific factors, including: sex hormones, sex chromosome complements and microbiomes, have been identified. However, there is a critical gap in our understanding of the mechanisms by which these factors mediate sex-specific responses. In addition, it is not known if or how these factors interact to regulate the overall responsiveness of the male vs. female immune systems. The current proposal will test whether gut microbiome metabolites, specifically short-chain fatty acids (SCFAs), induce sex-specific responses by promoting the bi-allelic expression of X-linked immune-related genes in females. Most previous microbiome studies have focused on identifying sex-specific microbiome populations with distinct metabolic capabilities to explain sexually dimorphic responses. However, our preliminary data suggests that similar levels of SCFAs can differentially regulate humoral immune responses in a manner that is XX-dependent. We hypothesize that SCFAs contribute to sexually dimorphic immune responses by utilizing epigenetic regulatory mechanisms to differentially influence immune-related gene expression in an XX vs. XY- dependent manner. This hypotheses will be addressed in two Specific Aims. Specific Aim 1 will determine if SCFA-mediated HDAC inhibition increases B cell activation by promoting the bi-allelic expression of X-linked immune-related genes. Specific Aim 2 will evaluate the potential for SCFAs to enhance humoral immune responses to heat-killed Streptococcus pneumoniae (HKSP)-immunization in an XX-dependent manner. By defining the underlying mechanisms that contribute to sex-specific response, the proposed research will contribute to the development of better treatment strategies to combat sex-biased autoimmune and inflammatory diseases, and improved vaccine efficacies. These studies are also relevant as gut microbiome metabolites are being marketed as potential immuno-therapeutics, due to their immunomodulatory activities. Prebiotics, probiotics and SCFA supplements are readily available over-the-counter, and most recently, SCFAs have been proposed as treatments for several immune-related disorders. However, few studies have investigated the potential for these compounds to exert sex-specific immune effects and, to our knowledge, no previous study has addressed the possibility that such effects may occur in a sex chromosome complement-dependent manner.