Microbiome and sex chromosome complement interact in sexually dimorphic immunity

项目摘要/摘要： 免疫反应的性别差异是众所周知的，女性不太容易受到感染，但 患自身免疫性疾病的可能性是男性的10倍。个人性别特有因素的参与， 包括：性激素、性染色体补体和微生物组。然而，在那里 在我们对这些因素调节特定性别反应的机制的理解上存在着严重的差距。 此外，目前尚不清楚这些因素是否或如何相互作用来调节男性与女性的总体反应。 女性免疫系统。 目前的提议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。以前的大多数微生物组研究都集中在识别性别特定的微生物组群上 具有不同的新陈代谢能力来解释性二态反应。然而，我们的初步数据 提示类似水平的单链脂肪酸可以以不同的方式调节体液免疫反应，即 依赖于XX。我们假设单链脂肪酸通过利用 表观遗传调控机制对XX和XY-免疫相关基因表达的不同影响 依赖的态度。这一假设将在两个具体目标中得到解决。具体目标1将决定是否 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细胞的激活 免疫相关基因。特定目标2将评估单链脂肪酸增强体液免疫的潜力。 对热灭活肺炎链球菌(HKSP)的反应-以XX依赖的方式免疫。 通过定义有助于特定性别反应的潜在机制，拟议的研究将 帮助制定更好的治疗策略，以对抗性别偏见的自身免疫和炎症性 疾病，以及改进的疫苗效力。这些研究也是相关的，因为肠道微生物组代谢产物 由于其免疫调节活性，被作为潜在的免疫治疗药物推向市场。益生元， 益生菌和SCFA补充剂很容易在柜台上买到，最近，SCFA已经 被建议用于治疗几种与免疫相关的疾病。然而，很少有研究调查 这些化合物发挥性别特异性免疫效应的可能性，据我们所知，以前没有研究过 已经解决了这种影响可能以性染色体互补依赖的方式发生的可能性。

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.