Sex Differences in Gut Permeability; Impact on Autoimmunity

肠道渗透性的性别差异；

• 批准号: 8820340
• 负责人: Gary S Gilkeson
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820340
• 关键词: Agonist; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmunity; Bacterial Infections; CD14 gene; Cells; Child; Chronic; Clinical; Communicable Diseases; Cytokine Activation; Data; Disease; Disease model; Effectiveness; Epithelial Cells; Estrogens; FCGR3B gene; Female of child bearing age; Goals; Gonadal Steroid Hormones; HIV; Hepatitis C; Hormone Receptor; Hormone replacement therapy; Human; Immune; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Interferons; Interleukin-1; Interleukin-6; Intervention; Investigation; Ligands; Lupus; Lymphocyte; Mediating; Microbe; Microbial Genetics; Modeling; Mucous Membrane; Mus; Organ; Pathogenesis; Patients; Permeability; Plasma; Play; Postmenopause; Predisposition; Premenopause; Prevalence; Production; Recombinant DNA; Resistance to infection; Risk; Role; Sex Bias; Sex Characteristics; Sexual Development; Signal Transduction; Systemic Lupus Erythematosus; TLR4 gene; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Tissues; Vaccines; Virus Diseases; Woman; adaptive immunity; base; cohort; cytokine; disorder risk; immune activation; in vivo; inhibitor/antagonist; insight; men; metagenomic sequencing; microbial; microbiome; monocyte; novel; novel strategies; public health relevance; receptor expression; research study; response; sex; vaccine response

DESCRIPTION (provided by applicant): A greater magnitude of gut microbial product translocation (MT) and gut permeability in women may have important clinical implications for risk of developing autoimmune diseases as well as resistance to infection and response to vaccines. Increases in the inflammatory CD14+CD16++ monocyte subset and enhanced monocyte activation in women may alter effector responses of these cells to bacterial and viral infection and to TLR agonists, resulting in an increased susceptibility to autoimmune disease in women compared to men. TLRs and TLR-signaling downstream cytokines (e.g., IFN-�IL-6, IL-1�TNF-�play a key role in the pathogenesis of autoimmune diseases, and treatments against specific cytokines or TLR inhibitors are effective in SLE patients and murine models. We hypothesize that sex hormone mediated permeable gut and resultant increased magnitude of MT are fundamental drivers for pro-inflammatory cytokine production monocyte activation and sex bias in autoimmune disease. Understanding these mechanisms is likely to provide insights crucial for the development of sex-specific interventions for autoimmune disorders and other diseases sharing sex differences such as Hepatitis C and HIV. Sex-based differences in MT provide a model for analysis of the effects of MT and altered innate immune responses on adaptive immunity and disease pathogenesis in vivo. If our hypothesis is correct-that heightened MT or altered TLR responsiveness in healthy women results in heightened persistent immune activation and pro-inflammatory cytokines, and that heightened inflammation results in enhanced susceptibility and heightened disease activity in SLE-, a therapeutic strategy (e.g., mucosal protector/microbes) may help reverse high levels of persistent inflammation, thereby helping to reestablish normal immunity/tolerance in autoimmune diseases. SPECIFIC AIM 1: Determine the role of sex hormones in gut permeability and the magnitude of microbial product translocation in healthy controls and patients with SLE in vivo and in vitro. Our preliminary data show that premenopausal women have higher plasma levels of total bacterial rDNA, a marker of MT in vivo, compared to men and postmenopausal women. To understand the impact of microbial products from plasma and the gut on systemic immunity and SLE, we will analyze microbial genetic potential by metagenomic sequencing in plasma. SPECIFIC AIM 2: Determine the role of sex hormones in TLR4 responsiveness and monocyte activation. We hypothesize that gut permeability and heightened MT result in monocyte activation in women. We will assess monocyte subset differentiation and potential drivers on monocytes. We will analyze the relatedness/correlation between MT, TLR4 responsiveness, monocyte activation, levels of sex hormones, and SLE disease activity. SPECIFIC AIM 3: Determine the impact of estrogen on gut permeability and monocyte activation in a cohort of postmenopausal women. In this aim, we will analyze the magnitude of MT and monocyte activation in 40 postmenopausal women before and after receiving hormone replacement therapy. By defining mechanisms of sex differences in gut mucosal integrity, MT and systemic immunity and by demonstrating a relationship among gut permeability, MT, TLR4 responsiveness and monocyte activation in vivo, we will establish the plausibility of this model in the pathogenesis of SLE. These findings have broader implications including vaccine responses, infectious disease risk, and risk of other autoimmune diseases.

描述（由申请人提供）： 女性的肠道微生物产物翻译（MT）和肠渗透性的更大程度可能对患上自身免疫性疾病以及对感染和对疫苗反应的抗性具有重要的临床意义。炎症性CD14+CD16 ++单核细胞子集的增加和女性的单核细胞激活增强可能会改变这些细胞对细菌和病毒感染以及TLR激动剂的效应子反应，从而增加女性对自身免疫性疾病的敏感性。 TLR和TLR信号下游细胞因子（例如IFN-IL-6，IL-1，IL-1 TNF游戏在自身免疫性疾病的发病机理中的关键作用，对特定细胞因子或特定细胞因子或TLR抑制剂的处理是有效的SLE患者和鼠模型。自身免疫性疾病中的细胞因子产生单核细胞激活和性别偏见。体内免疫学和疾病发病机理。感染，从而有助于重新建立自身免疫性疾病的正常免疫反应/耐受性。具体目标1：确定性辣椒在肠道渗透性中的作用以及在健康对照组中和体内SLE和体外患者中微生物产物易位的大小。我们的初步数据表明，与男性和绝经后妇女相比，绝经前女性的血浆总细菌rDNA水平较高，这是体内MT的标志。为了了解血浆和肠道对系统性免疫和SLE的影响，我们将通过血浆中的元基因组测序分析微生物遗传潜能。特定目标2：确定性激素在TLR4反应性和单核细胞激活中的作用。我们假设肠道渗透性和增强的MT导致女性单核细胞激活。我们将评估单核细胞分化和单核细胞上的潜在驱动因素。我们将分析MT，TLR4反应性，单核细胞激活，性激素水平和SLE病活动之间的相关性/相关性。具体目标3：确定绝经后妇女队列中雌激素对肠道通透性和单核细胞激活的影响。在此目标中，我们将分析接受Horsene替代疗法前后40名绝经后妇女的MT和单核细胞激活的大小。通过定义肠粘膜完整性，MT和系统性免疫的性别差异的机制，并通过体内证明肠道渗透性，MT，TLR4反应性和单核细胞激活之间的关系，我们将在体内建立此模型的合理性 SLE的发病机理。这些发现具有更广泛的影响，包括疫苗反应，传染病风险和其他自身免疫性疾病的风险。