Sex Differences in Gut Permeability; Impact on Autoimmunity

肠道渗透性的性别差异；

• 批准号: 8958705
• 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/8958705
• 关键词: Agonist; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmunity; Bacterial Infections; CD14 gene; Cells; 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/HCV; 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; 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; child bearing; cohort; cytokine; disorder risk; gender difference; immune activation; in vivo; inhibitor/antagonist; insight; men; metagenomic sequencing; microbial; microbiome; monocyte; mouse model; 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）： 女性肠道微生物产物易位（MT）和肠道通透性的增加可能对发展自身免疫性疾病的风险以及对感染的抵抗力和对疫苗的反应具有重要的临床意义。女性中炎性CD 14 + CD 16 ++单核细胞亚群的增加和单核细胞活化的增强可能会改变这些细胞对细菌和病毒感染以及TLR激动剂的效应反应，导致女性与男性相比对自身免疫性疾病的易感性增加。TLR和TLR信号传导下游细胞因子（例如，IFN-γ、IL-6、IL-1、TNF-γ在自身免疫性疾病的发病机制中起关键作用，针对特定细胞因子或TLR抑制剂的治疗在SLE患者和小鼠模型中是有效的。我们假设性激素介导的可渗透性肠道和由此产生的MT增加幅度是促炎细胞因子产生、单核细胞活化和自身免疫性疾病性别偏见的基本驱动因素。了解这些机制可能会为自身免疫性疾病和其他共享性别差异的疾病（如丙型肝炎和艾滋病毒）的性别特异性干预措施的发展提供至关重要的见解。MT的性别差异为分析MT和改变的先天免疫应答对体内适应性免疫和疾病发病机制的影响提供了模型。如果我们的假设是正确的-健康女性中MT反应性的增强或TLR反应性的改变导致持续免疫激活和促炎细胞因子的增强，并且炎症的增强导致SLE易感性的增强和疾病活动性的增强-一种治疗策略（例如，粘膜保护剂/微生物）可能有助于逆转高水平的持续性炎症，从而有助于在自身免疫性疾病中重建正常免疫/耐受。具体目标1：确定性激素在肠道通透性中的作用以及健康对照和SLE患者体内和体外微生物产物易位的幅度。我们的初步数据表明，绝经前妇女有较高的血浆水平的总细菌rDNA，在体内MT的标志物，男性和绝经后妇女相比。为了了解来自血浆和肠道的微生物产物对全身免疫和系统性红斑狼疮的影响，我们将通过血浆中的宏基因组测序来分析微生物的遗传潜力。具体目的2：确定性激素在TLR 4反应性和单核细胞活化中的作用。我们假设肠道通透性和MT升高导致女性单核细胞活化。我们将评估单核细胞亚群分化和单核细胞的潜在驱动因素。我们将分析MT、TLR 4反应性、单核细胞活化、性激素水平和SLE疾病活动性之间的相关性/相关性。特定目的3：确定雌激素对绝经后妇女肠道通透性和单核细胞活化的影响。在这个目标中，我们将分析MT和单核细胞活化的大小在40名绝经后妇女接受激素替代治疗前后。通过定义肠道粘膜完整性、MT和全身免疫的性别差异机制，并通过证明肠道通透性、MT、TLR 4反应性和体内单核细胞活化之间的关系，我们将建立该模型的可行性， SLE的发病机制。这些发现具有更广泛的意义，包括疫苗反应，传染病风险和其他自身免疫性疾病的风险。