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生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增加炎症性 CD14+CD16++ 单核细胞亚群和增强的单核细胞具有重要的临床意义。女性体内的 TLR 激活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 信号下游细胞因子（例如 IFN-αIL-6、IL-1αTNF-α）在自身免疫性疾病的发病机制中发挥着关键作用，针对特定细胞因子或 TLR 抑制剂的治疗对 SLE 患者和小鼠模型有效。我们认识到，性激素介导的渗透性肠道和由此产生的 MT 幅度的增加是促炎细胞因子产生、单核细胞激活和自身免疫性疾病中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提供重要的见解。针对自身免疫性疾病和其他具有性别差异的疾病（例如丙型肝炎和艾滋病毒）开发针对性别的干预措施。 MT 中基于性别的差异为分析 MT 和改变的先天免疫反应对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——健康女性中的 MT 或改变的 TLR 反应会导致持续的免疫激活和促炎细胞因子，并且第 13 种炎症会导致 SLE 的易感性和 Thief 病活性增强——这是一种治疗策略。 （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的免疫力/耐受性。 具体目标 1：确定性激素在肠道通透性中的作用以及微生物产物易位的程度。我们的体内和体外健康对照和 SLE 患者的初步数据表明，绝经前妇女的血浆总细菌 rDNA 水平较高，这是 MT 的标志物。体内，与男性和绝经后女性相比，为了了解血浆和肠道微生物产物对系统免疫和 SLE 的影响，我们将通过血浆中的宏基因组测序来分析微生物遗传潜力。具体目标 2：确定性激素在体内的作用。 TLR4 反应性和单核细胞激活。我们将评估女性的肠道通透性和单核细胞激活。分析 MT、TLR4 反应性、单核细胞活化、性激素水平和 SLE 疾病活动之间的相关性/相关性 具体目标 3：确定雌激素对绝经后妇女群体肠道通透性和单核细胞活化的影响。我们将通过定义肠道性别差异的机制来分析 40 名绝经后女性接受激素替代治疗前后 MT 和单核细胞活化的程度。粘膜完整性、MT 和全身免疫，并通过证明肠道通透性、MT、TLR4 反应性和体内单核细胞激活之间的关系，我们将在体内建立该模型的合理性 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。