Sex Differences in Gut Permeability; Impact on Autoimmunity

描述(由申请人提供)： 女性肠道微生物产物易位(MT)和肠道通透性的较大程度可能对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。女性炎症CD14+CD16+单核细胞亚群的增加和单核细胞活化的增强可能改变这些细胞对细菌和病毒感染以及对TLR激动剂的效应反应，导致女性比男性更容易患上自身免疫性疾病。TLR和TLR信号下游的细胞因子(如干扰素-�、IL-6、IL-1、�、肿瘤坏死因子-�)在自身免疫性疾病的发病机制中起关键作用，而针对特定细胞因子或TLR抑制剂的治疗对SLE患者和小鼠模型是有效的。我们假设，性激素介导的通透性肠道和由此导致的MT增加是自身免疫性疾病中促炎细胞因子产生、单核细胞激活和性别偏见的根本驱动因素。了解这些机制可能会为针对自身免疫性疾病和其他具有性别差异的疾病(如丙型肝炎和艾滋病毒)制定针对性别的干预措施提供至关重要的见解。MT的性别差异为分析MT和改变的先天免疫反应在获得性免疫和体内疾病发病机制中的作用提供了一个模型。如果我们的假设是正确的--即健康女性MT升高或TLR反应性改变会导致持续免疫激活和促炎细胞因子增加，而炎症增加导致SLE易感性增加和疾病活动增加，那么治疗策略(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，从而帮助重建自身免疫性疾病的正常免疫/耐受。具体目的1：确定性激素在健康对照和SLE患者体内和体外肠道通透性和微生物产物移位中的作用。我们的初步数据显示，与男性和绝经后女性相比，绝经前女性的血浆总细菌rDNA水平更高，这是体内MT的标志。为了了解来自血浆和肠道的微生物产物对系统免疫和SLE的影响，我们将通过血浆中的元基因组测序来分析微生物的遗传潜力。特异性目的2：确定性激素在TLR4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、TLR4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。具体目的3：确定雌激素对绝经后妇女队列中肠道通透性和单核细胞活化的影响。为此，我们将分析40名绝经后妇女在接受激素替代治疗前后MT和单核细胞的激活程度。通过定义肠道粘膜完整性、MT和系统免疫方面的性别差异的机制，以及通过在体内证明肠道通透性、MT、TLR4反应性和单核细胞激活之间的关系，我们将在 系统性红斑狼疮的发病机制。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。

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.