Systemic immunoregulatory consequences of bacterial translocation during health and disease

自身免疫性肝炎(AIH)是一种慢性、进行性、自体炎症性肝病，通常 对免疫抑制剂无效--AIH患者的唯一治疗选择。肝脏炎症，这会导致 临床AIH阶段被认为是肝组织损伤和纤维化的主要驱动因素。虽然可逆，但在 缺乏治疗的AIH进展为肝硬变和终末期肝病，需要肝移植 在大约10%的案例中。它的确切触发机制和AIH发展的潜在机制尚不清楚 尽管遗传和环境因素发挥着重要作用，但人们还是明白了。当地的肝脏微生物群有 已被确定为调节肝脏病理的一个关键环境因素。的扩展 共生菌如乳杆菌属。在肝脏内与增加的严重程度相关 实验性肝脏病理学和乳杆菌属。在AIH患者的肝脏中是富含的。我们的实验室最近 报道说，鲁氏乳杆菌(L.reuri)易位到内部组织，从而推动全身 缺乏造血表观遗传调节因子TET甲基胞嘧啶双加氧酶2的小鼠的炎症反应 细胞(Tet2VAV小鼠)。我们最近发现，这种小鼠患有AIH，是研究这种疾病的模型系统， 流行病学证据表明，TET2缺陷个体表现出肝脏疾病的基本特征。 AIH背后的致病机制，特别是肝脏微生物群如何驱动它，是 不清楚。干扰素-γ(干扰素-γ)产生TCRCD8T细胞(Tc1细胞)已被证实在中起重要作用 在AIH中的作用。缺失是对来自肝脏微生物区系的关键信号的理解，以及它们如何与 这种致病细胞的诱导。耐人寻味的是，L.reuri有效地将膳食色氨酸(Trp)分解为 芳烃受体(AhR)激动剂吲哚-3-甲醇(I3C)。在狼疮模型中，AhR配体源于 鸡冠埃希菌促进Th17驱动的自身免疫。在这里，基于我们的新数据和来自 文献中，我们提出了一个模型和可检验的假设，解释了路支杆菌是如何促进AIH的。我们将测试我们的 中心假说是罗氏乳杆菌通过释放I3C和/或补给罗氏乳杆菌而促进肝脏Tc1细胞免疫。 两种独立的AIH模型(Tet2VAV小鼠和刀豆蛋白A介导的肝炎)中的特异性Tc1细胞。 此外，我们假设抑制AhR信号转导的治疗方法可以预防L.reuri触发。 Tc1细胞介导的AIH样病理改变。我们将从三个具体目标来研究这一假说。在目标1中，我们将 确定L.reuri来源的I3C是否通过AhR直接作用于CD8T细胞，从而促进Tc1细胞效应器 驱动AIH样病理的功能。在目标2中，我们将定义L.reuri特异性CD8T细胞是否驱动AIH- 就像疾病一样。在目标3中，我们将定义针对CD8 T细胞内AhR信号的治疗方法(膳食 Trp，AhR阻断)在保护AIH样病理中的作用。这些目标将使我们更好地理解 AIH的病理生理学和评估AIH患者的合理治疗干预措施。

Autoimmune hepatitis (AIH) is a chronic, progressive, auto-inflammatory liver disorder that often becomes refractory to immunosuppressants-the sole therapeutic option for AIH patients. Hepatic inflammation, which sets the stage for overt AIH, is considered the main driver of hepatic tissue damage and fibrosis. While reversible, in the absence of treatment AIH progresses to cirrhosis and end stage liver disease, requiring liver transplantation in around 10% of cases. Its exact trigger and the underlying mechanisms by which AIH develops are poorly understood, although genetic and environmental factors play an important role. The local liver microbiome has been identified as one critical environmental factor that modulates hepatic pathology. The expansion of commensal bacteria such as Lactobacilli spp. within the liver is associated with an increased severity of experimental liver pathology, and Lactobacilli spp. are enriched in livers of AIH patients. Our lab recently published that Lactobacillus reuteri (L. reuteri) translocates to internal tissues and thereby drives systemic inflammation in mice that lack the epigenetic regulator Tet methylcytosine dioxygenase 2 (Tet2) in hematopoietic cells (Tet2VAV mice). We recently found that such mice have AIH and are a model system to study this disease, supported by epidemiological evidence that TET2 deficient individuals display cardinal features of liver disease. The pathogenetic mechanisms underlying AIH, and in particular how the liver microbiome may drive it, are unclear. Interferon- γ (IFN-γ) producing TCR CD8 T cells (Tc1 cells) have been identified to play an essential role in AIH. Missing is an understanding of the key signals from the liver microbiota and how they are linked to the induction of such pathogenic cells. Intriguingly, L. reuteri efficiently catabolizes dietary tryptophan (Trp) to the aryl hydrocarbon receptor (AhR) agonist indole-3-carbinol (I3C). In a lupus model, AhR ligands derived from E. gallinarum promoted Th17-driven autoimmunity. Here, based on our new data and this context from the literature, we propose a model and testable hypothesis explaining how L. reuteri promotes AIH. We will test our central hypothesis that L. reuteri promotes hepatic Tc1 cell immunity by releasing I3C and/or by fueling L. reuteri- specific Tc1 cells in two independent models of AIH (Tet2VAV mice and Concanavalin A-mediated hepatitis). Furthermore, we posit that therapeutic approaches that suppress AhR signaling protect from L. reuteri-triggered Tc1 cell mediated AIH-like pathology. We will investigate this hypothesis in three specific aims. In Aim 1 we will determine whether L. reuteri derived I3C acts directly on CD8 T cells via AhR, which promotes Tc1 cell effector function that drives AIH-like pathology. In Aim 2 we will define whether L. reuteri-specific CD8 T cells drive AIH- like disease. In Aim 3 we will define therapeutic approaches targeting AhR signaling within CD8 T cells (dietary Trp, AhR blockade) in protecting from AIH-like pathology. These aims will lead to a better understanding of the pathophysiology of AIH and assess rationale therapeutic interventions for patients with AIH.