Immunological Profiles and prognostic outcomes in patients with alcoholic hepatitis

项目摘要 酒精性肝炎是美国发病率和死亡率的主要原因。尽管它的复杂 在发病机制中，疾病过程中的关键驱动因素之一是先天性和适应性免疫系统的改变， 继发于过量饮酒的反应。这份申请是为了响应 酒精性肝炎临床和转化网络-转化研究（RFA-AA-18-003）。目标 我们的应用是为了更好地了解先天性和适应性免疫在免疫系统中的作用和机制。 酒精性肝炎的发病机制，因为这可能有助于我们确定新的治疗靶点，以治疗这种严重的 ALD的形式。提出了两个具体目标：目标1：确定以下因素的影响和预后意义： 微生物易位、免疫失调对AH患者疾病严重程度和预后的影响。在 为此，我们假设（i）免疫失调状态对基线疾病有影响， AH患者的严重程度和长期结局，以及（ii）随访期间持续的免疫激活 尽管禁欲，但对AH患者的结局有不利影响。我们发现乙醇引发 外周血单核细胞用于LPS诱导的炎症反应。在子目标#1.1中，我们将执行 对基线肠道通透性、微生物易位、免疫细胞、 在健康对照、无肝病的艾德和具有AH的那些中的活化/炎症。我们还发现 血浆IL-8，一种有效的中性粒细胞趋化因子，在AH患者中显著升高。感应 中性粒细胞的释放导致肝脏炎症/损伤， 从肝细胞的微粒（MP）;永久嗜中性粒细胞和肝损伤。在分目标1.2中，我们将 目的探讨IL-8和线粒体DNA（mitochondrial-DNA，mt-DNA）在AH中的作用及临床意义。 目的#2：确定滤泡辅助性T细胞改变的机制和意义， 啊关于酒精如何影响适应性免疫系统，人们知之甚少，尽管酒精会增加免疫系统的风险。 过度饮酒者的感染。滤泡性T辅助细胞（TFH）是一种CD 4 T细胞谱系 仅见于次级淋巴器官的生发中心反应。TFH的特殊功能 细胞是选择生发中心产生高亲和力抗体的B细胞。我们新颖的初步数据 首次显示了过量饮酒和ALD对循环TFH（cTFH）细胞的影响。在这 目的，我们假设过量饮酒导致cTFH细胞分化改变， 这些对cTFH细胞的作用增强并影响AH患者的存活结果。我们将测试 （i）AH患者具有cTFH细胞的失调，（ii）AH患者具有T细胞内源性或T细胞外源性 改变cTFH细胞分化的缺陷，和（iii）AH患者具有异常的B细胞应答继发性 cTFH细胞中的失调。我们的研究结果可能为AH的治疗提供线索， 与AH发病机制相关的免疫途径。

Project Summary Alcoholic hepatitis is a leading cause of morbidity and mortality in the US. Despites its complicated pathogenesis, one of the key drivers in the disease process is the alterations in the innate and adaptive immune responses secondary to excessive alcohol use. This application is in response to the funding opportunity “Alcoholic hepatitis clinical and translational network – translational research (RFA-AA-18-003)”. The goal of our application is to better understand the role and mechanism of innate and adaptive immunity in the pathogenesis of alcoholic hepatitis, as this may help us identify novel therapeutic targets to treat this severe form of ALD. Two specific aims are proposed: Aim# 1: Determine the impact and prognostic significance of microbial translocation, immune dysregulation on the disease severity and outcomes in patients with AH. In this aim, we hypothesized that (i) the state of immune dysregulation has the impact on baseline disease severity and long term outcome of patients with AH and (ii) persistent immune activation during the follow up despite abstinence is adversely affected outcomes of patients with AH. We found that ethanol primes peripheral blood mononuclear cells for LPS-induced inflammatory responses. In sub-aim#1.1, we will perform a detail cross sectional/longitudinal analysis on baseline gut permeability, microbial translocation, immune cell activation/inflammation in healthy controls, ED without liver diseases, and those with AH. We also found that plasma IL-8, a potent chemokine for neutrophils, were markedly elevated in patients with AH. The induction of neutrophils leads to hepatic inflammation/injury with the release of mitochrondrial-DNA containing microparticles (MPs) from the hepatocytes; perpetuating neutrophilia and liver injury. In sub-aim#1.2, we will determine the role and clinical significance of IL-8 and mitochrondrial-DNA (mt-DNA) in patients with AH. Aim#2: Determine the mechanism and significance of alteration in follicular helper T cells in patients with AH. Little is known about how alcohol affects the adaptive immune system, despite the increase risk of infections among those with excessive alcohol use. Follicular T helper (TFH) cells are a CD4 T cell lineage uniquely found in the germinal center reaction of secondary lymphoid organs. The specific function of TFH cells is to select B cells in the germinal center that produce high-affinity Abs. Our novel preliminary data showed, for the first time, on the effect of excessive drinking and ALD on circulating TFH (cTFH) cells. In this aim, we hypothesized that excessive alcohol consumption leads to altered cTFH cell differentiation, and that these effects on cTFH cells are augmented and impacted survival outcomes in patients with AH. We will test that (i) AH patients have dysregulation of cTFH cells, (ii) AH patients have T cell-intrinsic or T cell-extrinsic defects that alter cTFH cell differentiation, and, and (iii) AH patients have abnormal B cell responses secondary to dysregulation in cTFH cells. Our results may shed light on the treatment of AH by targeting specific immunological pathways linking to the pathogenesis of AH.