Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, Belgium; Université Libre de Bruxelles, Laboratory of Experimental Gastroenterology, Brussels, Belgium.
Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, Belgium.
J Hepatol. 2020 Aug;73(2):303-314. doi: 10.1016/j.jhep.2020.02.017. Epub 2020 Mar 4.
BACKGROUND & AIMS: Severe forms of alcohol-related liver disease are associated with increased susceptibility to infections which are associated with poor prognosis. The cellular and molecular mechanisms responsible for this altered host defense are incompletely understood.
We performed whole blood phenotypic analysis and ex vivo stimulation with various pathogen-associated molecular patterns (PAMPs). We included 34 patients with alcohol-related cirrhosis (18 of whom had biopsy-proven severe alcoholic hepatitis [sAH]), 12 healthy controls and 11 patients with chronic alcohol consumption without significant liver disease. We also evaluated the transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiles of CD14 monocytes from a subset of patients.
Circulating monocytes and conventional dendritic cells (DCs) from patients with sAH displayed complex alterations characterized by increased expression of both activating and inhibitory surface markers and an impaired pro-inflammatory response upon stimulation with PAMPs representative of gram-negative bacteria (lipopolysaccharide, Pam3CSK4) or fungal pathogens (Zymosan). Their decreased ability to produce more than 1 cytokine (polyfunctionality) upon PAMP stimulation correlated with the risk of developing infection at 28 days or mortality at 90 days. The presence of acute-on-chronic liver failure in patients with sAH did not significantly modify the immune profile of monocytes and DCs. Moreover, CD14 monocytes of patients with sAH displayed altered transcriptional and epigenomic profiles characterized by downregulation of key innate immune and metabolic pathways and upregulation of important immunomodulatory factors.
In patients with sAH, the altered transcriptional program and functional properties of monocytes that contribute to patients' susceptibility to infection have strong epigenetic determinants.
Patients with severe alcoholic hepatitis are at increased risk of infections, which contribute to the poor prognosis associated with the disease. Herein, we show that epigenetic determinants underly the immune cell dysfunction and inappropriate responses to pathogens that are associated with severe alcoholic hepatitis.
严重的酒精相关肝病与感染易感性增加有关，而感染与预后不良有关。导致这种宿主防御改变的细胞和分子机制尚不完全清楚。
我们进行了全血表型分析和用各种病原体相关分子模式（PAMPs）进行的离体刺激。我们纳入了 34 例酒精性肝硬化患者（其中 18 例有活检证实的严重酒精性肝炎[sAH]）、12 名健康对照者和 11 例无明显肝脏疾病的慢性酒精摄入患者。我们还评估了来自部分患者的 CD14 单核细胞的转录组（RNA-seq）和染色质可及性（ATAC-seq）图谱。
sAH 患者的循环单核细胞和常规树突状细胞（DCs）表现出复杂的改变，其特征为激活和抑制表面标志物的表达增加，以及用革兰氏阴性菌（脂多糖、Pam3CSK4）或真菌病原体（酵母聚糖）代表的 PAMP 刺激时促炎反应受损。它们在 PAMP 刺激下产生超过 1 种细胞因子的能力（多功能性）下降与 28 天内发生感染或 90 天内死亡的风险相关。sAH 患者的慢加急性肝衰竭的存在并未显著改变单核细胞和 DCs 的免疫表型。此外，sAH 患者的 CD14 单核细胞表现出改变的转录和表观基因组谱，其特征为关键固有免疫和代谢途径下调以及重要免疫调节因子上调。
在 sAH 患者中，导致患者易感染的单核细胞改变的转录程序和功能特性具有强烈的表观遗传决定因素。
严重酒精性肝炎患者感染风险增加，这导致与该疾病相关的预后不良。在此，我们表明，严重酒精性肝炎相关的免疫细胞功能障碍和对病原体的不当反应的潜在表观遗传决定因素。
