Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
PLoS One. 2021 Aug 5;16(8):e0255574. doi: 10.1371/journal.pone.0255574. eCollection 2021.
In alcoholic hepatitis (AH), dysfunctional T lymphocytes may contribute to the high mortality from infections. T lymphocyte activation is governed by the expression of co-stimulatory receptors such as 4-1BB balanced by inhibitory receptors such as Programmed Death receptor 1 (PD-1). 4-1BB expression is unaccounted for in AH, while PD-1 is elevated. We characterized expression of 4-1BB and PD-1 and the associated T lymphocyte functional status in AH and investigated whether these were associated with short-term mortality.
Thirty-five patients with AH (at diagnosis and days 7 and 90) were compared with healthy controls (HC). Spontaneous and in vitro stimulated receptor expression were quantified by flow cytometry, and plasma proteins by ELISA.
At diagnosis, the patients showed increased stimulated 4-1BB responses of CD4+ T lymphocytes. Also, the frequencies of PD-1+ T lymphocytes both with and without co-expressed 4-1BB were increased. Further, interferon-gamma was predominantly produced in T lymphocytes co-expressing 4-1BB. A decrease in the frequency of spontaneous 4-1BB+ T lymphocytes and an increase in soluble 4-1BB during the first week after diagnosis were associated with higher mortality at day 90 in AH. PD-1 expression showed no systematic dynamics related to mortality.
We found an increased stimulated 4-1BB response of T lymphocytes in AH and early loss of these lymphocytes was associated with a higher short-term mortality. This suggests a role of T lymphocyte 4-1BB expression in the progression of AH.
在酒精性肝炎（AH）中，功能失调的 T 淋巴细胞可能导致感染相关的高死亡率。T 淋巴细胞的激活受共刺激受体（如 4-1BB）的表达调控，而共刺激受体又受到抑制性受体（如程序性死亡受体 1（PD-1））的平衡。AH 中未考虑到 4-1BB 的表达，而 PD-1 则升高。我们描述了 AH 中 4-1BB 和 PD-1 的表达及其相关的 T 淋巴细胞功能状态，并研究了这些是否与短期死亡率相关。
将 35 例 AH 患者（诊断时以及第 7 天和第 90 天）与健康对照（HC）进行比较。通过流式细胞术定量检测自发和体外刺激的受体表达，并通过 ELISA 检测血浆蛋白。
在诊断时，患者表现出 CD4+T 淋巴细胞刺激后 4-1BB 反应增加。此外，PD-1+T 淋巴细胞的频率增加，无论是单独表达还是共表达 4-1BB。此外，在共表达 4-1BB 的 T 淋巴细胞中主要产生干扰素-γ。诊断后第一周内，自发 4-1BB+T 淋巴细胞频率下降和可溶性 4-1BB 增加与 AH 第 90 天的死亡率升高相关。PD-1 表达没有与死亡率相关的系统动态变化。
我们发现 AH 中 T 淋巴细胞的刺激 4-1BB 反应增加，早期这些淋巴细胞的丢失与短期死亡率升高相关。这表明 T 淋巴细胞 4-1BB 表达在 AH 的进展中起作用。
