Aarslev Kristian, Dige Anders, Greisen Stinne R, Kreutzfeldt Martin, Jessen Niels, Vilstrup Hendrik, Deleuran Bent, Grønbæk Henning
a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.
b Department of Biomedicine , Aarhus University , Aarhus C , Denmark.
Scand J Gastroenterol. 2017 Jan;52(1):93-99. doi: 10.1080/00365521.2016.1233576. Epub 2016 Sep 23.
Autoimmune hepatitis (AIH) is a chronic liver disease caused by impaired immune regulation. Programmed death-1 (PD-1) is an inhibitory receptor mainly expressed by T cells and with its ligands, PD-L1 and PD-L2 present on antigen-presenting cells. We hypothesised the PD-1 axis to be impaired in AIH and investigated systemic levels of soluble(s) PD-1 and T cells ability to up-regulate PD-1 following in vitro activation in AIH patients.
We included 67 AIH patients; 9 with active disease, 31 responders and 27 incomplete-responders to standard therapy. Forty-seven healthy controls (HC) were included for comparison. Soluble PD-1 was measured by enzyme-linked immunosorbent assay. The PD-1 expression on T cells was measured using flow cytometry before and after 48-h stimulation in vitro with CD3/CD28 in 13 AIH patients and 10 HC.
Soluble PD-1 was significantly elevated in AIH patients with active disease [0.24 ng/mL (range 0.16-0.28)] and in incomplete responders to standard therapy [0.17 (0.11-0.22)] compared with responders [0.11 (0.08-0.16), p = .008 and p = .01, respectively] and HC [0.12 (0.05-0.16), p = .02, both]. Following in vitro activation, PD-1 was significantly up-regulated (3.3-fold) on CD4 T cells from AIH patients compared with HC (1.5-fold) (p = .0006).
AIH patients with active disease and incomplete response to standard treatment have similarly increased sPD-1 levels. Further, AIH patients have increased ability to up-regulate PD-1 following in vitro activation. Together these data suggests an impaired PD-1 axis in AIH.
自身免疫性肝炎（AIH）是一种由免疫调节受损引起的慢性肝病。程序性死亡受体1（PD-1）是一种主要由T细胞表达的抑制性受体，其配体PD-L1和PD-L2存在于抗原呈递细胞上。我们推测AIH患者的PD-1轴存在缺陷，并研究了AIH患者中可溶性（s）PD-1的全身水平以及体外激活后T细胞上调PD-1的能力。
我们纳入了67例AIH患者，其中9例为活动性疾病患者，31例对标准治疗有反应者，27例对标准治疗反应不完全者。纳入47名健康对照者（HC）进行比较。采用酶联免疫吸附测定法检测可溶性PD-1。在13例AIH患者和10名HC中，用CD3/CD28体外刺激48小时前后，采用流式细胞术检测T细胞上的PD-1表达。
与有反应者[0.11（0.08-0.16），p = 0.008]和HC[0.12（（0.05-0.16），p = 0.02]相比，活动性疾病的AIH患者[0.24 ng/mL（范围0.16-0.28）]和标准治疗反应不完全者[0.17（0.11-0.22）]的可溶性PD-1显著升高。体外激活后，与HC（1.5倍）相比，AIH患者CD4 T细胞上的PD-1显著上调（3.三倍）（p = 0.0006）。
活动性疾病且对标准治疗反应不完全的AIH患者的sPD-1水平同样升高。此外，AIH患者在体外激活后上调PD-1的能力增强。这些数据共同表明AIH患者的PD-1轴存在缺陷。
