Autoimmunity ( IF 3.5 ) Pub Date : 2020-05-06 , DOI: 10.1080/08916934.2020.1755964 Timothy Hadley 1, 2 , Scott Gillespie 1 , Hillary Espinoza 2 , Jarod Prince 1 , Henning Gronbaek , Shanmuganathan Chandrakasan 1 , Subra Kuguthasan 1 , Vasantha L Kolachala 1 , Nitika A Gupta 1, 2
Introduction: Immune mediated liver diseases entail a broad category which are associated with increased morbidity and mortality amongst the paediatric population. Programmed Death 1 (PD1) is an inhibitory receptor mainly expressed by T cells, and when activated shed into plasma as soluble PD1(sPD1). The AIM of this study was to evaluate sPD1 levels in plasma of paediatric patients with Autoimmune Hepatitis (AIH), Primary Sclerosing Cholangitis (PSC), AIH and PSC overlap, Inflammatory Bowel Disease (IBD) alone, and concurrent PSC/IBD and AIH/IBD in order to identify a biomarker to response or predict relapse verses remission.
Methods: Plasma samples were collected from 41 paediatric patients. AIH patients were further categorized into active, incomplete responders and responders, based on response to standard therapy. sPD1 levels were measured and compared between PSC, PSC/AIH, IBD alone, PSC/IBD and AIH/IBD patients and between active AIH, incomplete responders and responders. Flow cytometry was performed to further analyze CD45RA+, CD3CD4, CD8, CCR7, CXCR3, CD38 and PD1.
Results: In the AIH group, those with active disease demonstrated a significantly higher sPD1 levels in comparison to responders (*p > .001). However, the incomplete responders didn’t show a reduction in sPD1 in comparison to active AIH and patients with IBD alone. Interestingly, patients with PSC showed significantly lower level of sPD1 compared to active AIH (*p < .002), whereas, patients with PSC in conjunction with AIH (*p < .006) or IBD (*p < .02) demonstrated a significant increase in sPD1. In addition, we have observed increased levels of circulating CD4 and CD8 bound PD1 in active AIH but not in PSC or responders suggesting T cells activation. CD4+ PD1 double positive cells demonstrated increased expression of CXCR3. Thus, suggesting the activation of PD1 + T cells is mediating through CXCR3 in Autoimmune hepatitis.
Conclusions: Our study demonstrates that sPD1 levels correlate with active disease state of AIH and IBD. sPD1 levels did not correlate with PSC. However, PSC in conjunction with AIH or IBD showed higher levels of sPD1. This suggests that T cell activation plays a critical role in active AIH and IBD but not in PSC. Soluble PDI levels could be used as a clinical biomarker to assess response in patients with AIH and for prospectively monitoring PSC patients for development of IBD or AIH.
中文翻译:
在儿童发作的自身免疫性肝炎和炎症性肠病中,可溶性PD1水平随疾病活动而增加。
简介:免疫介导的肝病涉及广泛的类别,与小儿人群的发病率和死亡率增加有关。程序性死亡1(PD1)是主要由T细胞表达的抑制性受体,激活后会以可溶性PD1(sPD1)的形式进入血浆。这项研究的目的是评估患有自身免疫性肝炎(AIH),原发性硬化性胆管炎(PSC),AIH和PSC重叠,仅是炎症性肠病(IBD)以及并发PSC / IBD和AIH /的小儿患者血浆中sPD1的水平IBD是为了识别对反应有反应或预测复发与缓解的生物标志物。
方法:从41名儿科患者中收集血浆样本。根据对标准疗法的反应,将AIH患者进一步分为活跃,不完全反应者和反应者。测量并比较了PSC,PSC / AIH,IBD,PSC / IBD和AIH / IBD患者以及活动性AIH,不完全应答者和应答者之间的sPD1水平。进行流式细胞术以进一步分析CD45RA +,CD3CD4,CD8,CCR7,CXCR3,CD38和PD1。
结果:在AIH组中,患有活动性疾病的人与响应者相比,sPD1水平显着更高(* p > .001)。然而,与活动性AIH和仅IBD患者相比,不完全应答者并未显示sPD1降低。有趣的是,与活动性AIH相比,PSC患者的sPD1水平显着降低(* p <.002),而与AIH(* p <.006)或IBD(* p <.02)证明sPD1显着增加。另外,我们已经观察到在活跃的AIH中循环CD4和CD8结合的PD1的水平增加,但在PSC或应答者中则没有提示T细胞活化。CD4 + PD1双阳性细胞显示CXCR3表达增加。因此,提示自身免疫性肝炎中PD1 + T细胞的激活是通过CXCR3介导的。
结论:我们的研究表明sPD1水平与AIH和IBD的活跃疾病状态相关。sPD1水平与PSC不相关。但是,PSC与AIH或IBD一起显示更高的sPD1水平。这表明T细胞活化在活性AIH和IBD中起关键作用,而在PSC中不起作用。可溶性PDI水平可用作临床生物标志物,以评估AIH患者的反应,并前瞻性地监视PSC患者的IBD或AIH的发展。