Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
Transplant Services, Children's Healthcare of Atlanta (CHOA), Atlanta, GA, USA.
Autoimmunity. 2020 Aug;53(5):253-260. doi: 10.1080/08916934.2020.1755964. Epub 2020 May 6.
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. 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. In the AIH group, those with active disease demonstrated a significantly higher sPD1 levels in comparison to responders (* > .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 (* < .002), whereas, patients with PSC in conjunction with AIH (* < .006) or IBD (* < .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. 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.
免疫介导的肝脏疾病包括广泛的类别，这些疾病与儿科人群的发病率和死亡率增加有关。程序性死亡 1（PD1）是一种主要由 T 细胞表达的抑制性受体，当被激活时会作为可溶性 PD1（sPD1）释放到血浆中。本研究的目的是评估自身免疫性肝炎（AIH）、原发性硬化性胆管炎（PSC）、AIH 和 PSC 重叠、炎症性肠病（IBD）单独以及并发 PSC/IBD 和 AIH/IBD 患儿血浆中 sPD1 水平，以鉴定反应或预测缓解与复发的生物标志物。采集了 41 名儿科患者的血浆样本。根据对标准治疗的反应，将 AIH 患者进一步分为活动期、不完全应答者和应答者。测量并比较了 PSC、PSC/AIH、IBD 单独、PSC/IBD 和 AIH/IBD 患者之间以及活动 AIH、不完全应答者和应答者之间的 sPD1 水平。进行流式细胞术进一步分析 CD45RA+、CD3CD4、CD8、CCR7、CXCR3、CD38 和 PD1。在 AIH 组中，与应答者相比，活动期疾病患者的 sPD1 水平显著升高（* > .001）。然而，不完全应答者与活动 AIH 和单独 IBD 患者相比，sPD1 没有降低。有趣的是，与活动 AIH 相比，PSC 患者的 sPD1 水平显著降低（* < .002），而 PSC 合并 AIH（* < .006）或 IBD（* < .02）患者的 sPD1 水平显著升高。此外，我们观察到活动 AIH 中循环 CD4 和 CD8 结合的 PD1 水平增加，但 PSC 或应答者中未观察到，提示 T 细胞激活。CD4+PD1 双阳性细胞表现出 CXCR3 表达增加。因此，提示 PD1+T 细胞的激活是通过 CXCR3 在自身免疫性肝炎中介导的。我们的研究表明，sPD1 水平与 AIH 和 IBD 的活动疾病状态相关。sPD1 水平与 PSC 不相关。然而，PSC 合并 AIH 或 IBD 显示出更高水平的 sPD1。这表明 T 细胞激活在活动 AIH 和 IBD 中起着关键作用，但在 PSC 中不起作用。可溶性 PDI 水平可作为评估 AIH 患者反应的临床生物标志物，并前瞻性监测 PSC 患者发展为 IBD 或 AIH 的情况。
