Sun Keshuai, Ma Shuoyi, Tian Siyuan, Zhang Miao, Liu Yansheng, Li Bo, Zhou Xia, Zheng Xiaohong, Zhou Xinmin, Wang Lu, Han Ying
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China.
Ann Transl Med. 2021 Jan;9(2):101. doi: 10.21037/atm-20-2427.
Primary biliary cholangitis (PBC) is an immune-mediated chronic cholestasis, in which T cell homeostasis plays an important role. Lysosomal-associated membrane protein 2 isoform A (LAMP-2A) has been implicated in the regulation of CD4T cell responses.
We comprehensively evaluated the immunobiology of CD4T cells in patients with PBC (PBC, n=42), chronic hepatitis B (CHB, n=20), and healthy control subjects (HC, n=20) by flow cytometry including activation status and LAMP-2A expression. Additionally, we investigated the activation responses of PBC-naïve CD4T cells by stimulation and tested the changes caused by deleting the gene encoding LAMP-2A.
Firstly, we found an increased activation status of circulating CD4T cells from PBC patients compared to the HC subjects, and PBC-naïve CD4T cells showed enhanced responses after stimulation . Secondly, PBC-naïve CD4T cells expressed a significantly higher level of LAMP-2A compared to the HC and CHB groups [PBC HC, 1,954.74 (1,254.28-3,057.14) 1,542.12 (961.18-2,277.98), P=0.03; CHB, 1,153.59 (726.87-1,275.48), P=0.02], and the overreactions of PBC-naïve CD4T cells could be reversed by interfering with LAMP-2A expression . Thirdly, the LAMP-2A expression level of PBC-naïve CD4T cells was related to disease severity and drug response.
An abnormally increased LAMP-2A expression of PBC-naïve CD4T cells might be related to excessive activation responses. LAMP-2A could be a novel therapeutic target for the treatment of PBC by reversing excessive responses and consequently reducing biliary injury.
原发性胆汁性胆管炎（PBC）是一种免疫介导的慢性胆汁淤积症，其中T细胞稳态起着重要作用。溶酶体相关膜蛋白2同工型A（LAMP-2A）与CD4T细胞反应的调节有关。
我们通过流式细胞术全面评估了PBC患者（PBC，n = 42）、慢性乙型肝炎患者（CHB，n = 20）和健康对照者（HC，n = 20）中CD4T细胞的免疫生物学特性，包括激活状态和LAMP-2A表达。此外，我们通过刺激研究了PBC初治CD4T细胞的激活反应，并测试了删除编码LAMP-2A的基因所引起的变化。
首先，我们发现与HC受试者相比，PBC患者循环CD4T细胞的激活状态增加，并且PBC初治CD4T细胞在刺激后显示出增强的反应。其次，与HC和CHB组相比，PBC初治CD4T细胞表达的LAMP-2A水平显著更高[PBC对HC，1,954.74（1,254.28 - 3,057.14）对1,542.12（961.18 - 2,277.98），P = 0.03；对CHB，1,153.59（726.87 - 1,275.48），P = 0.02]，并且通过干扰LAMP-2A表达可以逆转PBC初治CD4T细胞的过度反应。第三，PBC初治CD4T细胞的LAMP-2A表达水平与疾病严重程度和药物反应相关。
PBC初治CD4T细胞中LAMP-2A表达异常增加可能与过度激活反应有关。LAMP-2A可能是通过逆转过度反应从而减少胆汁损伤来治疗PBC的新治疗靶点。
