Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California at Davis, Davis, CA, USA.
J Autoimmun. 2019 Sep;103:102293. doi: 10.1016/j.jaut.2019.06.004. Epub 2019 Jun 27.
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease with an immunopathogenesis that includes highly differentiated cytotoxic T cell infiltration in portal areas. We have taken advantage of a large and well-defined cohort of patients with PBC, AIH, chronic hepatitis virus, and healthy controls to study for the presence of highly differentiated T cells which express the killer cell lectin-like receptor G1 (KLRG1). Such studies were performed using both liver and peripheral blood mononuclear cells. In particular, gene expression data (GSE79850) from 16 PBC patients stratified according to future risk of liver transplantation were analyzed for markers of highly differentiated cytotoxic T cells. Liver biopsy samples from 44 PBC patients were studied by immunohistochemistry and a separate cohort of PBC blood samples were studied by flow cytometry. Gene expression data demonstrated correlation of increased KLRG1 and cytotoxic lymphocyte molecules, such as granzyme B (GZMB) and perforin (PRF1), to disease severity as measured by future risk of liver transplantation. Immunohistochemistry demonstrated abundant infiltration of KLRG1+ cells into liver portal areas (mean of 45% of infiltrating cells, range 25-75%) positively correlated with hepatic inflammatory (r = 0.47, p = 0.001) and hepatic fibrosis (r = 0.34, p = 0.021) scores. KLRG1+ lymphocyte liver portal area infiltration was positively correlated with serum alkaline phosphatase (r = 0.45, p = 0.005) and GGT (r = 0.40, p = 0.014), and AST (r = 0.35, p = 0.033) levels. Mononuclear blood flow cytometry studies showed KLRG1+ lymphocytes had greater levels of cytotoxic molecules (granzyme B and perforin), inflammatory cytokines (IFN-γ and TNF-α) and inflammatory chemokine receptors (CCR5 and CX3CR1) than KLRG1-counterparts. However, clearly the most significant data was that found in liver with the intense portal infiltrates that are unique to PBC. Conclusion: Highly cytotoxic KLRG1+ lymphocytes have invaded PBC liver portal areas. Liver KLRG1 gene expression and the abundance of KLRG1+ lymphocytes are positively correlated with disease biomarkers used as clinical trial outcome measures (liver transplantation and serum alkaline phosphatase), suggesting the targeting of KLRG1+ lymphocytes as a rational approach for PBC therapeutic drug development.
原发性胆汁性胆管炎（PBC）是一种慢性自身免疫性肝病，其免疫发病机制包括门脉区高分化细胞毒性 T 细胞浸润。我们利用一个由大量明确的 PBC、AIH、慢性肝炎病毒和健康对照患者组成的队列，来研究表达杀伤细胞凝集素样受体 G1（KLRG1）的高分化 T 细胞的存在情况。使用肝和外周血单个核细胞进行了此类研究。特别是，根据未来肝移植风险对 16 名 PBC 患者进行分层，对其基因表达数据（GSE79850）进行了分析，以寻找高分化细胞毒性 T 细胞的标志物。对 44 名 PBC 患者的肝活检样本进行免疫组织化学研究，对另一批 PBC 血液样本进行流式细胞术研究。基因表达数据表明，KLRG1 和细胞毒性淋巴细胞分子（如颗粒酶 B（GZMB）和穿孔素（PRF1））的增加与未来肝移植风险所衡量的疾病严重程度相关。免疫组织化学显示，大量 KLRG1+细胞浸润肝门区（浸润细胞的平均值为 45%，范围为 25-75%）与肝炎症（r=0.47，p=0.001）和肝纤维化（r=0.34，p=0.021）评分呈正相关。KLRG1+淋巴细胞肝门区浸润与血清碱性磷酸酶（r=0.45，p=0.005）和 GGT（r=0.40，p=0.014）以及 AST（r=0.35，p=0.033）水平呈正相关。单核细胞血流细胞术研究表明，KLRG1+淋巴细胞具有更高水平的细胞毒性分子（颗粒酶 B 和穿孔素）、炎症细胞因子（IFN-γ 和 TNF-α）和炎症趋化因子受体（CCR5 和 CX3CR1），而 KLRG1 对应的淋巴细胞则没有。然而，最显著的数据显然是在 PBC 特有的肝门浸润的肝中发现的。结论：高细胞毒性 KLRG1+淋巴细胞已浸润 PBC 肝门区。肝 KLRG1 基因表达和 KLRG1+淋巴细胞的丰度与用作临床试验终点测量的疾病生物标志物（肝移植和血清碱性磷酸酶）呈正相关，这表明靶向 KLRG1+淋巴细胞是 PBC 治疗药物开发的合理方法。
Zotero 插件