Objective Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR− myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. Design Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15−CD11b+HLA-DR− cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. Results Circulating CD14+CD15−CD11b+HLA-DR− M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. Conclusion Immunosuppressive CD14+HLA-DR− M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.

中文翻译：

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CD14 + CD15 - HLA-DR - 髓源性抑制细胞损害急性-慢性肝衰竭患者的抗菌反应

目的 急性慢性肝衰竭 (ACLF) 患者的免疫麻痹是感染易感性和死亡率增加的原因。免疫抑制性单核 CD14+HLA-DR− 髓源性抑制细胞 (M-MDSCs) 最近已被鉴定为平息免疫介导疾病中的抗菌反应。我们试图描述 M-MDSC 在 ACLF 患者中的功能和来源，并探索增强抗菌反应的潜在目标。设计 将 ACLF 患者 (n=41) 与健康受试者 (n=25) 和肝硬化患者 (n=22) 或急性肝功能衰竭 (n=30) 进行比较。根据 M-MDSC 的定义鉴定 CD14+CD15-CD11b+HLA-DR-细胞，并进行详细的免疫表型分析。通过混合淋巴细胞反应评估 T 细胞活化的抑制。先天免疫功能的评估包括响应 Toll 样受体（TLR-2、TLR-4 和 TLR-9）刺激的细胞因子表达和使用流式细胞术和活细胞成像技术的吞噬作用测定。结果 ACLF患者（55%的CD14+细胞）循环CD14+CD15-CD11b+HLA-DR-M-MDSCs显着扩增。M-MDSC 显示免疫抑制特性，显着降低 T 细胞增殖（p = 0.01），响应 TLR 刺激产生更少的肿瘤坏死因子-α/白细胞介素-6（所有 p<0.01），并减少大肠杆菌的细菌摄取（p <0.001)。在疾病演变过程中 HLA-DR 的持续低表达与继发感染和 28 天死亡率有关。反复的 TLR-2 和 TLR-4 刺激在体外扩大了 M-MDSC。相比之下，TLR-3 激动在体外重建了 HLA-DR 表达和先天免疫功能。结论 免疫抑制性 CD14+HLA-DR-M-MDSCs 在 ACLF 患者中扩增。它们通过抑制 T 细胞功能、减弱抗菌先天免疫反应、与继发感染、疾病严重程度和预后相关来描述。TLR-3 激动剂逆转 M-MDSC 扩增和先天免疫功能，值得进一步评估作为潜在的免疫治疗剂。