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摘要: 脓毒症是由感染引起的宿主反应失调，导致危及生命的器官功能障碍的综合征。脓毒症的免疫反应通常分为免疫亢进和免疫抑制两个阶段，免疫抑制被认为是导致患者继发感染和死亡率增加的主要原因。本文综述脓毒症免疫抑制的主要机制，包括免疫细胞的功能障碍、免疫抑制细胞因子的释放、免疫调节细胞的过度活化、免疫检查点的表达增加以及近年来备受关注的表观遗传失调等。同时，也总结了目前现有的及一些新的免疫治疗策略，包括免疫刺激性细胞因子（如GM-CSF、IL-7、IL-15）、免疫检查点抑制剂（如PD-1/PD-L1抗体、CTLA-4抗体、TIM-3抗体）及新兴免疫治疗方法（如间充质干细胞、钙卫蛋白抑制剂、髓样细胞触发受体1抑制剂）。本文聚焦表观遗传调控机制和间充质干细胞等新兴免疫治疗，旨在为脓毒症患者个体化精准免疫治疗提供理论支持。Abstract: Sepsis is a syndrome caused by a dysregulated host response to infection that leads to life-threatening organ dysfunction. The immune response in sepsis is usually divided into two stages: hyperimmunity and immunosuppression. Immunosuppression is considered as the main cause of secondary infection and increased mortality in patients. This article reviews the main mechanisms of immunosuppression in sepsis, including dysfunction of immune cells, release of immunosuppressive cytokines, excessive activation of immunomodulatory cells, increased expression of immune checkpoints, and epigenetic dysregulation that have attracted much attention in recent years. At the same time, it also summarizes the existing and some new immunotherapy strategies. It includes immunostimulatory cytokines （such as GM-CSF, IL-7, IL-15）, immune checkpoint inhibitors （such as PD-1/PD-L1 antibody, CTLA-4 antibody, TIM-3 antibody） and emerging immunotherapy methods （such as mesenchymal stem cells, calprotectin inhibitors, triggering receptor expressed on myeloid cells 1 inhibitors）. This article focuses on epigenetic regulation mechanisms and emerging immunotherapies such as mesenchymal stem cells, aiming to provide theoretical support for individualized precision immunotherapy in patients with sepsis.
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Key words:
- Sepsis /
- Immunosuppression /
- Immunotherapy /
- Epigenetic dysregulation
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图 1 脓毒症免疫抑制的机制
注：IL-4：白细胞介素-4；TGF-β：转化生长因子-β；Th1：1型辅助性T细胞；Th2：2型辅助性T细胞；Treg：调节性T细胞；DC：树突状细胞；M：单核巨噬细胞；M2：M2型巨噬细胞；MDSCs：髓源性抑制细胞；NK：自然杀伤细胞；T cell：T淋巴细胞；PD-1/PD-L1：程序性细胞死亡受体-1/程序性死亡配体-1；LAG-3：淋巴细胞活化基因-3；CTLA-4：细胞毒性T淋巴细胞抗原-4；TIM-3：T细胞免疫球蛋白及黏蛋白分子-3；MHC-II：主要组织相容性复合体II；Me：甲基化；Ac：乙酰化；HMT：组蛋白甲基转移酶；HDM：组蛋白去甲基化酶；HAT：组蛋白乙酰转移酶；HDAC：组蛋白去乙酰化酶；DNMT：DNA甲基转移酶；TET：DNA去甲基化酶。
Figure 1. Mechanisms of immunosuppression in sepsis
图 2 脓毒症效应细胞和调节细胞的免疫抑制机制
注：CCR7：趋化因子受体7。
Figure 2. Immunosuppressive mechanisms of effector and regulatory cells in sepsis
图 3 免疫抑制细胞因子释放增加致脓毒症免疫抑制机制
注：IL-4：白细胞介素-4；TGF-β：转化生长因子-β；Th1：1型辅助性T细胞；Treg：调节性T细胞；M1：M1型巨噬细胞；MDSCs：髓源性抑制细胞。
Figure 3. Increased release of immunosuppressive cytokines leads to immunosuppression in sepsis
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