Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark, and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (P.G.); Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California (A.J.T.); and Research Laboratory, Nordland Hospital, Bodø, Norway, Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway (T.E.M.); Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway (T.E.M.); and Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway (T.E.M.).
Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark, and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (P.G.); Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California (A.J.T.); and Research Laboratory, Nordland Hospital, Bodø, Norway, Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway (T.E.M.); Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway (T.E.M.); and Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway (T.E.M.)
Pharmacol Rev. 2021 Apr;73(2):792-827. doi: 10.1124/pharmrev.120.000072.
The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the name "complement." Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. SIGNIFICANCE STATEMENT: The complement system is the host's defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host's enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.
补体系统是在 19 世纪末期被发现的，它是一种不耐热的血浆成分，可以“补充”抗体杀死微生物，因此得名“补体”。补体也是先天免疫系统的一部分，通过识别病原体相关分子模式来保护宿主。然而，补体的功能远不止于抗感染防御。它有助于器官发育，如塑造神经元突触，促进组织再生和修复，并迅速与许多过程（包括导致血栓炎症的止血）结合和协同作用。补体是一把双刃剑。虽然它通常保护宿主，但当失调或过度激活时，它可能会导致组织损伤，例如在创伤和败血症以及严重的 2019 年冠状病毒病（COVID-19）中观察到的全身性炎症反应中。缺血再灌注损伤（心肌梗死、中风和移植功能障碍）和慢性神经和风湿性疾病中产生的损伤相关分子模式会激活补体，从而增加破坏性炎症。尽管有许多疾病可能通过调节补体来改善，但只有少数罕见疾病被批准用于针对补体的临床治疗。目前正在有效治疗的疾病包括阵发性夜间血红蛋白尿、非典型溶血性尿毒综合征、重症肌无力和视神经脊髓炎谱系障碍。不幸的是，罕见疾病排除了强有力的临床试验。越来越多的证据表明，补体是许多更常见疾病的致病驱动因素，这表明未来可能需要补体治疗，但这需要进行强有力的临床试验；正在进行的一个例子是 COVID-19 疾病。本综述旨在讨论补体在疾病发病机制中的作用，并讨论未来用补体靶向疗法治疗这些疾病的药理学策略。意义：补体系统是宿主防御的朋友，它可以保护宿主免受入侵病原体的侵害，促进组织修复，并维持内环境稳定。补体是一把双刃剑，因为当它失调或过度激活时，它就会成为宿主的敌人，导致组织损伤、器官衰竭，最坏的情况下，还会导致死亡。许多急性和慢性疾病都有可能通过药理学治疗来避免补体依赖性损伤，从治疗罕见疾病的已有疗法到可能治疗 COVID-19 大流行这样的大量患者群体的未来疗法都有涉及。
Zotero 插件
