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Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics
Pharmacological Reviews ( IF 19.3 ) Pub Date : 2021-04-01 , DOI: 10.1124/pharmrev.120.000072 Peter Garred 1 , Andrea J Tenner 1 , Tom E Mollnes 2
Pharmacological Reviews ( IF 19.3 ) Pub Date : 2021-04-01 , DOI: 10.1124/pharmrev.120.000072 Peter Garred 1 , Andrea J Tenner 1 , Tom E Mollnes 2
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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.
中文翻译：
补体系统的治疗靶向：从罕见疾病到流行病
补体系统于 19 世纪末被发现，是一种不耐热的血浆成分，可以“补充”抗体来杀死微生物，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的分子模式来保护宿主。然而，补体的多功能性远远超出了感染防御的范围。它有助于器官发育，例如塑造神经元突触、促进组织再生和修复，以及快速参与和协同许多过程，包括导致血栓炎症的止血。互补是一把双刃剑。尽管它通常可以保护宿主，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) 中出现的全身炎症反应。缺血再灌注损伤（心肌梗死、中风和移植功能障碍）以及慢性神经系统和风湿性疾病期间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。尽管有可能改善补体调节的疾病有很多，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睡眠性血红蛋白尿症、非典型溶血性尿毒症综合征、重症肌无力和视神经脊髓炎谱系疾病。不幸的是，罕见疾病无法进行强有力的临床试验。越来越多的证据表明补体是许多常见疾病的致病驱动因素，这表明未来补体疗法有机会，但这需要强有力的临床试验；一个持续存在的例子是 COVID-19 疾病。 本综述旨在讨论补体在疾病发病机制中的作用，并讨论通过补体靶向疗法治疗这些疾病的未来药理学策略。
更新日期：2021-03-09
中文翻译：
补体系统的治疗靶向：从罕见疾病到流行病
补体系统于 19 世纪末被发现，是一种不耐热的血浆成分，可以“补充”抗体来杀死微生物，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的分子模式来保护宿主。然而，补体的多功能性远远超出了感染防御的范围。它有助于器官发育，例如塑造神经元突触、促进组织再生和修复，以及快速参与和协同许多过程，包括导致血栓炎症的止血。互补是一把双刃剑。尽管它通常可以保护宿主，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) 中出现的全身炎症反应。缺血再灌注损伤（心肌梗死、中风和移植功能障碍）以及慢性神经系统和风湿性疾病期间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。尽管有可能改善补体调节的疾病有很多，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睡眠性血红蛋白尿症、非典型溶血性尿毒症综合征、重症肌无力和视神经脊髓炎谱系疾病。不幸的是，罕见疾病无法进行强有力的临床试验。越来越多的证据表明补体是许多常见疾病的致病驱动因素，这表明未来补体疗法有机会，但这需要强有力的临床试验；一个持续存在的例子是 COVID-19 疾病。 本综述旨在讨论补体在疾病发病机制中的作用，并讨论通过补体靶向疗法治疗这些疾病的未来药理学策略。
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