Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics.
Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics.
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DOI：
10.1124/pharmrev.120.000072
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发表时间：
2021-04
影响因子：
21.1
通讯作者：
Mollnes TE
中科院分区：
文献类型：
--
作者：
Garred P;Tenner AJ;Mollnes TE
补体系统在世纪末被发现是一种热不稳定的血浆成分，它在杀死微生物时“补充”抗体，因此被称为“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性防御。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，并迅速参与和协同许多过程，包括止血导致血栓炎症。互补是一把双刃剑。虽然它通常可以保护宿主，但当失调或过度激活时可能会导致组织损伤，例如在创伤和败血症以及2019年严重冠状病毒病（COVID-19）中观察到的全身炎症反应。在缺血-再灌注损伤（心肌梗死、中风和移植功能障碍）以及慢性神经系统疾病和风湿性疾病中产生的损伤相关分子模式激活补体，从而增加损伤性炎症。尽管存在一长串具有改善补体调节潜力的疾病，但只有少数罕见疾病被批准用于靶向补体的临床治疗。目前正在有效治疗的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肌萎缩性疾病。不幸的是，罕见疾病排除了可靠的临床试验。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，这表明未来补体治疗有机会，但这需要强有力的临床试验;一个正在进行的例子是COVID-19疾病。本文综述了补体在疾病发病机制中的作用，并探讨了未来补体靶向治疗这些疾病的药理学策略。补体系统是宿主的防御朋友，通过保护其免受入侵病原体的侵害，促进组织修复和维持体内平衡。补体是一把双刃剑，因为当失调或过度激活时，它会成为宿主的敌人，导致组织损伤，器官衰竭，最严重的情况下会导致死亡。许多急性和慢性疾病都是药物治疗的候选者，以避免补体依赖性损伤，从罕见疾病的成熟治疗到2019年大流行性冠状病毒病等大型患者群体的未来可能治疗。
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. 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.
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影响因子：
5.3
作者：
Alawieh, Ali M.;Langley, E. Farris;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen
DOI：
10.4049/jimmunol.1202339
发表时间：
2012-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Abe T;Hosur KB;Hajishengallis E;Reis ES;Ricklin D;Lambris JD;Hajishengallis G
通讯作者：
Hajishengallis G
影响因子：
4.2
作者：
Bellander, BM;Singhrao, SK;Svensson, M
通讯作者：
Svensson, M
影响因子：
5.3
作者：
Alawieh, Ali;Langley, E. Farris;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen
影响因子：
0.7
作者：
Basdemirci, Muserref;Sen, Askin;Ceylaner, Serdar
通讯作者：
Ceylaner, Serdar