Canonical and non-canonical functions of the complement system in health and disease.
Canonical and non-canonical functions of the complement system in health and disease.
复制标题
补体系统在健康和疾病中的规范和非规范功能。
DOI：
10.1111/bph.15503
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发表时间：
2021
影响因子：
7.3
通讯作者：
Köhl,Jörg
中科院分区：
文献类型：
--
作者：
Wenzel,Ulrich;Kemper,Claudia;Köhl,Jörg
补体系统形成30多种可溶性蛋白质和细胞结合受体的网络，其作为先天免疫系统的一部分执行多种传感器和效应器功能。很好地理解，补体系统通过调理作用和微生物的直接裂解保护宿主免受不利的微生物环境的影响。在21世纪世纪初取得的进展表明，它有助于组织和器官的完整性，有效地消除改变或死亡的细胞。此外，补体系统的功能仅限于血清的原始观点在过去二十年中不断扩展。此外，许多补体蛋白和受体与细胞外和细胞内功能的结构和相互作用已经在分子上被定义（Forneris et al.，2012年）。除了已知的经典活化途径之外，还描述了非经典机制，其不仅在循环中而且在免疫细胞中导致补体因子的裂解和活化。细胞内补体系统已被命名为“补体体”（Arbore et al.，2017; Kolev等人，2014年）。事实上，许多研究表明补体系统与其他先天免疫传感器系统具有多重和双向的相互作用，并调节先天和获得性免疫的免疫应答（Hajishengallis et al. 2017年）。有趣的是，该系统还直接干预细胞和组织的分化并调节细胞代谢，从而显著促进细胞稳态（West等人，2020年）。从进化的角度来看，补体的这些非经典功能并不奇怪，因为该系统已经存在了12亿年，使其成为我们免疫系统中最古老的部分之一。补体甚至可能已经进化出了与抵抗病原体不同的最初目的，而是作为细胞应激的内在传感器。我们还将讨论如何更仔细地研究关键补体成分的演变，不仅使补体和代谢之间的功能联系相当“可预测”，但也可能为发现补体在基本细胞过程中的其他作用提供线索。补体激活的非经典途径和在过去十年中发现的多种新功能使补体系统比以往任何时候都更成为免疫学的重要研究领域和热门话题，特别是鉴于正在进行的冠状病毒大流行。越来越多的临床病症涉及补体系统的病理贡献，这激发了对治疗干预的新兴趣，为了调节这种宿主防御途径（Pandey等人，2017年）。基于这些发现，制药工业已经鉴定了补体系统，特别是过敏毒素及其受体，作为炎性疾病中潜在的和有希望的靶标（Ricklin et al.，2018年）。在2007年，FDA批准了针对C5的抗体（依库珠单抗）用于治疗阵发性睡眠性血红蛋白尿症（PNH），后来用于治疗非典型溶血综合征（阿胡斯）和自身免疫性神经肌肉疾病（Legendre et al.，2013年）。目前正在临床试验中评估针对补体级联反应各个阶段的20多种候选药物，其他药物正在临床前开发中。例如，ChemoCentryx报告了其III期试验的成功完成，表明口服C5 a 1受体拮抗剂（avacopan）在抗神经细胞瘤细胞质中上级皮质类固醇治疗。
The complement system forms a network of more than 30 soluble proteins and cell-bound receptors that perform multiple sensor and effector functions as part of the innate immune system. It is well appreciated that the complement system protects the host from a hostile microbial environment through opsonization and direct lysis of microorganisms. Progress made at the beginning of the 21st century showed that it contributes to the integrity of tissues and organs by effectively eliminating altered or dead cells. Moreover, the original view that the functions of the complement system are limited to serum has been continuously expanded over the last two decades. Further, the structure and interaction of many complement proteins and receptors with extracellular and intracellular functions have been molecularly defined (Forneris et al., 2012). In addition to the known canonical activation pathways, noncanonical mechanisms have been described, which lead to cleavage and activation of complement factors not only in the circulation but also in immune cells. The intracellular complement system has been named the “complosome”(Arbore et al., 2017; Kolev et al., 2014). In fact, many studies indicate that the complement system has multiple and bidirectional interactions with other innate immunity sensor systems and regulates immune responses of innate and acquired immunity (Hajishengallis et al., 2017). Interestingly, the system also directly intervenes with the differentiation of cells and tissues and regulates cell metabolism, thus contributing significantly to cell homeostasis (West et al., 2020). From an evolutionary point of view, these non-canonical functions of complement are not surprising given that the system has been around for 1.2 billion years, making it one of the oldest parts of our immune system. Complement may even have evolved with an initial purpose distinct from protection against pathogens but rather as an intrinsic sensor of cellular stress. We will also discuss how taking a closer look into the evolution of key complement components not only made the functional connection between complement and metabolism rather ‘predictable’but may also give clues for the discovery of additional roles for complement in basic cellular processes. The non-canonical pathways of complement activation and the multiple novel functions uncovered during the past decade make the complement system more than ever an important field of research and hot topic in immunology in particular in light of the ongoing coronavirus pandemic.The increasing number of clinical conditions that involve a pathological contribution from the complement system has spurred a renewed interest in therapeutic interventions, in order to modulate this host defence pathway (Pandey et al., 2017). Based on these findings, the pharmaceutical industry has identified the complement system, and specifically the anaphylatoxins and their receptors, as potential and promising targets in inflammatory diseases (Ricklin et al., 2018). In 2007, an antibody against C5 (eculizumab) was approved by the FDA for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) and later for the atypical haemolytic syndrome (aHUS) and autoimmune neuromuscular disorders (Legendre et al., 2013). More than 20 candidate drugs, targeting various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. For example, ChemoCentryx reported the successful completion of their Phase III trial showing that the orally administered C5a 1 receptor antagonist (avacopan) was superior to corticosteroid treatment in antineutrophil cytoplasmic …