The complement system

In summary, the complement system represents a remarkably complex system of interacting proteins noteworthy for several features:

• 1.(1) The assembly and activation of complex proteolytic enzymes, each composed of more than one protein, which act sequentially on specific substrates.
• 2.(2) The biological activity of these enzymes requires the transfer of proteins from the fluid phase to the surface of target cells. This is possible, at least in part, by the ability of C3b and C4b to bind covalently to such surfaces.
• 3.(3) The system is extremely efficient; each of the proteolytically generated fragments appears to perform an important physiological function.
• 4.(4) The final event is the assembly of a macromolecular structure able to penetrate the cell membrane and in so doing lyse the cell.

     

The complement system in teleosts

Complement, an important component of the innate immune system, is comprised of about 35 individual proteins. In mammals, activation of complement results in the generation of activated protein fragments that play a role in microbial killing, phagocytosis, inflammatory reactions, immune complex clearance, and antibody production. Fish appear to possess activation pathways similar to those in mammals, and the fish complement proteins identified thus far show many homologies to their mammalian counterparts. Because information about complement proteins, regulatory proteins, and complement receptors in fish is far from complete, it is unclear whether all the complement functions that have been identified in mammals also occur in fish. However, it has been clearly demonstrated that fish complement can lyse foreign cells and opsonise foreign organisms for destruction by phagocytes. There are also indications that complement fragments participate in inflammatory reactions. Fish possess multiple isoforms of several complement proteins, such as C3 and factor B. It has been hypothesised that the function of this diversity in complement proteins serves to expand their innate immune recognition capacity and response. Understanding the functions of complement in fish and the roles the individual proteins, including the various isoforms, play in host defence, is important not only for understanding the evolution of this system but also for the development of new strategies in fish health management.     

The complement system and its biological activities

The complement system is a non specific humoral defence mechanism which can be triggered by various effectors : immune-complexes, extrinsic proteases, bacterial cell-wall polysaccharides, viral membranes. Different peptides or multimolecular complexes are formed by a cascade of proteolytic cleavages; they take an active part in the inflammatory response and may contribute to different pathological manifestations.     

The ancient origin of the complement system

The complement system has been thought to originate exclusively in the deuterostomes. Here, we show that the central complement components already existed in the primitive protostome lineage. A functional homolog of vertebrate complement 3, CrC3, has been isolated from a 'living fossil', the horseshoe crab (Carcinoscorpius rotundicauda). CrC3 resembles human C3 and shows closest homology to C3 sequences of lower deuterostomes. CrC3 and plasma lectins bind a wide range of microbes, forming the frontline innate immune defense system. Additionally, we identified CrC2/Bf, a homolog of vertebrate C2 and Bf that participates in C3 activation, and a C3 receptor-like sequence. Furthermore, complement-mediated phagocytosis of bacteria by the hemocytes of horseshoe crab was also observed. Thus, a primitive yet complex opsonic complement defense system is revealed in the horseshoe crab, a protostome species. Our findings demonstrate an ancient origin of the critical complement components and the opsonic defense mechanism in the Precambrian ancestor of bilateral animals.     

补体系统的进化

补体系统中的大多数组织成员有着特征性的结构域及其特有的结构域组合形式,这使得我们可以利用基因组数据研究分析补体系统的起源与进化。综合文献报道和数据分析,发现补体系统的某些结构域存在于低等的后口动物,甚至在原口动物中也有大量分布,但哺乳动物中特有的结构域组合方式只在后口动物中存在。这些揭示了补体系统拥有比适应性免疫更早的起源,完善的补体系统可能形成在后口动物中的无脊椎动物,而更为原始的补体系统雏形则在原口动物中已经出现。就近些年的研究成果作一综述,以期系统阐明补体系统的起源与进化。     

The complement system and circulating immune complexes in burn patients

The results of the study of humoral immunity in 80 burn patients are presented. A typical feature of all burn patients was a decrease in the total activity of the alternative path of the activation of complement and its factors B and D, beginning from the first day after the trauma. The character of changes in the functional activity of components C1-C5 of the classical path depended on the area of damages with their activation if burn area was less than 20% of the skin surface and deactivation if the burn area exceeded 20%.     

The Kaposi's sarcoma-associated herpesvirus complement control protein mimics human molecular mechanisms for inhibition of the complement system

Kaposi's sarcoma-associated human herpesvirus (KSHV) is thought to cause Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Previously, we reported that the KSHV complement control protein (KCP) encoded within the viral genome is a potent regulator of the complement system; it acts both as a cofactor for factor I and accelerates decay of the C3 convertases (Spiller, O. B., Blackbourn, D. J., Mark, L., Proctor, D. G., and Blom, A. M. (2003) J. Biol. Chem. 278, 9283-9289). KCP is a homologue to human complement regulators, being comprised of four complement control protein (CCP) domains. In this, the first study to identify the functional sites of a viral homologue at the amino acid level, we created a three-dimensional homology-based model followed by site-directed mutagenesis to locate complement regulatory sites. Classical pathway regulation, both through decay acceleration and factor I cleavage of C4b, required a cluster of positively charged amino acids in CCP1 stretching into CCP2 (Arg-20, Arg-33, Arg-35, Lys-64, Lys-65, and Lys-88) as well as positively (Lys-131, Lys-133, and His-135) and negatively (Glu-99, Glu-152, and Asp-155) charged areas at opposing faces of the border region between CCPs 2 and 3. The regulation of the alternative pathway (via factor I-mediated C3b cleavage) was found to both overlap with classical pathway regulatory sites (Lys-64, Lys-65, Lys-88 and Lys-131, Lys-133, His-135) as well as require unique, more C-terminal residues in CCPs 3 and 4 (His-158, His-171, and His-213) and CCP 4 (Phe-195, Phe-207, and Leu-209). We show here that KCP has evolved to maintain the spatial structure of its functional sites, especially the positively charged patches, compared with host complement regulators.     

Artificial inhibition of the complement system

A great number of natural substances affect the complement system in addition to its natural regulators. Among the complement effectors, the most important are inhibitors of the activation cascade. The necessity of searching for preparations capable of a purposeful effect on complement by inhibition of single stages of the activation cascade and without influence on its other functions is connected with the current importance of use in medicine of novel therapeutic regulators of the complement system. Important directions are the search for complement inhibitors that (a) interfere with the rejection of transplants; (b) can replace C1 inhibitor in hereditary angioedema; and (c) have a high anti-inflammatory activity in the therapy of rheumatic diseases, diabetes, and other autoimmune disorders. It is expedient to use the available techniques for the directed detection of the action of medicinal substances on complement, which allow the determination of their action on the complement system at various stages of the cascade of its activation.     

Viral mimicry of the complement system

The complement system is a potent innate immune mechanism consisting of cascades of proteins which are designed to fight against and annul intrusion of all the foreign pathogens. Although viruses are smaller in size and have relatively simple structure, they are not immune to complement attack. Thus, activation of the complement system can lead to neutralization of cell-free viruses, phagocytosis of C3b-coated viral particles, lysis of virus-infected cells, and generation of inflammatory and specific immune responses. However, to combat host responses and succeed as pathogens, viruses not only have developed/adopted mechanisms to control complement, but also have turned these interactions to their own advantage. Important examples include poxviruses, herpesviruses, retroviruses, paramyxoviruses and picornaviruses. In this review, we provide information on the various complement evasion strategies that viruses have developed to thwart the complement attack of the host. A special emphasis is given on the interactions between the viral proteins that are involved in molecular mimicry and the complement system.     

Artificial inhibition of the complement system

A great number of natural substances affect the complement system in addition to its natural regulators. Among the complement effectors, the most important are inhibitors of the activation cascade. The necessity of searching for preparations capable of a purposeful effect on complement by inhibition of single stages of the activation cascade and without influence on its other functions is connected with the current importance of use in medicine of novel therapeutic regulators of the complement system. Important directions are the search for complement inhibitors that (a) interfere with the rejection of transplants; (b) can replace C1 inhibitor in hereditary angioedema, and (c) have a high anti-inflammatory activity in the therapy of rheumatic diseases, diabetes, and other autoimmune disorders. It is expedient to use the available techniques for the directed detection of the action of medicinal substances on complement, which allow the determination of their action on the complement system at various stages of the cascade of its activation.     

Serine proteases of the complement system

The complement system in blood plasma is a major mediator of innate immune defence. The function of complement is to recognize, then opsonize or lyse, particulate materials, including bacteria, yeasts and other microrganisms, host cell debris and altered host cells. Recognition occurs by binding of complement proteins to charge or saccharide arrays. After recognition, a series of serine proteases is activated, culminating in the assembly of complex unstable proteases called C3/C5 convertases. These activate the complement protein C3, which acts as an opsonin. The complement serine proteases include the closely related C1r, C1s, MASPs 1-3 (80-90 kDa), C2 and Factor B (100 kDa), Factor D (25 kDa) and Factor I (85 kDa). Each of these has unusually restricted specificity and low enzymic activity. The C1r, C1s and MASP group occur as proenzymes. When activated, they are regulated, like many plasma serine proteases, by a serpin, C1-inhibitor. C2 and Factor B, however, have complex multiple regulation by a group of complement proteins called the Regulation of Complement Activation (or RCA) proteins, whereas Factors I and D appear to have no natural inhibitors. Advances in structure determination and protein-protein interaction properties are leading to a more detailed understanding of the complement-system proteases, and are indicating possible new routes for potential therapeutic control of complement.     

补体系统在动脉粥样硬化中的作用

动脉粥样硬化是由脂质和纤维在动脉内膜下的过度沉积造成的,脂代谢紊乱和免疫功能失衡是其最重要的发病机制.补体系统是固有免疫的重要组成部分,是炎症反应的关键启动因子,补体系统介导的免疫应答在动脉粥样硬化的发生中发挥着重要作用.众多研究表明,动脉粥样硬化斑块中存在多种补体成分以及活化产物,提示补体系统的活化和后续的级联反应是...