As discussed previously, complement activation can result in C3 deposition on the surface of virions. This can dramatically increase antibody titres, modulate the proliferation of mature B cells, and protect the B-cells from CDmediated elimination 8 , The C3-coated immune complexes on FDCs are then presented to B-cells in the germinal center for optimal B-cell responses, including: antibody production, somatic hypermutation, class switching, and affinity maturation 87 , FDCs can then retain the C3-coated complexes within the lymphoid for extended periods of time to generate memory B-cells and promote survival Alternatively, some aspects of the complement system can suppress certain responses of adaptive immunity: stimulation of CR3 on DCs can suppress the release of inflammatory cytokines 98 and C1q-differentiated DCs demonstrate an increased phagocytic capacity but reduced expression of CD80, CD83, and CD86 required for T cell activation It is apparent that the complement system has important implications for virus neutralization and development of the adaptive immune response.
As our knowledge of virus and complement interactions improves, this can inform novel approaches for intervention and the development of therapeutics and vaccines. One such example is the use of rupintrivir against rhinoviral infections.
Rhinoviruses encode a cytosolic 3C protease which cleaves intracellular C3 to avoid the intracellular mechanisms of complement, mentioned previously.
Rupintrivir inhibits the viral cytosolic 3C protease to increase susceptibility of the virus to intracellular complement immunity 6. Similarly, the use of Fab fragments could prevent the C4 inhibition of human adenovirus 5 vector for its use in adenoviral gene therapy to promote efficient transgene delivery Due to the multifaceted and complex immune functions of the complement system, direct manipulation of complement would need to be carefully considered.
Inhibition of the complement system could increase susceptibility to other diseases, whilst over-stimulation could result in autoimmunity and damage to host cells. A method of complement stimulation through inhibition of the CD59 regulator has been proposed for the treatment of latent HIV-1 infection in cells. The use of provirus stimulants and a CD59 inhibitor showed a dose-response effect of cell sensitization to antibody-dependent cell-mediated lysis and reduced viral load. Aside from the target cells, no significant non-specific cytolytic effects were observed in vitro.
CD59 protects host cells from complement activity, is ubiquitously expressed, and so its inhibition has the potential to damage host cells , Deletion of CD59 in mice did not have a lethal outcome, however absence of the complement regulatory protein did lead to intravascular haemolysis and thrombosis Treatment in the context of HIV-1 infection would be short-term however and could be an exception for an otherwise incurable disease.
Similar approaches have been considered for other life-threatening diseases such as cancerous conditions , Methods of complement inhibition have also demonstrated therapeutic benefit. Use of a C5aR antibody to block the pro-inflammatory effects of C5a in MERS-CoV infected hDPP4 -transgenic mice resulted in: lower concentrations of pro-inflammatory cytokines, reduced viral replication in lung tissues, reduced lung and spleen tissue damage, and a reduction of viral antigen and microglia activation in the brain Excessive complement activation and similar lung pathology during SARS-CoV infection has also been observed in H5N1 influenza cases, where the use of C3aR and C5aR antagonists reduced signs of acute lung injury and viral load in H5N1-infected mice Symptoms of severe disease involve major alveolar damage, wide-spread lung inflammation, and progressive respiratory failure , Thus, the widespread lung inflammation observed in severe cases of COVID could be exacerbated by excessive complement activation.
So, it seems plausible that the lung inflammation in severe cases of COVID is exacerbated by excessive complement activation and this pathologic inflammation could be attenuated through use of complement inhibitors. Clinical trials are currently being conducted with the use of a C5a inhibitor, the monoclonal antibody IFX-1, which has proven to be well tolerated in clinical trial participants and aims to reduce inflammation whilst preserving MAC formation The IFX-1 monoclonal antibody targets a specific conformational epitope of the C5a molecule to block its anaphylatoxin activity, whilst C5b and downstream complement activity are preserved Eculizumab is a monoclonal antibody which targets the C5 molecule to prevent cleavage into C5a and C5b, and therefore inhibits all downstream complement activity Because the efficacy and safety of eculizumab is already well characterized , it is logical that this would take precedence over lesser-known options for urgent clinical trials.
The use of eculizumab has already proven beneficial for treatment of severe cases of COVID, which shows that complement is partly responsible for the symptoms in severe cases It would be interesting to compare the effects of preserving the MAC during infection with the enveloped SARS-CoV-2, as it may offer an antiviral, as well as an anti-inflammatory, effect.
But it is also possible that Coronaviruses have an intrinsic evasion mechanism, perhaps similar to the ones described in this review, to avoid the lytic activity of the MAC. Another important consideration could be the stage of infection for implementing complement inhibitors: maintaining complement activity may have a beneficial impact early on in infection for virus neutralization and the development of adaptive immunity, and intervention may only be required to treat excessive inflammation in severe cases.
The complement system has several important considerations for vaccine development, one example being its involvement in antibody dependent enhancement ADE. ADE is commonly observed when non-neutralizing antibodies are present following initial priming of the immune system. Non-neutralizing antibodies can still bind the viral target with the potential to cross-link with Fc receptors, or activate complement and interact with complement receptors, to enhance viral infection of host cells But complement activation can have a positive effect against viral infections in the presence of some non-neutralizing antibodies.
Use of the non-neutralizing influenza virus M2 extracellular vaccine in mice required functional C3 to confer protection and induce effective humoral and cell-mediated immune responses A similar effect has been reported for monoclonal antibodies against human cytomegalovirus HCMV. Certain HCMV monoclonal antibodies rely on complement for viral neutralization, which appears distinct from CDC or virolysis, and is likely the result of blocking virus-host interactions Complement activity has also been implicated for optimal protection with non-neutralizing antibody mABG8 against Crimean-Congo haemorrhagic fever virus infection in adult mice Complement has been shown to augment antibody-mediated neutralization of WNV in vitro and the addition of C1q has been shown to lower the antibody concentrations required for WNV neutralization in vitro , which correlated with protective effects observed in vivo C1q was also shown to mediate effects of ADE from Flavivirus infections in a subclass specific manner, whilst MBL, factor B, or C5 depletion had no significant effect Although IgG subclasses are known to bind C1q with varying avidities, the mechanism to explain this effect on ADE has not been identified.
This could highlight the importance of selecting the right antibody subclass when considering monoclonal antibody therapies. In general, vaccines which effectively engage the complement system may gave rise to a more potent, virolytic serological response.
For HIV vaccination in macaques, the presence of complement augmented virus neutralization and complement-mediated neutralizing antibody titres correlated with vaccine-mediated protection Other approaches have modified vaccines to utilize aspects of the complement system for increased antigen immunogenicity, such as complement component C3d.
When bound to an antigen, C3d can dramatically reduce the B-cell activation threshold for a stronger, more antigen-specific antibody response 8 , , C3d also bears T-cell epitopes so even with a lack of CR2 expression, the peptide can be internalized and presented on HLA II molecules to autoreactive T-helper cells and enhance antibody responses , C3d does not interact with other components of the complement system and so the associated risks are reduced, however a large enough reduction in the B-cell activation threshold could potentially lead to antibody-mediated autoimmune responses.
C3d has been used as a vaccine adjuvant against several different viruses. Similarly, use of hepatitis E virus peptide HEV-p for DNA vaccination in mice had enhanced anti-HEV-p antibody titres and avidity when fused with three tandem C3d copies as genetic adjuvants C3d has also been used as genetic adjuvant for DNA vaccines against Newcastle disease virus and HIV-1 for increased efficacy and higher, longer-lasting antibody titres , Fusion of C3d to target antigens is another approach for the development of safer, more immunogenic DNA vaccines.
Coupling of C3d to the secretory form of Influenza virus haemagglutinin in mice provided an effective and safer mechanism for mucosal vaccination compared to the use of other adjuvants i. So, the use of C3d as an adjuvant can help to overcome the low immunogenicity associated with DNA vaccines, whilst maintaining their safety. In the examples where viral-mediated complement activation has been more extensively studied, a viral mechanism is often identified which protects the virus from certain antiviral functions, such as the acquisition of CD46, CD55, CD59 to protect from MAC formation or the expression of a regulatory protein to inhibit the complement cascade at various points.
The viruses which activate complement would consequently trigger the downstream antiviral effects, both intracellularly and extracellularly. Therefore, it seems plausible that these viruses would utilize a mechanism, similar to the ones described in this review, to evade this antiviral activity and promote their survival. If such a regulatory protein or process is identified, then these may present as possible antiviral targets, similar to the targeting of the rhinovirus 3C protease with rupintrivir 6.
The complex interplay between viruses and the complement system can have profound implications for protection via innate immunity and the development of effective adaptive immunity.
Such developments can also be applied for non-viral pathogens including bacteria, fungi, protozoa and to broader, more systemic functions of the complement system including: interferon signaling , , metabolism , brain development , and the coagulation system Components of the complement system form an ancient aspect of innate immunity in vertebrates and even some invertebrates , Therefore, many animals which act as viral hosts or reservoirs for zoonoses also have an active complement system for targeting pathogens i.
Further viral mechanisms of complement regulation may therefore exist which have not yet been identified and the plasticity of viral genomes could result in the emergence of novel protein regulatory functions. Identifying these novel interactions could be important for the development and augmentation of vaccines and therapeutics or even the possibility of utilizing viral-derived regulatory proteins as therapeutic complement inhibitors in other diseases The benefits from understanding complement mechanisms in viral diseases may have relevance for the current SARS-CoV-2 outbreak.
Previous research has demonstrated the impact of the complement system in coronavirus infections and other diseases, and this knowledge has led to the consideration of several complement inhibitors as therapeutics for severe cases of COVID JM wrote the manuscript and designed the tables and figures.
All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The complement system. Cell Tissue Res. The complement system: history, pathways, cascade and inhibitors. Eur J Microbiol Immunol. Mannose-binding lectin binds to Ebola and Marburg envelope glycoproteins, resulting in blocking of virus interaction with DC-SIGN and complement-mediated virus neutralization.
J Gen Virol. Active human complement reduces the Zika virus load via formation of the membrane-attack complex. Front Immunol. Glycoprotein C of herpes simplex virus type 1 prevents complement-mediated cell lysis and virus neutralization. J Infect Dis. Intracellular sensing of complement C3 activates cell autonomous immunity. Therapeutic Interventions in the Complement System. Google Scholar. Immunol Lett. Human T cell derived, cell-bound complement iC3b is integrally involved in T cell activation.
Duncan AR, Winter G. The binding site for C1q on IgG. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. Novel evasion mechanisms of the classical complement pathway. J Immunol. Kaul M, Loos M. Dissection of C1q capability of interacting with IgG time-dependent formation of a tight and only partly reversible association. J Biol Chem. Human monoclonal IgG isotypes differ in complement activating function at the level of C4 as well as C1q.
J Exp Med. Direct binding of C1q to apoptotic cells and cell blebs induces complement activation. Eur J Immunol. Human immunodeficiency virus type 1 activates the classical pathway of complement by direct C1 binding through specific sites in the transmembrane glycoprotein gp Virus Res.
Evidence that complement protein C1q interacts with C-reactive protein through its globular head region. Fibronectin binds to the C1q component of complement. The interaction of human plasma fibronectin with a subunit of the first component of complement, C1q. PubMed Abstract Google Scholar. The proteoglycan decorin binds C1q and inhibits the activity of the C1 complex. Rainard P. Activation of the classical pathway of complement by binding of bovine lactoferrin to unencapsulated Streptococcus agalactiae.
Biochemical and functional characterization of the interaction between pentraxin 3 and C1q. Scand J Immunol. Structure and activation of C1, the complex initiating the classical pathway of the complement cascade. Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to protease-activated receptors 1 and 4.
Structural basis of complement membrane attack complex formation. Nat Commun. Human M-ficolin is a secretory protein that activates the lectin complement pathway. The two major oligomeric forms of human mannan-binding lectin: chemical characterization, carbohydrate-binding properties, and interaction with MBL-associated serine proteases. Characterization of the complex between mannose-binding lectin trimer and mannose-binding lectin-associated serine proteases.
Microbiol Immunol. Structure of a C-type mannose-binding protein complexed with an oligosaccharide. Characterization of the oligomer structure of recombinant human mannan-binding lectin.
Biosynthesis of human ficolin, an Escherichia coli-binding protein, by monocytes: comparison with the synthesis of two macrophage-specific proteins, C1q and the mannose receptor. Ficolins: novel pattern recognition molecules of the innate immune response. Structural insights into the recognition properties of human ficolins. J Innate Immun. Human L-Ficolin Ficolin-2 and its clinical significance. Biomed Res Int. New functional ligands for ficolin-3 among lipopolysaccharides of Hafnia alvei.
Heteromeric Complexes of native collectin kidney 1 and collectin liver 1 are found in the circulation with MASPs and activate the complement system. Proteolytic activities of two types of mannose-binding lectin-associated serine protease. MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. C3 adsorbed to a polymer surface can form an initiating alternative pathway convertase. Nilsson B, Nilsson Ekdahl K. The tick-over theory revisited: is C3 a contact-activated protein?
Lachmann PJ. The amplification loop of the complement pathways. Adv Immunol. Quantitative modeling of the alternative pathway of the complement system. The central role of the alternative complement pathway in human disease. Membrane attack by complement: the assembly and biology of terminal complement complexes.
Immunol Res. New insights into the immune functions of complement. Nat Rev Immunol. Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly. The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis. Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation.
Complement factor P is a ligand for the natural killer cell-activating receptor NKp Sci Immunol. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.
Mol Immunol. A C3 H20 recycling pathway is a component of the intracellular complement system. J Clin Investig. On the functional overlap between complement and anti-microbial peptides. Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways. The endothelium is an extrahepatic site of synthesis of the seventh component of the complement system.
Clin Exp Immunol. Characteristics and biological variations of M-Ficolin, a pattern recognition molecule, in plasma. Production of complement components by cells of the immune system. Selective expression of clusterin SGP-2 and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro.
Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Investig Ophthalmol Vis Sci. Differential expression of complement regulatory proteins decay-accelerating factor CD55 , membrane cofactor protein CD46 and CD59 during human spermatogenesis. J Leukoc Biol. Murine CD93 C1qRp contributes to the removal of apoptotic cells in vivo but is not required for C1q-mediated enhancement of phagocytosis.
CD93 is rapidly shed from the surface of human myeloid cells and the soluble form is detected in human plasma. Activation of human neutrophils by C3a and C5A. C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway. C3a and C5a stimulate chemotaxis of human mast cells. The human C3a receptor is expressed on neutrophils and monocytes, but not on B or T lymphocytes.
Expression of a functional anaphylatoxin C3a receptor by astrocytes. J Neurochem. Activated human T lymphocytes express a functional C3a receptor. Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a-C3aR interaction. The Anaphylatoxin C3a receptor expression on human M2 macrophages is down-regulated by stimulating the histamine H4 receptor and the IL-4 receptor.
Differential expression of complement receptors on human basophils and mast cells. Human T cells express the C5a receptor and are chemoattracted to C5a.
Up-regulation of C5a receptor expression and function on human monocyte derived dendritic cells by prostaglandin E2. The C1q and collectin binding site within C1 q receptor cell surface calreticulin. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro : calreticulin and CD91 as a common collectin receptor complex.
Direct interaction between CD91 and C1q. FEBS J. Expression of Complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. Tumor-promoting phorbol esters stimulate C3b and C3b' receptor-mediated phagocytosis in cultured human monocytes. Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis. Comp Inflamm. Pascual M, Schifferli JA.
The binding of immune complexes by the erythrocyte complement receptor 1 CR1. Download Complement system. Zaahira Gani, Cambridge, UK. Figure 1. Complement pathways. Bitesize category Systems and Processes. Related Articles Phagocytosis. Dendritic Cells: Migration. Complement System. Co-Receptors: Function. Antigen Processing and Presentation. Subsequently, activated B cells initiate the formation of germinal centers GCs , where CRs on B cells enhance BCR signaling, leading to effective differentiation into plasma and memory B cells 89 , FDCs are central to this process as they are specialized stromal cells that secrete the B-lymphocyte chemoattractant, help to organize GCs, and provide effective means of trapping and retaining antigen within B-cell follicles and displaying them to both naive and GC B cells FDCs express relatively high levels of CR1 and CR2 and effectively retain C3-coated immune complexes within the lymphoid follicles, promoting the antigen selection of high-affinity GC B cells Furthermore, post-GC B cells require complement on FDCs for an efficient maintenance of long-term memory B cells, affinity maturation, and effective recall responses The roles of complement in humoral immunity can be illustrated by the characterization of mice bearing deficiencies in both complement components and CRs Studies have demonstrated the importance of an intact complement classical pathway C1q, C3, or C4 in humoral response to both thymus-dependent and thymus-independent antigens These and other studies highlight the critical role complement plays in the generation of robust antibody response at several levels of B-cell biology.
In view of the impressive repertoire of activities mediated by complement that influence the generation of effective humoral responses, involvement of complement in the other wing of adaptive immunity, the T-cell response, would be expected.
Indeed, Janeway's conceptualization of the 'adjuvant effect' being due to the influence of the innate immune system on acquired immunity, nearly two decades ago, provided a framework for studying the contributions of innate immunity to T-cell-mediated immune responses However, the finding that priming of both CD4 and CD8 T cells was reduced in C3-deficient mice during pulmonary influenza challenge suggested a more generalized role of complement A potential role of complement in T-cell immune responses to viral and alloantigens has now been demonstrated in a number of other studies , , , The mechanisms of this influence are not as well characterized as those related to humoral immunity, and as such represent a crucial area of study in understanding the roles complement plays in regulating adaptive immune responses.
Characterization of the potential role of complement in T-cell immunity has been facilitated by the use of a DAF-deficient mouse model , DAF deficiency led to increased complement activation in various in vivo settings, and this presumably allowed the potential modulating effect of complement on T-cell immunity to be amplified and more easily detectable than otherwise in normal mice.
AP-mediated production of C3a and engagement of C3aR have also been proposed to occur in normal i. One issue that could potentially contradict these hypotheses, and thus remains to be resolved by more careful studies, is whether anaphylatoxin receptors are actually expressed in T cells and professional APCs i. At the whole animal level, C5aR has been shown to be essential for the modulating effect of complement on T-cell immunity in various models.
For example, it has been demonstrated that mice treated with C5aR antagonists produced fewer antigen-specific CD8 T cells, following infection with influenza type A Adding further support is the observation that mice bearing a targeted C5aR deficiency show reduced response to pulmonary infections with Pseudomonas aeruginosa , characterized by impaired pulmonary clearance, despite seemingly normal neutrophilic infiltration C5aR has also been shown in mice to mediate a synergistic effect with Toll-like receptor TLR -4 in eliciting a stronger inflammatory response with signaling from both innate immune receptors than with either alone This link is credible because, like complement, the TLR system recognizes conserved pathogenic motifs and is often activated simultaneously with the complement system, indicating that it is plausible that these two effectors of the innate immune system may cooperate in their functions with potential effects on T-cell immune responses , Cross-linking of CD46 on macrophages by certain pathogenic antigens, such as the pili from Nesseria or Hemagglutinin from measles virus leads to the impairment of IL production by APCs , The measles virus is notorious for suppressing T-cell responses during the course of infection, and the suppression of IL production by APCs through subversion of CD46 may be one such mechanism for this pathogenic activity Cross-linking of CR1, which has regulatory properties discussed previously, on T cells has been shown to inhibit proliferation and reduce IL-2 production DAF, in addition to those roles seen previously in suppressing T-cell responses in vivo , may also play a role in costimulation.
Overall, these results serve to illustrate a functional role of complement activation with regard to T-cell biology. There seems to be sufficient evidence supporting a link between complement activation and enhanced T-cell immune response at the organismal level. Although various hypotheses have been proposed, there is yet to be a consensus regarding the precise mechanism by which complement regulates T-cell immunity. Ongoing studies in this field should provide an improved understanding of this question and contribute to the development of complement-based therapeutic strategies in human diseases relating to microbial infection, autoimmune disorders, and organ transplantation.
Infectious diseases represent a major health, social, and economic burden. The importance of complement to host defense, and the control of infection, as a whole can be appreciated by the consequences observed when complement functions are compromised as a result of genetic deficiency, pathogenic interference, or other mechanisms.
Given that complement has coevolved with pathogens for millions of years, it is perhaps not surprising to find that pathogens have developed mechanisms to inhibit complement activation and effector functions, thereby subverting or avoiding this powerful component of innate immunity and increasing their ability to survive and replicate within the host. Given the disease burden associated with infection with microorganisms and the requirement of novel and effective antibiotics in order to combat them, the study of complement and its roles in defense has significant clinical implications.
As discussed throughout, animals deficient in various complement components have a variety of phenotypes related to host defense, including increased susceptibility to infection, impaired T- and B-cell responses, reduction in phagocytic activity, and ability to clear pathogens and other immune complexes, among many others.
In humans, individuals deficient in one of the major complement effector pathways, most commonly opsonization and lytic pathways, present with increased susceptibility to infection 1 , 11 , Deficiency or defect in opsonization pathways, including the production of antibody and phagocytic ability, results in early and recurrent infections with pyrogenic bacteria with the most common organisms being S.
Defect in the assembly or function of the MAC, or deficiency in the components needed for its generation, is associated with neisserial disease, especially infection with Neisseria meningitidis Due to the central role of C3 in the complement system, deficiency of C3 results in defects in both opsonization and lysis, and thus is strongly associated with recurrent infections by the organisms mentioned above Deficiency of AP components properdin and Factor D is rare, but is also a risk factor in some cases for infection with the same organisms as C3 deficiency, while deficiency in unique classical pathway components e.
Interestingly, endemic meningococcal infections are associated with deficiency of MAC proteins, especially C6, in which prevalence of meningococcal infection is increased but mortality is decreased Finally, deficiency of MBL predisposes children to recurrent pyrogenic infection the ages of which 6 months to 2 years suggest that the MBL is critical during the interval between the loss of passively acquired maternal antibody and maturation of their personal immune system 1 , Therefore, complement is indispensable for host defense against certain pathogens and represents an effective innate defense against common infections.
Many organisms, recognizing the potency of complement activity, have devised strategies to circumvent or subvert complement to increase survival or enhance their virulence. A given pathogen may utilize multiple strategies and molecules to evade host complement attack, as overcoming the powerful, immediate role of complement is imperative from a pathogenic perspective.
Bacteria can interfere with complement on nearly every level of complement activation Staphylococcus aureus produces a membrane protein, Staphylococcal protein A SpA , whose predominant biological function is the binding to the Fc region of IgG, which not only is effective in inhibiting Fc-receptor-mediated phagocytosis but also is highly capable of limiting complement activation via the classical pathway by interfering with the binding of C1q Similar immunoglobulin-binding proteins, such as protein G and protein L can be found in an array of other pathogens Furthermore, opsonization by C3 fragments can be inhibited.
For instance, Pseudomonas aeruginosa secretes active proteases that cleave C3b and prevent C3b deposition, and S. Inhibition of MAC assembly and reduction of cytolytic ability can be achieved simply by virtue of having a thick cell wall, as is the case for Gram-positive bacteria , In other cases, pathogens can inhibit the assembly or function of the MAC as in the case of Borrelia burgdorferi , which encodes a 80 kDa surface protein that shares functional similarities with human CD59, the inhibitor of MAC assembly Pathogens utilize other mechanisms to escape complement as well.
They may interact with host regulators, such as binding Factor H, which increases the degradation of C3b and reduces formation of C3 convertase, thereby limiting complement activity This phenomenon is well characterized in the Nesseria family of pathogens, including N. Interestingly, recent structural determinations of the N. In addition to Factor H binding, both viruses and bacteria may incorporate or recruit other host complement regulatory proteins, encode structural mimics of complement regulatory proteins, or simply encode unique regulatory proteins that serve to inhibit complement activity and thereby render the pathogen resistant to complement effectors , Alternatively, pathogens may inhibit chemotaxis and recruitment of leukocytes by interfering with receptors that mediate these activities, most notably C5aR and the related formyl peptide receptor The chemotaxis inhibitory protein of S.
Some pathogens go further and subvert the complement system in order to enhance their virulence. This was alluded to previously when discussing the complement regulatory protein CD46, which was first described as a receptor for the measles virus and may contribute to the ability of measles to suppress the immune system , CD46 may also act as a cellular receptor for major bacterial strains, including N.
DAF is a receptor for many picornaviruses, such as echoviruses and coxsakieviruses, which use different binding locations on DAF and require accessory molecules such as ICAM-1 in order to internalize , CR2, as discussed above, plays a crucial role in B cells in the binding of C3 fragments.
Human immunodeficiency virus exploits complement on multiple levels to increase its virulence It activates complement in the absence of antibody, which seems counterintuitive as this would normally result in virolysis. However, this is avoided by complement regulators contained in the viral membrane including DAF, which is subverted during the budding process from infected cells, and Factor H, which is attached secondarily Furthermore, C3b deposition allows the virus to utilize CRs to enhance the efficiency of infection The role of complement in the immune system, and consequently on human health, has expanded dramatically.
It is a well-characterized and an evolutionarily ancient component of host defense, impairment of which leads to susceptibility to infection.
It has the ability to recognize well-conserved antigens derived from common pathogens, and to do so immediately and robustly. Activation of proteolytic cascades leads to the identification and persecution of the surface identified as foreign and allows complement to contain, control, and finally clear invading microorganisms. In performing these functions, complement represents a cornerstone of the innate defense against infection and provides a vital first-line barrier to invading pathogens.
It is not surprising that the most evolutionarily successful pathogens have developed ways to circumvent or subvert complement in order to utilize host resources. The ways in which pathogens manipulate complement continue to be uncovered at a rapid rate and represent an exciting avenue of research. Further understanding of host-pathogen interactions and the roles complement plays in these interactions may help to develop more effective pharmacological agents against infection and reduce health-care burden.
On top of these important contributions to innate immunity, complement plays a vital role in shaping adaptive immune responses, functionally integrating it into the ability of the host to combat invasion from a wide range of pathogens. Since complement represents such an evolutionarily well-conserved mechanism of host defense, it is not surprising to find that it has been integrated into the relatively newer acquired immune responses.
Complement has now been shown to play a role in both B- and T-cell responses at the organismal level. However, the exact mechanism s by which complement mediates T-cell immunity has yet to be determined. A careful, integrated study of complement effects on B- and T-cell biology will provide valuable insight into the in vivo biology of complement and may have implications for infectious disease as well as immunological disorders, such as in the cases of multiple sclerosis and organ transplantation.
In conclusion, complement is a multifaceted and robust effector, which bridges the innate and adaptive immune systems. It is vital to host defense, and the extent of its influence is becoming increasingly appreciated as additional information regarding the far-reaching effects of its activation is uncovered.
Further study should produce significant dividends in our understanding of host defense as an integrated process and the roles complement plays in bridging innate and adaptive immunity.
Walport MJ. First of two parts. N Engl J Med ; — New York: Garland Publishing, Google Scholar. New York: Marcel Dekker Inc. Book Google Scholar. The complement system of the nurse shark: hemolytic and comparative characteristics. Science ; — C6-like and C3-like molecules from the cephalochordate, amphioxus, suggest a cytolytic complement system in invertebrates. J Mol Evol ; 54 — Immunogenetics ; 55 — Sea urchin coelomocytes specifically express a homologue of the complement component C3.
J Immunol ; — CAS Google Scholar. The ancient origin of the complement system. EMBO J ; 24 — The innate immune repertoire in cnidaria—ancestral complexity and stochastic gene loss. Genome Biol ; 8 :R Origin and Evolution of the Vertebrate Immune System.
Berlin: Springer Edition, Second of two parts. Medzhitov R, Janeway C Jr. Innate immunity. Decoding the patterns of self and nonself by the innate immune system. Gordon S. Pattern recognition receptors: doubling up for the innate immune response. Cell ; — The collectins in innate immunity. Curr Opin Immunol ; 8 — Primitive complement system—recognition and activation. Mol Immunol ; 41 — The structure of MBL-associated serine protease-2 reveals that identical substrate specificities of C1s and MASP-2 are realized through different sets of enzyme-substrate interactions.
J Mol Biol ; — Identification of the C1q-binding sites of human C1r and C1s: a refined three-dimensional model of the C1 complex of complement. J Biol Chem ; — Serine proteases of the classical and lectin pathways: similarities and differences. Immunobiology ; — MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway.
Immunity ; 15 — MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity. Hourcade DE. Properdin and complement activation: a fresh perspective. Curr Drug Targets ; 9 — Purification and crystallization of human anaphylatoxin, C3a. Hoppe Seylers Z Physiol Chem ; — X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2. Structures of complement component C3 provide insights into the function and evolution of immunity.
Nature ; — Factor B structure provides insights into activation of the central protease of the complement system. Nat Struct Mol Biol ; 14 — The crystal structure of C2a, the catalytic fragment of classical pathway C3 and C5 convertase of human complement. The role of properdin in the assembly of the alternative pathway C3 convertases of complement. Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly.
Activator-specific requirement of properdin in the initiation and amplification of the alternative pathway complement. Blood ; — Generation of C5a in the absence of C3: a new complement activation pathway.
Nat Med ; 12 — Complement and coagulation: strangers or partners in crime? Trends Immunol ; 28 — Control of the complement system. Adv Immunol ; 61 — Complement factor I and cofactors in control of complement system convertase enzymes. Methods Enzymol ; — Turnberg D, Botto M. The regulation of the complement system: insights from genetically-engineered mice. Mol Immunol ; 40 — Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis.
Int J Biochem Cell Biol ; 31 — Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat Immunol ; 10 — Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Identification of the second heparin-binding domain in human complement factor H. Human protectin CD59 , an 18,—20, MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers.
Immunology ; 71 :1—9. Esser AF. The membrane attack complex of complement. Assembly, structure and cytotoxic activity. Toxicology ; 87 — Quantitative analysis of adenine nucleotides during the prelytic phase of cell death mediated by C5b Complement mediated cell death is associated with DNA fragmentation.
Cell Death Differ ; 7 — Frank MM. Annihilating host defense. Nat Med ; 7 — Anaphylatoxins: C3a and C5a. Adv Immunol ; 26 :1— Evolution of anaphylatoxins, their diversity and novel roles in innate immunity: insights from the study of fish complement.
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