How can complement be activated

Binding of CR1 to the complement opsonin fragments serves to mediate clearance of immune complexes, especially in erythrocytes, and to mediate phagocytosis by neutrophils and monocytes Furthermore, CR1 plays a role in antigen presentation to B cells and is also a potent inhibitor of both the classical pathway and the AP of complement activation by exhibiting decay-accelerating activity for both C3 and C5 convertases, as well as cofactor activity for Factor-I-mediated cleavage of C3b and C4b Nevertheless, it is the principal CR enhancing B-cell immunity and will be discussed at length below, along with similar adaptive immune functions for CR1.

CRIg is a more recently identified CR of the immunoglobulin superfamily expressed on a restricted subset of tissue-resident macrophages, including the Kupffer cells in the liver Kupffer cells from CRIg-deficient mice are unable to efficiently clear C3-opsonized particles, resulting in increased mortality in the host in response to infection CRIg may represent an important component of phagocytosis not only in the reticuloendothelial system of which the Kupffer cells are dominant but also in other resident tissue macrophages, such as alveolar macrophages of the lung and foam cells in atherosclerotic plaques 75 , The three terminal effector pathways of complement work in concert to protect the host from common pathogenic invasions.

Many of the functions of complement activation take place through the use of germline-transmitted molecules that recognize relatively few pathogens, but are able to do so immediately and thus represent an important effector of the innate immune system.

As discussed below, deficiency in these pathways leads to an impaired host immune response to common pathogens. However, the ability of complement to participate in host defense is not limited to these innate immune activities and effector systems of complement also contribute to efficient adaptive immune responses at several levels.

The aforementioned functions of the complement system, oposonization, lysis, and generation of the inflammatory response through soluble mediators, are paradigmatic and represent a well-characterized component of an innate host defense. It has become increasingly appreciated that complement functions in host defense extend beyond innate immune responses. The finding that B lymphocytes bound C3 raised the question as early as in the s as to whether the complement system was involved in adaptive immune responses Subsequent work demonstrated that depletion of C3 impaired humoral immune responses and provided direct evidence that efficient adaptive responses were contingent on an intact complement system in some cases Further study in animals bearing natural complement deficiencies implicated the classical pathway as a crucial mechanism for efficient antigen trapping and retention in lymphoid tissues e.

The humoral arm of the adaptive immune response is tasked with protecting extracellular spaces through the generation of effector and memory B cells, and B-cell-produced antibodies, leading to neutralization and opsonization of pathogen and providing immunological memory against reinfection.

The potency of this response stems from a complex interplay of immune mechanisms, contingent on the strength of antigenic stimuli and the presence of helper T-cell assistance, among many other factors 2.

Complement effectors are engaged with humoral immunity at multiple stages of B-cell differentiation and can influence B-cell biology on several levels 89 , As alluded to previously, complement enhances B-cell immunity principally through CRs, CR1 CD35 and CR2 CD21 , expressed on B lymphocytes and follicular dendritic cells FDCs , and binding to the complement opsonins in a concerted effort with the phagocytic system 75 , 90 , Thus, complement can be viewed as a 'natural adjuvant' and as an instructor of the humoral immune response The functional consequence of this modulation of B-cell signaling can be observed in multiple settings.

B cells first express the CDCDCD81 coreceptor as they migrate from the bone marrow into the periphery, generally referred to as the transitional stage that has important implications in the elimination of self-reactive B cells and in the positive selection of B1 cells B1 cells, which are the chief sources of natural antibody with repertoires that are highly biased toward conserved antigens e.

These mice also have reduced numbers of B1a cells and show impaired generalized antibody production In addition to modulating B1 activity and the production of natural antibodies, cross-linking of the CDCDCD81 coreceptor complex with BCR enhances B-cell immunity in later stages of B-cell differentiation as well.

Coupling C3d to low-affinity antigen, which if uncoupled would cause B-cell death, results in not only survival but also B-cell activation and production of antibody, suggesting a role of complement in the 'instruction' of naive B cells in the periphery Similarly, activation of mature peripheral and follicular B cells by complement-opsonized antigen leads to their migration to the lymphoid T-cell:B-cell boundary, where helper T cells provide costimulation via CD40, leading to B-cell activation and expansion.

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. Activation of the early components of the classical complement pathway under physiologic conditions.

Google Scholar. Toward a structure-based comprehension of the lectin pathway of complement. Mol Immunol 56 — Structural and functional overview of the lectin complement pathway: its molecular basis and physiological implication. Arch Immunol Ther Exp Warsz 61 — M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement.

Scand J Immunol 62 — L-ficolin is a pattern recognition molecule specific for acetyl groups. J Biol Chem —9. MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. Immunity 15 — The serine protease domain of MASP enzymatic properties and crystal structure in complex with ecotin. PLoS One 8 :e Small mannose-binding lectin-associated protein plays a regulatory role in the lectin complement pathway.

Quantitative characterization of the activation steps of mannan-binding lectin MBL -associated serine proteases MASPs points to the central role of MASP-1 in the initiation of the complement lectin pathway. Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: two genes, five proteins and many functions?

Biochim Biophys Acta — A true autoactivating enzyme. Structural insight into mannose-binding lectin-associated serine protease-2 activations. Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. Structural basis for activation of the complement system by component C4 cleavage. Trends Mol Med 14 — C1 inhibitor, a multi-functional serine protease inhibitor. Thromb Haemost — A new role for Cinhibitor in homeostasis: control of activation of the first component of human complement.

Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet — Galanakis DK, Ghebrehiwet B. A unique property of a plasma proteoglycan, the C1q inhibitor. An anticoagulant state resulting from its binding to fibrinogen. J Clin Invest 93 — Complement C1q-target proteins recognition is inhibited by electric moment effectors. J Mol Recognit 20 — The classical activation pathway of the human complement system is specifically inhibited by calreticulin from Trypanosoma cruzi.

In silico and in vitro studies on the protein-protein interactions between Brugia malayi immunomodulatory protein calreticulin and human C1q. PLoS One 9 :e MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation. Mol Immunol 54 — Mol Immunol 40 —9. Complement component C3 binds to activated normal platelets without preceding proteolytic activation and promotes binding to complement receptor 1.

Identification of a novel mode of complement activation on stimulated platelets mediated by properdin and C3 H2O. Properdin: binding to C3b and stabilization of the C3b-dependent C3 convertase. Hourcade DE. The role of properdin in the assembly of the alternative pathway C3 convertases of complement.

Properdin: emerging roles of a pattern-recognition molecule. Annu Rev Immunol 28 — Identification of tubular heparan sulfate as a docking platform for the alternative complement component properdin in proteinuric renal disease. Complement alternative pathway acts as a positive feedback amplification of neutrophil activation. Blood —9. Myeloperoxidase directs properdin-mediated complement activation.

Weibel—Palade bodies — sentinels of acute stress. Nat Rev Nephrol 5 —6. Platelet activation leads to activation and propagation of the complement system. J Exp Med —9. Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis.

Severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes. Hematin promotes complement alternative pathway-mediated deposition of C3 activation fragments on human erythrocytes: potential implications for the pathogenesis of anemia in malaria. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome.

Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science — Insights into complement convertase formation based on the structure of the factor B-cobra venom factor complex. EMBO J 28 — Recombinant and native zymogen forms of human complement factor D. The role of mannose-binding lectin-associated serine protease-3 in activation of the alternative complement pathway.

Essential role of mannose-binding lectin-associated serine protease-1 in activation of the complement factor D. Clin Exp Immunol — Factor B structure provides insights into activation of the central protease of the complement system. Nat Struct Mol Biol 14 —8. Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor.

Nat Immunol 10 —7. The tick-over theory revisited: formation and regulation of the soluble alternative complement C3 convertase C3 H2O Bb.

Mol Immunol 45 —9. The structure of C2b, a fragment of complement component C2 produced during C3 convertase formation. Acta Crystallogr D Biol Crystallogr 65 — Smith M, Kerr M. Cleavage of the second component of complement by plasma proteases: implications in hereditary C1-inhibitor deficiency.

Immunol 56 — Aplan A. Bradykinin and the pathogenesis of hereditary angioedema. World Allergy Organ J. Complement driven by conformational changes. Nat Rev Immunol 8 — The C3 convertase of the alternative pathway of human complement.

Enzymic properties of the bimolecular proteinase. Front Immunol 4 Properdin, a positive regulator of complement activation, is expressed in human T cell lines and peripheral blood T cells. Expression of properdin in human monocytes. Properdin, a positive regulator of complement activation, is released from secondary granules of stimulated peripheral blood neutrophils. Properdin plays a protective role in polymicrobial septic peritonitis.

Semi-extended solution structure of human myeloma immunoglobulin D determined by constrained X-ray scattering. Pangburn MK. Analysis of the natural polymeric forms of human properdin and their functions in complement activation.

Local release of properdin in the cellular microenvironment: role in pattern recognition and amplification of the alternative pathway of complement. Front Immunol 3 Native polymeric forms of properdin selectively bind to targets and promote activation of the alternative pathway of complement.

Structural basis for the stabilization of the complement alternative pathway C3 convertase by properdin. Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement. Structural basis for engagement by complement factor H of C3b on a self surface. Nat Struct Mol Biol 18 — Structure of C3b-factor H and implications for host protection by complement regulators.

Nat Immunol 10 — Dissection of CR1, factor H, membrane cofactor protein, and factor B binding and functional sites in the third complement component. Structural basis for complement factor I control and its disease-associated sequence polymorphisms. Physiologic inactivation of fluid phase C3b: isolation and structural analysis of C3c, C3d,g alpha 2D , and C3g.

J Immunol —6. A human cell-surface antigen defined by a monoclonal antibody and controlled by a gene on human chromosome 1. Ann Hum Genet 49 —9. Membrane cofactor protein: importance of N- and O-glycosylation for complement regulatory function.

Role of membrane cofactor protein CD46 in regulation of C4b and C3b deposited on cells. Membrane cofactor protein MCP or CD46 : newest member of the regulators of complement activation gene cluster.

Annu Rev Immunol 9 — Structure of the extracellular portion of CD46 provides insights into its interactions with complement proteins and pathogens. PLoS Pathog 6 :e Dissecting sites important for complement regulatory activity in membrane cofactor protein MCP; CD Functional mapping of the interactions between complement C3 and regulatory proteins using atypical hemolytic uremic syndrome-associated mutations.

Blood Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele. Structure-function analysis of the active sites of complement receptor type 1. Cell — Identification of residues within the segment of human complement component C3 important for its interaction with factor H and with complement receptor 1 CR1, CD A cluster of positively charged amino acids in the C4BP alpha-chain is crucial for C4b binding and factor I cofactor function.

Structural requirements for the complement regulatory activities of C4BP. Mutations in alpha-chain of C4BP that selectively affect its factor I cofactor function. Mol Immunol 46 — Arranged sevenfold: structural insights into the C-terminal oligomerization domain of human C4b-binding protein. Structural requirements for the intracellular subunit polymerization of the complement inhibitor C4b-binding protein. Biochemistry 41 — Characterization of the interaction of human C4b-binding protein with physiological ligands.

Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med — Blood —5. Von Willebrand Factor is a cofactor in complement regulation. Blood 6 —7. Decay accelerating activity of complement receptor type 1 CD Two active sites are required for dissociating C5 convertases. Structure and function of decay accelerating factor CD J Lab Clin Med — Molecular dissection of interactions between components of the alternative pathway of complement and decay accelerating factor CD Decay-accelerating factor must bind both components of the complement alternative pathway C3 convertase to mediate efficient decay.

J Immunol —9. Structure-function analysis of decay-accelerating factor: identification of residues important for binding of the Escherichia coli Dr adhesin and complement regulation. Infect Immun 70 — Human alternative complement pathway: membrane-associated sialic acid regulates the competition between B and beta1 H for cell-bound C3b.

Control of the amplification convertase of complement by the plasma protein beta1H. Whaley K, Ruddy S. Modulation of the alternative complement pathways by beta 1 H globulin. Complement factor H-ligand interactions: self-association, multivalency and dissociation constants.

Zipfel PF, Skerka C. Immunol Today 20 — Each of the three binding sites on complement factor H interacts with a distinct site on C3b.

Structural analysis of the C-terminal region modules 18—20 of complement regulator factor H FH. PLoS One 7 2 :e Both domain 19 and domain 20 of factor H are involved in binding to complement C3b and C3d. Mol Immunol 47 — Structural basis for sialic acid-mediated self-recognition by complement factor H. Nat Chem Biol 11 1 — The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome.

Structure of complement factor H carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syndrome. EMBO J 25 — Mutations of factor H impair regulation of surface-bound C3b by three mechanisms in atypical hemolytic uremic syndrome. Multimeric interactions between complement factor H and its C3d ligand provide new insight on complement regulation. The C-terminus of complement regulator factor H mediates target recognition: evidence for a compact conformation of the native protein.

Structural basis for complement factor H linked age-related macular degeneration. The central portion of factor H modules is compact and contains a structurally deviant CCP module.

Solution structure of CCP modules illuminates functional architecture of the complement regulator, factor H. A new map of glycosaminoglycan and C3b binding sites on factor H. Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis. Identification of the second heparin-binding domain in human complement factor H.

The proteoglycan glycomatrix: a sugar microenvironment essential for complement regulation. Inflammation 4 Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration-linked single nucleotide polymorphism. Localization of the third heparin-binding site in the human complement regulator factor H1.

Mol Immunol 43 — Molecular interactions between complement factor H and its heparin and heparan sulfate ligands. Factor h and properdin recognize different epitopes on renal tubular epithelial heparan sulfate. Functional evaluation of factor H genetic and acquired abnormalities: application for atypical hemolytic uremic syndrome aHUS. Methods Mol Biol — Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions.

Complementing the sugar code: role of GAGs and sialic acid in complement regulation. Mol Innate Immun 6 Complement factor H polymorphism and age-related macular degeneration. Science —4. Complement factor H variant increases the risk of age-related macular degeneration. Complement factor H polymorphism in age-related macular degeneration.

Science —9. Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids. Weismann D, Binder CJ. The innate immune response to products of phospholipid peroxidation. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Complement factor H binds at two independent sites to C-reactive protein in acute phase concentrations. Dimerization of complement factor H-related proteins modulates complement activation in vivo.

J Clin Invest — Hum Mol Genet 19 — Bubeck D. The making of a macromolecular machine: assembly of the membrane attack complex.

Biochemistry 53 — C5 convertase of the alternative complement pathway: covalent linkage between two C3b molecules within the trimolecular complex enzyme. Covalent binding of C3b to C4b within the classical complement pathway C5 convertase.

Determination of amino acid residues involved in ester linkage formation. J Biol Chem —6. Formation of covalently linked C3-C3 dimers on IgG immune aggregates. Eur J Immunol 21 —9. Substrate recognition by complement convertases revealed in the C5-cobra venom factor complex.

EMBO J 30 — Pangburn MK, Rawal N. Structure and function of complement C5 convertase enzymes. Biochem Soc Trans 30 — Rawal N, Pangburn MK. Formation of high affinity C5 convertase of the classical pathway of complement.

Fischer E, Kazatchkine MD. Surface-dependent modulation by H of C5 cleavage by the cell-bound alternative pathway C5 convertase of human complement. J Immunol —4. A molecular concept of the properdin pathway.

Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12 —7. Molecular intercommunication between the complement and coagulation systems.

Generation of C5a by phagocytic cells. Am J Pathol — Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Interaction between the coagulation and complement system. Adv Exp Med Biol —9. Plasminogen is a complement inhibitor. Interplay between fibrinolysis and complement: plasmin cleavage of iC3b modulates immune responses. J Thromb Haemost 13 4 —8.

Assembly and regulation of the membrane attack complex based on structures of C5b6 and sC5b9. Cell Rep 1 —7. The membrane attack complex of complement: relation of C7 to the metastable membrane binding site of the intermediate complex C5b Bhakdi S, Tranum-Jensen J.

Complement lysis: a hole is a hole. Immunol Today 12 — Beyond lysis: how complement influences cell fate. Clin Sci — Cytolysis of nucleated cells by complement: cell death displays multi-hit characteristics.

Formation of transmural complement pores in serum-sensitive Escherichia coli. Infect Immun 55 — Lewis LA, Ram S. Meningococcal disease and the complement system. Virulence 5 — Morgan BP. Complement membrane attack on nucleated cells: resistance, recovery and non-lethal effects. Biochem J :1— Rat brain Thy-1 glycoprotein.

The amino acid sequence, disulphide bonds and an unusual hydrophobic region. The recovery of human polymorphonuclear leucocytes from sublytic complement attack is mediated by changes in intracellular free calcium.

Biochem J —8. Restriction of complement-mediated membrane damage by the eighth component of complement: a dual role for C8 in the complement attack sequence. A serum protein SP40,40 modulates the formation of membrane attack complex of complement on erythrocytes.

Mol Immunol 26 — SC5b-7, SC5b-8 and SC5b-9 complexes of complement: ultrastructure and localization of the S-protein vitronectin within the macromolecules. Eur J Immunol 19 — Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9. Structure of a soluble, glycosylated form of the human complement regulatory protein CD Structure 2 — High-resolution structures of bacterially expressed soluble human CD J Physiol — Human protectin CD59 , an 18,, MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers.

Immunology 71 :1—9. Defining the CDC9 binding interaction. Structure of human C8 protein provides mechanistic insight into membrane pore formation by complement. Mapping the intermedilysin-human CD59 receptor interface reveals a deep correspondence with the binding site on CD59 for complement binding proteins C8alpha and C9.

Platelet-activating factor and kinin-dependent vascular leakage as a novel functional activity of the soluble terminal complement complex. Recovery of human neutrophils from complement attack: removal of the membrane attack complex by endocytosis and exocytosis. Moskovich O, Fishelson Z. Live cell imaging of outward and inward vesiculation induced by the complement c5b-9 complex.

Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement. Nature —2. The role of the anaphylatoxins in health and disease. Chemotaxis by mouse macrophage cell lines.

Characterization of C3a anaphylatoxin receptor on guinea-pig macrophages. Immunology 79 —8. C3a activates reactive oxygen radical species production and intracellular calcium transients in human eosinophils. Eur J Immunol 24 — Activation of human neutrophils by C3a and C5A.

Comparison of the effects on shape changes, chemotaxis, secretion, and respiratory burst. FEBS Lett —4. C3a activates the respiratory burst in human polymorphonuclear neutrophilic leukocytes via pertussis toxin-sensitive G-proteins. Blood 83 — Is the complement activation product C3a a proinflammatory molecule?

Re-evaluating the evidence and the myth. Chronic myelogenous leukemia-derived basophilic granulocytes express a functional active receptor for the anaphylatoxin C3a. Eur J Immunol 23 — Histamine-induced inhibition of normal human basophil chemotaxis to C5a.

Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells. J Invest Dermatol —6. Human T cells express the C5a receptor and are chemoattracted to C5a.

Modulation of the antitumor immune response by complement. Nat Immunol 9 — Novel function of C4a anaphylatoxin. Release from monocytes of protein which inhibits monocyte chemotaxis. Complement anaphylatoxin C4a inhibits C5a-induced neointima formation following arterial injury. Mol Med Rep 10 — Barnum SR. C4a: an anaphylatoxin in name only. J Innate Immun Structural definition of the C5a C terminus by two-dimensional nuclear magnetic resonance spectroscopy. Proteins 28 —7. Carboxypeptidase N: a pleiotropic regulator of inflammation.

Mol Immunol 40 — Targeted disruption of the gene encoding the murine small subunit of carboxypeptidase N CPN1 causes susceptibility to C5a anaphylatoxin-mediated shock.

Protein Sci 22 — Structure of human desArg-C5a. Acta Crystallogr D Biol Crystallogr 66 —7. Two different transduction pathways are activated by C3a and C5a anaphylatoxins on astrocytes.

Brain Res Mol Brain Res — Structural and functional characterization of human and murine C5a anaphylatoxins. Acta Crystallogr D Biol Crystallogr 70 — Sulfation of tyrosine in the human C3a receptor is essential for binding of C3a anaphylatoxin. Mol Immunol 42 —7. Mery L, Boulay F. Evidence that the extracellular N-terminal domain of C5aR contains amino-acid residues crucial for C5a binding.

Eur J Haematol 51 —7. Two-site binding of C5a by its receptor: an alternative binding paradigm for G protein-coupled receptors. Structure-function relationships of human C5a and C5aR.

An activation switch in the ligand binding pocket of the C5a receptor. A comprehensive structure-function map of the intracellular surface of the human C5a receptor. Identification of critical residues. Essential role for the second extracellular loop in C5a receptor activation. Nat Struct Mol Biol 12 —6. C5a delays apoptosis of human neutrophils by a phosphatidylinositol 3-kinase-signaling pathway.

Kidney Int 61 — Activation of the loop is promoted in the presence of bacterial and fungal cell walls, but is inhibited by molecules on the surface of normal mammalian cells. This pathway is activated by the binding of mannose-binding lectin MBL to mannose residues on the pathogen surface. This pathway is initiated by the splitting of C5 , and attachment of C5b to a target. C6, C7, C8 and C9 unite with C5b, and this membrane-attack complex MAC , when inserted into the outer membrane of some bacteria, can contribute to their death by lysis.

Red cells which have antibody bound to the cell surface can also activate the classical and lytic pathways, and become susceptible to lysis. The complement system plays a critical role in inflammation and defence against some bacterial infections. Complement may also be activated during reactions against incompatible blood transfusions, and during the damaging immune responses that accompany autoimmune disease. Deficiencies of individual complement components or inhibitors of the system can lead to a variety of diseases Table 1 , which gives some indication of their role in protection against disease.

Register Log in. Complement System Download complement system.