How does complement protect

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. Role of complement receptor 1 CR1; CD35 on epithelial cells: a model for understanding complement-mediated damage in the kidney. Identification of the membrane receptor for the complement fragment C3d by means of a monoclonal antibody. Structural Immunology of Complement Receptors 3 and 4.

Complement receptor 3 ligation of dendritic cells suppresses their stimulatory capacity. CR3 is the dominant phagocytotic complement receptor on human dendritic cells. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens.

The multiligand-binding protein gC1qR, Putative C1q receptor, is a mitochondrial protein. C1q-mediated chemotaxis by human neutrophils: involvement of gClqR and G-protein signalling mechanisms. Biochem J. Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR.

Analysis of the interaction between globular head modules of human C1q and its candidate receptor gC1qR. C5L2, a nonsignaling C5A binding protein. Membrane cofactor protein of complement is present on human fibroblast, epithelial, and endothelial cells. Membrane cofactor protein CD46 protects cells from complement- mediated attack by an intrinsic mechanism.

Soluble forms of membrane cofactor protein CD46, MCP are present in plasma, tears, and seminal fluid in normal subjects. Nat Immunol. Complement 1 inhibitor is a regulator of the alternative complement pathway. Human factor H and C4b-binding protein serve as factor I-cofactors both encompassing inactivation of C3b and C4b.

Regulation of complement activation by C-reactive protein: targeting of the inhibitory activity of C4b-binding protein. Arthr Res Ther. C8 binding protein bears I antigenic determinants. Ann Hematol. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N.

Identification of the complement decay-accelerating factor DAF on epithelium and glandular cells and in body fluids. Decay-accelerating factor must bind both components of the complement alternative pathway C3 convertase to mediate efficient decay. Decay-accelerating factor regulates T-cell immunity in the context of inflammation by influencing costimulatory molecule expression on antigen-presenting cells. Human protectin CD59 , an 18,, MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers.

CD59 functions as a signal-transducing molecule for human T cell activation. Alternative roles for CD Cell Immunol. Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9. Complement factor H: using atomic resolution structure to illuminate disease mechanisms.

Adv Exp Med Biol. Insights into the effects of complement factor H on the assembly and decay of the alternative pathway C3 proconvertase and C3 convertase. Kishore U, Sim RB. Factor H as a regulator of the classical pathway activation. Role of human factor I and C3b receptor in the cleavage of surface-bound C3bi molecules. J Biochem. Hourcade DE. The role of properdin in the assembly of the alternative pathway C3 convertases of complement. Complement inhibition by human vitronectin involves non-heparin binding domains.

Complement and bacterial infections: from molecular mechanisms to therapeutic applications. Activation of the complement system by Cryptococcus neoformans leads to binding of iC3b to the yeast. Infect Immun. Human C1-inhibitor suppresses malaria parasite invasion and cytoadhesion via binding to parasite glycosylphosphatidylinositol and host cell receptors. A human serum mannose-binding protein inhibits in vitro infection by the human immunodeficiency virus. Virus complement evasion strategies.

Complement and viral pathogenesis. Viral-derived complement inhibitors: current status and potential role in immunomodulation. Exp Biol Med. Complement evasion strategies of viruses: an overview. Front Microbiol. Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity.

J Virol. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 Infection. PLoS Med. Complement-dependent lysis of influenza A virus-infected cells by broadly cross-reactive human monoclonal antibodies. The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses. Inflamm Aller Drug Targets. C5a receptor-deficient dendritic cells promote induction of Treg and Th Lectin-dependent enhancement of ebola virus infection via soluble and transmembrane C-type lectin receptors.

High-dose mannose-binding lectin therapy for Ebola virus infection. Interaction of mannose-binding lectin with HIV type 1 is sufficient for virus opsonization but not neutralization.

Complement opsonization of HIV-1 enhances the uptake by dendritic cells and involves the endocytic lectin and integrin receptor families. Complement opsonization promotes herpes simplex virus 2 infection of human dendritic cells. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. A single asparagine-linked glycosylation site of the severe acute respiratory syndrome coronavirus spike glycoprotein facilitates inhibition by mannose-binding lectin through multiple mechanisms.

The SARS coronavirus spike glycoprotein is selectively recognized by lung surfactant protein D and activates macrophages. Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection.

Tissue Antigens. Direct complement restriction of flavivirus infection requires glycan recognition by mannose-binding lectin. Cell Host Microbe. Differential mechanisms of complement-mediated neutralization of the closely related paramyxoviruses simian virus 5 and mumps virus.

Gupta P, Tripathy AS. Alternative pathway of complement activation has a beneficial role against Chandipura virus infection.

Med Microbiol Immunol. Complement-mediated neutralization of a potent neurotropic human pathogen, Chandipura virus, is dependent on C1q. Intracellular complement — the complosome — in immune cell regulation. Complement C4 prevents viral infection through capsid inactivation. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. Binding of Flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation.

West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H. Inhibition of the membrane attack complex by Dengue Virus NS1 through interaction with vitronectin and terminal complement proteins. Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. A novel factor I activity in Nipah Virus inhibits human complement pathways through cleavage of C3b.

A factor I-like activity associated with chikungunya virus contributes to its resistance to the human complement system. Human immunodeficiency virus type 1 incorporates both glycosyl phosphatidylinositol-anchored CD55 and CD59 and integral membrane CD46 at levels that protect from complement-mediated destruction. The paramyxoviruses simian virus 5 and mumps virus recruit host cell CD46 to evade complement-mediated neutralization. Complement-mediated enhancement of HIV-1 infection in peripheral blood mononuclear cells.

Scand J Infect Dis. The good and evil of complement activation in HIV-1 infection. Cell Mol Immunol. Anti-HIV-1 antibodies trigger non-lytic complement deposition on infected cells. EMBO Rep. Mechanism of complement inactivation by glycoprotein C of herpes simplex virus. Barnum SR. C4a: an anaphylatoxin in name only.

Chemotactic responses of human peripheral blood monocytes to the complement-derived peptides C5a and C5a des Arg. C3a is a chemotaxin for human eosinophils but not for neutrophils. C3a stimulation of neutrophils is secondary to eosinophil activation.

Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release. Differential effects of the complement peptides, C5a and C5a des Arg on human basophil and lung mast cell histamine release.

Kubota Y. The effect of human anaphylatoxins and neutrophils on histamine release from isolated human skin mast cells. J Dermatol. Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells.

J Investig Dermatol. The C5a receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid. Anaphylatoxin-induced histamine release with human leukocytes: studies of C3a leukocyte binding and histamine release. Chronic myelogenous leukemia-derived basophilic granulocytes express a functional active receptor for the anaphylatoxin C3a. The degradation product of the C5a anaphylatoxin C5adesarg retains basophil-activating properties.

Degranulation from human eosinophils stimulated with C3a and C5a. Int Arch Aller Immunol. C3a activates reactive oxygen radical species production and intracellular calcium transients in human eosinophils. The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization.

AP-1 activation through endogenous H2O2 generation by alveolar macrophages. Free Radic Biol Med. Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells. Expression of the receptor for complement C5a CD88 is up-regulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human central nervous system.

Am J Pathol. The receptor for complement anaphylatoxin C3a is expressed by myeloid cells and nonmyeloid cells in inflamed human central nervous system: analysis in multiple sclerosis and bacterial meningitis. Protein Sci. The role of complement factor C3 in lipid metabolism. Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma. The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculature in vitro and in vivo.

Agents Actions. Williams TJ. Vascular permeability changes induced by complement-derived peptides. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. Serum proteomic fingerprints of adult patients with severe acute respiratory syndrome. Clin Chem. Emerg Microbes Infect. Autoantibodies against human epithelial cells and endothelial cells after severe acute respiratory syndrome SARS -associated coronavirus infection.

J Med Virol. Dengue virus induces increased activity of the complement alternative pathway in infected cells. J Virolo. Complement contributes to inflammatory tissue destruction in a mouse model of ross river virus-induced disease. C5a, produced by this process, attracts macrophages and neutrophils and also activates mast cells. This pathway involves complement components C1 , C2 and C4. The pathway is triggered by antibody-antigen complexes binding to C1 , which itself has three subcomponents C1q , C1r and C1s.

The pathway forms a C3 convertase, C4b2a , which splits C3 into two fragments; the large fragment, C3b , can covalently attach to the surface of microbial pathogens and opsonise them; the small fragment, C3a , activates mast cells , causing the release of vasoactive mediators such as histamine.

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. Formation of the pore leads to the targeted lysis of the surface upon which it is assembled, accompanied with a dysregulation of ion concentrations across the membrane and loss of mitochondrial polarity.

B Anaphylatoxins are potent proinflammatory molecules generated from the cleavage of C4, C3, and C5 into C4a, C3a, and C5a C4a not shown , respectively. Binding of anaphylatoxins to the N-terminal region of their cognate receptors, C3aR and C5aR, allows conformational changes to the intracellular domains to induce G-protein coupling and downstream signaling.

The effects of this binding depend on the cell type on which the anaphylatoxin receptor is expressed; and some of the most important cell types and effects in the innate immune response are summarized.

C Generation of the C3b fragments by C3 convertases of all three activation pathways initiates the opsonization pathway of complement, an important effector in the 'tagging' and clearance of foreign bodies. Fc receptors bind to the Fc region of antibody. Binding of the complement receptors to opsonized bodies mediates their sequestration and uptake by phagocytic cells, most commonly macrophages and neutrophils.

MAC assembly and targeted lysis are vital effectors of the antipathogenic activities of complement, but certain pathogens have evolved mechanisms of self-protection that can limit the destructive potential and enable the pathogen to avoid persecution Therefore, it is crucial for complement activation to engage and recruit other components of the immune system through the generation of potent proinflammatory molecules that serve as both an alert signal to the immune system as a whole and also as potent chemoattractants to certain classes of leukocytes Figure 3B.

Anaphylatoxin molecules are evolutionarily related to one another and as such share a relatively high degree of homology, as well as somewhat overlapping functions in the generation of the immune response C5a has been shown to be considerably more potent than C3a and C4a in inducing biologically relevant responses, with C4a being the weakest to the extent that physiologically potent functions in humans and a cognate receptor have yet to be described for this molecule 51 , Anaphylatoxins are potent phlogistic molecules whose physiological functions include many hallmark proinflammatory activities, such as increases in vascular permeability, smooth muscle contraction, leukocyte recruitment, and increases in other accoutrements of white blood-cell responses e.

Inactivation of anaphylatoxin molecules is an important determinant of the duration and extent of their potent functions and represents an alternative mechanism to control complement activation. Cleavage of the N-terminal arginine of both C5a and C3a by serum carboxypeptidases i.

The third and final major effector arm enabling the activated complement cascade to protect the host from infection lies in the ability of phagocytic cells to recognize, ingest, and eliminate cells coated with opsonins generated as a result of complement activation Figure 3C. CR1 CD35 is a multifunctional receptor that is expressed in the majority of peripheral blood cells and binds with high affinity to C4b and C3b, as well as to iC3b, C3dg, C1q, and mannose-binding protein 76 , 77 , 78 , 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.