CR 2009139

npg Complement in host immunity
Cell Research (2010) 20:34-50.

34 npg
© 2010 IBCB, SIBS, CAS All rights reserved 1001-0602/10 $ 32.00
REVIEW www.nature.com/cr
Complement and its role in innate and adaptive immune

responses
Jason R Dunkelberger1, Wen-Chao Song1
1
Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of
Medicine, 1254 BRB II/III, 421 Curie Blvd, Philadelphia, PA, 19104, USA
The complement system plays a crucial role in the innate defense against common pathogens. Activation of com-
plement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen
as well as in the generation of the classical inflammatory response through the production of potent proinflammatory
molecules. More recently, however, the role of complement in the immune response has been expanded due to ob-
servations that link complement activation to adaptive immune responses. It is now appreciated that complement is
a functional bridge between innate and adaptive immune responses that allows an integrated host defense to patho-
genic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen
interactions as well as the organization and orchestration of the host immune response. This review attempts to sum-
marize the roles that complement plays in both innate and adaptive immune responses and the consequences of these
interactions on host defense.
Keywords: complement, innate immunity, adaptive immunity, inflammation, host defense
Cell Research (2010) 20:34-50. doi: 10.1038/cr.2009.139; published online 15 December 2009
Introduction nity is composed of those immunological effectors that

provide robust, immediate, and nonspecific immune re-
The mammalian immune system is a remarkable sponses. These include evolutionarily primitive humoral,
complex of biochemical processes enabling efficient de- cellular, and mechanical processes that nevertheless play
tection and prosecution of pathogens that threaten host a vital role in the protection of the host from pathogenic
viability. The incredible complexity of mammalian im- challenge.
mune systems is required to provide adequate defense The complement system comprises a far-reaching and
in spite of the impressive number of pathogens and host vital component of innate immunity and represents one
processes that cause disease. Immune processes have of the major effector mechanisms of the innate immune
traditionally been divided into two broad, but intercon- system. Discovered in 1896 by Bordet as a heat-labile
nected, subsystems on the basis of their functions in component of serum, it was so named for its ability to
host defense. The adaptive immune system is organized ‘complement’ the antibacterial properties of antibody in
around two classes of specialized lymphocytes, T and B the heat-stabile fraction of serum. It is now appreciated
cells, which display an extremely diverse repertoire of that complement is a complex network of plasma and
antigen-specific recognition receptors that enable specific membrane-associated serum proteins which can elicit
identification and elimination of pathogens, as well as highly efficient and tightly regulated inflammatory and
adaptive immune measures that ensure tailored immune cytolytic immune responses to infectious organisms
responses, as well as long-lived immunological memory (bacteria, viruses, parasites), tissue damaged by physical,
against reinfection. In contrast, the innate arm of immu- chemical, or neoplastic insults, and other surfaces identi-
fied as ‘nonself’.
For many years after its discovery, the role of comple-
Correspondence: Wen-Chao Song
ment in immunity was thought to be confined to innate
Tel: +215-573-6641; Fax: +215-746-8941 immune responses with no impact on adaptive immune
E-mail: Songwe@upenn.edu responses, in much the same way as innate immunity, in
Cell Research | Vol 20 No 1 | January 2010

Jason R Dunkelberger and Wen-Chao Song npg
35
general, was relegated to those functions of immunity mechanisms of the adaptive immune response to infec-
that involved prevention and confinement of infection tion.
while adaptive immunity provided effectors required to The complement system can be activated through three
clear the infection. The ability to separate the functions major pathways: classical, lectin, and alternative (Figure
of the two arms of immunity was called into question as 1) [1, 2, 11]. Initiation of the classical pathway occurs
early as the 1970s, and since then the body of knowledge when C1q, in complex with C1r and C1s serine proteases
illustrating the interplay between the adaptive and innate (the C1 complex), binds to the Fc region of complement-
wings of immunity has grown dramatically. Similarly, fixing antibodies (generally IgG1 and IgM) attached to
the ability of complement to not only affect robust innate pathogenic surfaces. Autocatalytic activation of C1r and
immune responses but also to interface with and influ- C1s in turn cleaves C4 and C2 into larger (C4b, C2a) and
ence T- and B-cell biology and adaptive responses has smaller (C4a, C2b) fragments. The larger fragments as-
become increasingly appreciated. This review attempts sociate to form C4bC2a on pathogenic surfaces, and the
to summarize the roles that complement biology plays complex gains the ability to cleave C3 and is termed the
in the immune response, both in the innate detection and C3 convertase. Generation of the C3 convertase, which
elimination of pathogenic infections and in the modula- cleaves C3 into the anaphylatoxin C3a and the opsonin
tion of adaptive immune responses. C3b, is the point at which all complement activation
cascades converge [2]. When C3 is cleaved into C3b, it
Complement origins and activation exposes an internal thioester bond that allows stable co-
valent binding of C3b to hydroxyl groups on proximate
Complement is a system of more than 30 proteins in carbohydrates and proteins. This activity underpins the
the plasma and on cell surfaces, amounting to more than entire complement system by effectively ‘tagging’ mi-
3 g/L and constituting more than 15% of the globular croorganisms as foreign, leading to further complement
fraction of plasma [1]. This array of proteins is organized activation on and around the opsonized surface and ter-
into a hierarchy of proteolytic cascades that start with the minating in the production of anaphylatoxins and assem-
identification of pathogenic surfaces and lead to the gen- bly of the MAC [1, 11].
eration of potent proinflammatory mediators (anaphyla- The lectin pathway functions in an analogous, but
toxins), opsonization (‘coating’) of the pathogenic sur- immunoglobulin-independent, fashion. As opposed
face through various complement opsonins (e.g., C3b), to recognizing antigen-antibody immune complexes,
and targeted lysis of the pathogenic surface through the the lectin pathway employs germline-encoded pattern-
assembly of membrane-penetrating pores known as the recognition receptors (PRRs), such as mannose-binding
membrane attack complex (MAC) [2, 3]. Complement lectin (MBL) and ficolins, to conduct nonself recognition
represents an evolutionarily ancient component of host [2]. Antigen-recognition receptors (e.g., antibody, T-cell
defense, and the evolutionary survival value of comple- receptors) of the adaptive immune system hypothetically
ment serves to accentuate the important roles it plays in have the ability to recognize every possible antigen by
host defense. Originally, it was thought to be a unique way of their incredible somatic diversity. PRRs, in con-
vertebrate feature, showing high degrees of homology in trast, focus on a few highly conserved structures present
structure and function among the higher vertebrates as in large groups of microorganisms popularly referred to
phylogentically ancient as the nurse shark [4]. However, as pathogen-associated molecular patterns (PAMPs) [12].
genomic and functional studies on complement effector Examples of PAMPs include endotoxin or lipopolysac-
molecules have discovered complement analogs in even charide of Gram-negative bacteria, lipoteichoic acid of
more ancient phyla, including Cephalochordata (lance- Gram-positive bacteria, and β-glucan of fungi [13, 14].
lets), Urochordata (tunicates), and Echinodermata (sea MBL is a well-characterized receptor of the collectin
urchins) [5-7]. More recently, functional C3 was identi- family, so termed because of the fusion of a collagenous
fied in horseshoe crab (Carcinoscorpius rotundicauda) domain to a calcium-dependant lectin domain, which are
and cnidarian anthrozoans (Nematostella vectensis [starlet synthesized in the liver and secreted into the plasma as
sea anemone]), demonstrating that the complement sys- a component of the acute-phase response [12, 13]. MBL
tem is ancient [8, 9]. Adaptive immunity is, by contrast, can bind to common carbohydrate PAMPs on Gram-
much younger and is generally considered restricted to positive and Gram-negative bacteria and yeast, as well
jawed vertebrates [10]. Furthermore, adaptive immune as on some viruses and parasites [15, 16]. Similar to the
processes are rooted in the earlier innate immune pro- C1 complex of the classical pathway, MBL is complexed
cesses, providing logical evidence for why complement with MBL-associated serine proteases (MASPs)-1, -2,
(and innate immunity in general) would integrate with and -3 which are functionally and structurally similar
www.cell-research.com | Cell Research

36
CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY
Antigen: antibody PAMP recognition by Spontaneous hydrolysis/

immune complexes lectins pathogenic surfaces
Initiation
Factor D
C1q Antibody MBL Carbohydrate C3(H2O) Factor B
Microbe surface
C3
C1r/C1s MASPs Factor B

C4
C3b
C2 Properdin Factor D
Amplification
Amplification
loop
C4a, C3a, C5a C3b

C3 and C5
convertases
C5b-9
Termination
Inflammation Lysis Opsonization
Figure 1 The complement pathway. Complement can be activated through three pathways: classical, lectin, and alternative.
The classical pathway is activated when C1q binds to antibody attached to antigen, activating C1r and C1s, which cleave C4
and C2. The lectin pathway is activated when mannose-binding lectin (MBL) encounters conserved pathogenic carbohydrate
motifs, activating the MBL-associated serine proteases (MASPs) and again cleaving C4 and C2. C4 and C2 cleavage prod-
ucts form the classical and lectin pathway C3 convertase, C4bC2a, which cleaves C3 into C3b and C3a. A second molecule
of C3b can associate with C4bC2a to form the C5 convertase of the classical and lectin pathways, C4bC2aC3b. The alterna-
tive pathway (AP) is activated when C3 undergoes spontaneous hydrolysis and forms the initial AP C3 convertase, C3(H2O)
Bb, in the presence of Factors B and D, leading to additional C3 cleavage and eventual formation of the AP C3 convertase
(C3bBb) and AP C5 convertase (C3bBbC3b). Properdin facilitates AP activation by stabilizing AP convertases. All three path-
ways culminate in the formation of the convertases, which in turn generate the major effectors of the complement system:
anaphylatoxins (C4a/C3a/C5a), the membrane attack complex (MAC), and opsonins (e.g., C3b). Anaphylatoxins are potent
proinflammatory molecules derived from the cleavage of C4, C3, and C5. The MAC is a terminal assembly of complement
components C5b through C9, which can directly lyse targeted surfaces. C3b induces phagocytosis of opsonized targets and
also serves to amplify complement activation through the AP.
(although not identical, see Harmat et al. [17]; Bally et (which also contains an activated thioester bond), which
al. [18]; Gal et al. [19]) to C1s and C1r, such that the will bind to Factor B in turn allowing cleavage of Fac-
binding of MBL to pathogenic surfaces leads to the acti- tor B into Bb and Ba by Factor D and forming the initial
vation of associated MASPs, cleavage of C2 and C4, and AP C3 convertase, C3(H2O)Bb [2]. This C3 convertase
ultimately to the generation of the C3 convertase of both forms the basis of an amplification loop in which
classical and lectin pathways, C4bC2a [12, 13, 17-23]. C3(H2O)Bb starts to convert C3 into C3b and C3a, in an
The AP is mechanistically distinct from the classi- analogous fashion to the C3 convertase (C4bC2a) of the
cal and lectin pathways (Figure 1). It is initiated by the classical and lectin pathways. C3b generated in such a
low-level, spontaneous hydrolysis of C3 (which is very fashion can bind to surfaces in the vicinity and associate
abundant in the plasma) to the C3b analog, C3(H2O) with Factor B, which can in turn be activated by Factor

37
D to form C3bBb, the predominant AP C3 convertase [1, confined to appropriate pathogenic surfaces, and genera-
11]. This complex can be further stabilized by properdin tion of potent effectors needs to be tightly regulated to
(Factor P), which helps to amplify AP activation [24]. prevent collateral damage to healthy host tissues. There-
As a consequence of this constitutive activation, and due fore, many steps involved in complement activation are
to the ability to form a feedback amplification pathway, checked by inhibitors so that the final system represents
there are a number of complement inhibitory proteins re- an intricate, homeostatic balance between the efficient
sponsible for confining complement activation to appro- detection and destruction of pathogens and the minimiza-
priate contexts to prevent errant complement activation tion of bystander tissue damage. Complement regulation
in the healthy host, which will be discussed below. occurs predominantly at two steps within the cascades,
Further insight into the formation of C3 convertases of at the level of the convertases, both in their assembly
all three pathways has been afforded through structural and in their enzymatic activity, and during assembly of
determinations of key C3 convertase components. Due the MAC (Figure 2) [36]. Upon generation of C4b and
to the size of C3, determination of its complete structure C3b fragments (through upstream complement activa-
remained elusive for many years. Solving the structures tion) and their covalent linkage to cellular surfaces, they
of the smaller cleavage products of C3, including C3a experience one of the two fates. The first, which prevents
and C3d (discussed below), eventually culminated in these molecules from forming active convertases, is the
the structural determination of intact C3 which afforded catabolism of C3b and C4b via the constitutively active
extensive insight into C3’s activation, regulation, and serine protease Factor I which can cleave C3b and C4b
biological functions [25-27]. Insight into the arrange- into inactive fragments, such as iC3b, C3c, and C3dg
ment and activation of the AP C3 convertase has recently (Figure 2A) [37]. To prevent nonspecific C3b degra-
been gained as a result of the structural determinations of dation, for instance in the case of proper complement
both Factor B and the AP proconvertase, C3bB [28, 29]. activation, Factor I requires cofactors for its proteolytic
Similarly, the catalytic function of the classical pathway activity. These cofactors include membrane cofactor pro-
C3 and C5 convertases has been illuminated through the tein (MCP; CD46), complement receptor 1 (CR1), and
structural determination of C2a, allowing insight into the Factor H which are either intrinsic membrane proteins on
architecture and biological activities of this pathway [30]. host cells or have various mechanisms to ensure prefer-
Two additional mechanisms for the initiation of ential cofactor activity on host surfaces, and thereby limit
complement activation have recently been described, complement activation in these contexts and prevent by-
which introduce novel models for complement activation stander tissue damage [38-40].
with currently undefined physiological roles. The first The second potential fate for deposited C3b/C4b frag-
mechanism involves properdin, which has a canonical ments is to form active convertases, consistent with their
role in AP activation by stabilizing the AP C3 convertase normal biological imperative. To prevent unregulated C3
C3bBb. However, additional evidence has demonstrated convertase formation in the event that C3b deposition
that properdin could promote de novo C3 convertase as- cannot be controlled, there are several complement in-
sembly when immobilized to an inert surface and initiate hibitors that possess inhibitory and/or decay-accelerating
C3 convertase formation on microbial surfaces (such activity for convertases. A primary example of this cat-
as Neisseria gonorrhoeae) [31, 32]. The novel role of egory of complement inhibitors is decay-accelerating
properdin in AP complement initiation was supported by factor (DAF; CD55), which serves to inhibit assembly
evidence from a properdin knockout mouse model [33]. of new C3 convertases and shorten the half-life of pre-
Additionally, it has been reported that C3 and C5 can be formed convertases, thereby limiting their ability to par-
directly cleaved by proteases unrelated to the comple- ticipate in further complement activation [36, 38]. Other
ment cascade, such as kallikrein and thrombin (which complement inhibitors with decay-accelerating activity
are involved in coagulation), leading to an additional include CR1, Factor H, C4-binding protein (C4BP), and
source of anaphylatoxins (C5a and C3a) and establishing the rodent-specific regulator Crry (Figure 2B) [38]. New
a novel and potentially important connection between the structural advances have helped to elucidate the mecha-
complement and coagulation cascades [34, 35]. nistic basis of convertase regulation. A recent study has
solved the structure of the first four domains of Factor H
Regulation of complement activation in complex with C3b, suggesting that Factor H destabi-
lizes the AP C3 convertase through competition and also
Due to the destructive potential of complement activa- provides a binding platform for Factor I-mediated pro-
tion, especially in light of the potent feedback amplifica- teolysis of C3b, thereby limiting the AP [41]. Similarly,
tion ability of the AP, complement activities need to be determination of the structure of the AP C3 convertase

38
A Factor I cofactor activity stabilized by a bacterial immune-evasion protein staphy-

Factor I iC3b lococcal complement inhibitor (SCIN) (discussed below)
C3b C3dg
MCP C3c helped to elucidate mechanisms of both C3 convertase
CR1
structure/function and microbial evasion strategies [42].
Factor H
Host-specific protection is generally achieved by en-
suring host-specific expression patterns of complement
C4b
Factor I C4c regulators. While many of the complement regulators are
C4d
MCP
intrinsic membrane proteins in host cells, the fluid-phase
C4BP
CR1
inhibitor Factor H achieves host-specific protection by
binding polyanions, such as sialic acid and heparin,
B Decay-accelerating activity for C3 convertases which make up an essential component of eukaryotic,
C4b but not prokaryotic, cell surfaces [38, 43]. The func-
Classical
pathway C4bC2a
C2a tional consequence of this mechanism is that Factor H is
DAF
CR1 preferentially targeted to host surfaces, where it exerts
C4BP cofactor and decay-accelerating activities to prevent C3
Bb
Alternative C3bBb C3b
convertase formation and leads to the catabolism of C3b
pathway DAF to its degradation products (e.g., iC3b, C3dg). The final
Factor H
level of complement control, necessary in situations in
CR1
which there is rampant complement activation, is to in-
C Inhibition of lysis hibit the assembly of the lytic MAC via of membrane-
C9
bound (CD59) or fluid-phase (vitronectin, S protein)
MAC inhibition inhibitors (Figure 2C) [38, 44]. Thus, the array of
C5b-8 prevents C9 binding and polymerization
CD59 complement inhibitory proteins serves to check comple-
Vitronectin
S protein
ment activation in the healthy host and upon complement
activation as a response to infection, helping to confine
the destructive activities of complement to appropriate
D Clevage of the anaphylatoxins
surfaces to minimize bystander tissue damage.
C5a
C5a des Arg
Carboxypeptidase N
Effectors of the complement system
C3a
C3a des Arg
Carboxypeptidase B
Carboxypeptidase R Complement activation, regardless of the pathway,
Figure 2 Complement regulation. Complement activity must be converges on the generation of three broad effector path-
regulated to prevent bystander damage to the host. (A) Factor ways that serve to enable the complement to fulfill its
I-mediated cleavage of C3b and C4b prevents them from form- physiological imperatives in host defense: (1) direct lysis
ing active convertases and requires cofactor activity, so that of targeted surfaces by way of the MAC assembly, (2)
complement can be activated in appropriate contexts. These alerting and priming the immune system by way of the
cofactors include the membrane-bound membrane cofactor generation of potent proinflammatory anaphylatoxins,
protein (MCP) and complement receptor 1 (CR1), as well as
and (3) opsonization and clearance of target surfaces by
the fluid-phase Factor H and C4-binding protein (C4BP). (B)
C3 convertases are regulated by proteins containing decay-
way of the complement opsonins (C4b, C3b, C3bi) and
accelerating activity, which serve to inhibit assembly of new engagement of CRs on phagocytic cells, such as mac-
C3 convertases and shorten the half-life of the preformed con- rophages and neutrophils (Figure 3) [1, 2, 11]. MAC as-
vertases, limiting their ability to participate in complement acti- sembly is germinated when C3b, following its deposition
vation. Proteins with decay-accelerating activity for the classical on cell surfaces, associates with C3 convertases of all
C3 convertase include decay-accelerating factor (DAF), CR1, three pathways to form the C5 convertases; C4bC2aC3b
and C4BP. AP inhibitors with this activity are DAF, Factor H, and
(classical and lectin pathways) and C3bBbC3b (AP) [2,
CR1. (C) The MAC is the lytic complex of complement and its
assembly can be inhibited by the membrane-bound CD59 and
3]. C5 convertases are the staging points for the terminal
the fluid-phase vitronectin and S protein. (D) Anaphylatoxins complement activation and cleave C5 into anaphylatox-
are very potent proinflammatory molecules and their activity is ins C5a and C5b. C5b liberation exposes a binding site
limited by removal of their N-terminal arginine residue by serum for C6, and the subsequent C5bC6 binds reversibly to the
carboxypeptidases, including carboxypeptidase N, B, and R. targeted surfaces and forms the molecular foundation for
Formation of the ‘des-Arg’ forms of C5a and C3a limits their the MAC (Figure 3A) [45]. C7 associates with C5bC6,
ability to interact with their cognate receptors, C5aR and C3aR, creating C5b-7, which is integrated into the phospholipid
respectively.

39
A MAC assembly
C5b
C8
C9
C6
C7
15 nm
Microbe lipid bilayer 10 nm

B Anaphylatoxins and inflammatory response
C3a C5a Chemotaxis
cytokine production
phagocytosis
Macrophage
NH2
Chemotaxis
NH2
C3aR C5aR oxidative burst
Neutrophil phagocytosis
degranulation
Degranulation
COOH Basophil
COOH
α Degranulation
α γ GTP chemtaxis
Eosinophil
GDP β
Degranulation
GDP
GTP β γ chemtaxis
Mast cell
C Opsonization and phagocytosis
C1q MBL: Antibody: C3b/ C3b cleavage products

Microbe
mannose antigen C4b (iC3b, C3c, C3dg)
CR1 CR2 CR4 Fc

CRIg
(CD35) (CD21) CR3 (CD11c/CD18) receptors
(CD11b/CD18)
Microbe
Phagocytic cell
Phagocytic cell
Figure 3 Effectors of the complement system. The function of complement in innate host defense is accomplished through
three broad effector pathways; lysis, inflammation, and opsonization/phagocytosis. (A) Complement activation and the gener-
ation of C5 convertases lead to the liberation of the C5 product, C5b. C5b forms the basis of the MAC assembly. C5b first as-
sociates with C6, C7, and the targeted surface. C8 associates with this complex and is partially inserted into the membrane.
This allows C9 to insert into the lipid bilayer, where approximately 12-15 C9 molecules will form a stably inserted pore with
~10nm diameter. 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 confor-
mational 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 clear-
ance of foreign bodies. Opsonic fragments, such as C3b and its cleavage products, are recognized by complement receptors
1-4 (CR1-4) and CRIg. 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.

40
membrane bilayer and induces the membrane insertion of for C5a) of the rhodopsin family [55-60]. Binding of
C8α and C8β, forming unstable pores. C9 binds to C8α anaphylatoxins to extracellular, N-terminal regions of the
and initiates polymerization of multiple C9 molecules to anaphylatoxin receptors allows conformational changes
form stable inserted pores with a maximum diameter of to the intracellular, C-terminal regions of the receptors,
10 nm (up to 13 C9 molecules) [45]. This C5b-9 com- resulting in coupling to G-proteins, predominantly per-
plex is the fully formed MAC, and is effective in induc- tussis toxin-sensitive Giα, to induce downstream signaling
ing cell lysis in a variety of targets through a multi-hit cascades [61-65]. Activities of anaphylatoxins are con-
process. MAC lytic activity is characterized by a rapid fined by cell types that express their receptors, predomi-
increase in [Ca2+]i, followed by loss of both mitochondri- nantly thought to be cells of myeloid origin, including
al polarity and adenine nucleotide pools (e.g., ADP, ATP) granulocytes (basophils, eosinophils, and neutrophils),
[46]. Whether cell death is apoptotic or necrotic seems monocytes/macrophages, mast cells, and some dendritic
to be a function of C5b-9 quantity, and fragmentation of cells, although there are numerous reports of receptor
DNA has been detected in as little as 30 min after treat- expression in a number of nonmyeloid cell types [54, 59,
ment with a lytic dosage of complement, illustrating the 60, 66-73]. Inactivation of anaphylatoxin molecules is an
destructive potential of the terminal pathway of comple- important determinant of the duration and extent of their
ment activation [45, 47]. potent functions and represents an alternative mechanism
MAC assembly and targeted lysis are vital effectors of to control complement activation. Cleavage of the N-ter-
the antipathogenic activities of complement, but certain minal arginine of both C5a and C3a by serum carboxy-
pathogens have evolved mechanisms of self-protection peptidases (i.e., carboxypeptidase N) rapidly converts
that can limit the destructive potential and enable the each to the ‘des-arg’ form (Figure 2D) [2].
pathogen to avoid persecution [48]. Therefore, it is cru- The third and final major effector arm enabling the
cial for complement activation to engage and recruit oth- activated complement cascade to protect the host from
er components of the immune system through the gen- infection lies in the ability of phagocytic cells to recog-
eration of potent proinflammatory molecules that serve nize, ingest, and eliminate cells coated with opsonins
as both an alert signal to the immune system as a whole generated as a result of complement activation (Figure
and also as potent chemoattractants to certain classes of 3C). Recognition of opsonic complement fragments,
leukocytes (Figure 3B). Anaphylatoxins, C3a, C4a, and including Factor I-generated proteolytic fragments of
C5a, are highly related, pleiotropic, proinflammatory C3b (iC3b, C3c, and C3dg), by phagocytic cells is ac-
molecules ~9 kDa in size (74-77 residues) generated as complished through three families of CRs; the short
products of proteolytic activation of C3, C4, and C5 by consensus repeat module-containing CR1 and CR2, the
upstream complement proteases, namely C3 convertase, β2 integrin family members CR3 and CR4, and the im-
activated C1s, and C5 convertase, respectively [2, 3, 49]. munoglobulin superfamily member CRIg [74, 75]. CR1
Anaphylatoxin molecules are evolutionarily related to (CD35) is a multifunctional receptor that is expressed
one another and as such share a relatively high degree of in the majority of peripheral blood cells and binds with
homology, as well as somewhat overlapping functions high affinity to C4b and C3b, as well as to iC3b, C3dg,
in the generation of the immune response [50]. C5a has C1q, and mannose-binding protein [76-79]. Binding of
been shown to be considerably more potent than C3a and CR1 to the complement opsonin fragments serves to
C4a in inducing biologically relevant responses, with mediate clearance of immune complexes, especially in
C4a being the weakest to the extent that physiologically erythrocytes, and to mediate phagocytosis by neutro-
potent functions (in humans) and a cognate receptor have phils and monocytes [79]. In addition to phagocytosis,
yet to be described for this molecule [51, 52]. Anaphyla- interaction of CR1 with its ligands plays further roles in
toxins are potent phlogistic molecules whose physiologi- host defense against infection by promoting secretion of
cal functions include many hallmark proinflammatory proinflammatory molecules, such as interleukin (IL)-1α,
activities, such as increases in vascular permeability, IL-1β, and prostaglandins [80]. Furthermore, CR1 plays
smooth muscle contraction, leukocyte recruitment, and a role in antigen presentation to B cells and is also a po-
increases in other accoutrements of white blood-cell re- tent inhibitor of both the classical pathway and the AP of
sponses (e.g., chemotaxis, migration, and phagocytosis), complement activation by exhibiting decay-accelerating
as well as promoting the production and release of other activity for both C3 and C5 convertases, as well as co-
inflammatory mediators (e.g., histamine) [53, 54]. factor activity for Factor-I-mediated cleavage of C3b and
The functional responses of anaphylatoxins are medi- C4b [79]. CR2 (CD21) is very similar to CR1, but lacks
ated by their interactions with cognate 7-transmembrane several N-terminal domains important for the binding
G-protein-coupled receptors (C3aR for C3a, C5aR/C5L2 of C3b/C4b and complement regulatory activities and

41
will only bind to iC3b/C3d/C3dg [81]. Nevertheless, it that efficient adaptive responses were contingent on an
is the principal CR enhancing B-cell immunity and will intact complement system in some cases [85]. Further
be discussed at length below, along with similar adaptive study in animals bearing natural complement deficiencies
immune functions for CR1. CR3 and CR4 are transmem- implicated the classical pathway as a crucial mechanism
brane heterodimers composed of an α-subunit (CD11b or for efficient antigen trapping and retention in lymphoid
CD11c, respectively) and a common β-chain (CD18) that tissues (e.g., splenic follicles), suggesting that a major
belong to the integrin family and perform functions not function of the complement system was to localize for-
only in the phagocytosis of opsonized surfaces but also eign antigens into immune sites important for lympho-
in leukocyte trafficking, adhesion, migration, and costim- cytes responses [86-88].
ulation, which all have important consequences in the The humoral arm of the adaptive immune response
defense of the host against pathogenic invasion [75, 82]. is tasked with protecting extracellular spaces through
CRIg is a more recently identified CR of the immuno- the generation of effector and memory B cells, and B-
globulin superfamily expressed on a restricted subset of cell-produced antibodies, leading to neutralization and
tissue-resident macrophages, including the Kupffer cells opsonization of pathogen and providing immunological
in the liver [83]. Kupffer cells from CRIg-deficient mice memory against reinfection. The potency of this response
are unable to efficiently clear C3-opsonized particles, stems from a complex interplay of immune mechanisms,
resulting in increased mortality in the host in response to contingent on the strength of antigenic stimuli and the
infection [83]. CRIg may represent an important compo- presence of helper T-cell assistance, among many other
nent of phagocytosis not only in the reticuloendothelial factors [2]. Complement effectors are engaged with hu-
system (of which the Kupffer cells are dominant) but moral immunity at multiple stages of B-cell differentia-
also in other resident tissue macrophages, such as alveo- tion and can influence B-cell biology on several levels [89,
lar macrophages of the lung and foam cells in atheroscle- 90]. As alluded to previously, complement enhances B-
rotic plaques [75, 83]. cell immunity principally through CRs, CR1 (CD35) and
The three terminal effector pathways of complement CR2 (CD21), expressed on B lymphocytes and follicular
work in concert to protect the host from common patho- dendritic cells (FDCs), and binding to the complement
genic invasions. Many of the functions of complement opsonins in a concerted effort with the phagocytic sys-
activation take place through the use of germline-trans- tem [75, 90, 91]. CR2 forms a receptor complex with the
mitted molecules that recognize relatively few pathogens, signaling protein CD19 and the tetraspan protein CD81
but are able to do so immediately and thus represent an to form the B-cell coreceptor complex (CD21-CD19-
important effector of the innate immune system. As dis- CD81), which supports an enhanced signal via the B-cell
cussed below, deficiency in these pathways leads to an receptor (BCR; e.g., surface immunoglobulin) when it
impaired host immune response to common pathogens. encounters antigen coated with complement opsonins
However, the ability of complement to participate in host (e.g., C3d), resulting in the reduction of B-cell activation
defense is not limited to these innate immune activities threshold by several orders of magnitude [92, 93]. Thus,
and effector systems of complement also contribute to complement can be viewed as a ‘natural adjuvant’ and as
efficient adaptive immune responses at several levels. an instructor of the humoral immune response [94].
The functional consequence of this modulation of
Complement system in adaptive immunity: B-cell B-cell signaling can be observed in multiple settings. B
regulation and humoral immunity cells first express the CD21-CD19-CD81 coreceptor as
they migrate from the bone marrow into the periphery,
The aforementioned functions of the complement sys- generally referred to as the transitional stage that has
tem, oposonization, lysis, and generation of the inflam- important implications in the elimination of self-reactive
matory response through soluble mediators, are paradig- B cells and in the positive selection of B1 cells [95]. B1
matic and represent a well-characterized component of cells, which are the chief sources of natural antibody with
an innate host defense. It has become increasingly ap- repertoires that are highly biased toward conserved anti-
preciated that complement functions in host defense ex- gens (e.g., nuclear antigens), are a long-lived and physi-
tend beyond innate immune responses. The finding that ologically distinct population of B cells [2]. Complement
B lymphocytes bound C3 raised the question as early as seems to function in the selection and maintenance of B1
in the 1970s as to whether the complement system was cells, as CR2-deficient mice have an altered repertoire of
involved in adaptive immune responses [84]. Subsequent natural antibody, which can be observed by a marked re-
work demonstrated that depletion of C3 impaired hu- duction in injury following ischemia/reperfusion despite
moral immune responses and provided direct evidence normal levels of IgM [96, 97]. These mice also have re-

42
duced numbers of B1a cells and show impaired general- in humoral response to both thymus-dependent and
ized antibody production [98]. thymus-independent antigens [108]. In many cases, mice
In addition to modulating B1 activity and the produc- deficient in CR1/2 (a single gene Cr1/2 encodes both
tion of natural antibodies, cross-linking of the CD21- proteins in mice) exhibit similar impairment, suggesting
CD19-CD81 coreceptor complex with BCR enhances that pro-humoral responses are mediated by these recep-
B-cell immunity in later stages of B-cell differentiation tors [89]. For example, mice deficient in CR1/2 and C3
as well. Coupling C3d to low-affinity antigen, which (if exhibited markedly reduced IgM (and IgG) levels, failure
uncoupled) would cause B-cell death, results in not only in isotype switch to IgG, and decreased antigen uptake
survival but also B-cell activation and production of an- in response to T-independent type II polysaccharide an-
tibody, suggesting a role of complement in the ‘instruc- tigens[109, 110]. Similar results were established for T-
tion’ of naive B cells in the periphery [99]. Similarly, dependant antigens, such as keyhole limpet hemocyanin
activation of mature peripheral and follicular B cells by and bacteriophage ΦX174, as well as viral and bacterial
complement-opsonized antigen leads to their migration pathogens, such as herpes simplex virus, West Nile virus,
to the lymphoid T-cell:B-cell boundary, where helper T and Streptococcus pneumoniae [98, 111-114]. These and
cells provide costimulation via CD40, leading to B-cell other studies highlight the critical role complement plays
activation and expansion. Subsequently, activated B cells in the generation of robust antibody response at several
initiate the formation of germinal centers (GCs), where levels of B-cell biology.
CRs on B cells enhance BCR signaling, leading to effec-
tive differentiation into plasma and memory B cells [89, Complement system in adaptive immunity: T-cell
90]. This is supported by the observation that antigen- immunity
specific B cells lacking CR1/CR2 fail to survive within a
GC when put in competition with WT B cells, insinuat- In view of the impressive repertoire of activities me-
ing that coreceptor signaling is vital to clonal selection diated by complement that influence the generation of
of B cells and in the absence of this complement-assisted effective humoral responses, involvement of comple-
cosignaling, B cells fail to compete and undergo cell ment in the other wing of adaptive immunity, the T-cell
death [100]. FDCs are central to this process as they are response, would be expected. Indeed, Janeway’s con-
specialized stromal cells that secrete the B-lymphocyte ceptualization of the ‘adjuvant effect’ being due to the
chemoattractant, help to organize GCs, and provide ef- influence of the innate immune system on acquired im-
fective means of trapping and retaining antigen within munity, nearly two decades ago, provided a framework
B-cell follicles and displaying them to both naive and for studying the contributions of innate immunity to
GC B cells [101]. FDCs express relatively high levels of T-cell-mediated immune responses [115]. Initially, it was
CR1 and CR2 and effectively retain C3-coated immune suggested that complement was much more important in
complexes within the lymphoid follicles, promoting the B-cell biology as many of the complement/CR-deficient
antigen selection of high-affinity GC B cells [92]. Fur- models developed apparently normal T-cell responses,
thermore, post-GC B cells require complement on FDCs yet humoral responses were impaired [112, 116]. How-
for an efficient maintenance of long-term memory B ever, the finding that priming of both CD4 and CD8 T
cells, affinity maturation, and effective recall responses [102]. cells was reduced in C3-deficient mice during pulmonary
In addition to the CRs, CR1 and CR2, some evidence influenza challenge suggested a more generalized role of
suggests a role of anaphylatoxins in the modulation of B- complement [117]. A potential role of complement in T-
cell biology. B cells have been reported to express C3aR; cell immune responses to viral and alloantigens has now
and both ligands, C3a and C3adesArg, have been shown to been demonstrated in a number of other studies [118-121].
negatively regulate the polyclonal immune response, as The mechanisms of this influence are not as well charac-
well as limit the secretion of TNF-α and IL-6 [103, 104]. terized as those related to humoral immunity, and as such
Conversely, C5a has been reported to play a role in the represent a crucial area of study in understanding the
trafficking and migration of various B-cell populations, roles complement plays in regulating adaptive immune
including GC B cells and tonsillar memory and naїve B responses.
cells [105-107]. Characterization of the potential role of complement
The roles of complement in humoral immunity can in T-cell immunity has been facilitated by the use of a
be illustrated by the characterization of mice bearing DAF-deficient mouse model [122, 123]. DAF deficiency
deficiencies in both complement components and CRs led to increased complement activation in various in
[90]. Studies have demonstrated the importance of an vivo settings, and this presumably allowed the potential
intact complement classical pathway (C1q, C3, or C4) modulating effect of complement on T-cell immunity to

43
be amplified and more easily detectable than otherwise in pathogenic motifs and is often activated simultaneously
normal mice. For example, it has been shown that DAF- with the complement system, indicating that it is plausi-
deficient mice present with an enhanced TH1 response ble that these two effectors of the innate immune system
characterized by hypersecretion of interferon-γ and IL-2 may cooperate in their functions with potential effects on
and suppression of IL-10 following antigen restimula- T-cell immune responses [134, 135].
tion [122, 123]. DAF–/– mice also showed heightened Complement inhibitory proteins, namely MCP, DAF,
pathology in the mouse model of multiple sclerosis, ex- and CR1, have also been implicated in the direct modula-
perimental autoimmune encephalomyelitis [122, 124]. tion of APC or T-cell function. Cross-linking of CD46 on
Furthermore, DAF–/– mice displayed an enhanced T-cell macrophages by certain pathogenic antigens, such as the
immune response in a model of lymphocytic choriomen- pili from Nesseria or Hemagglutinin from measles virus
ingitis virus (LCMV) infection [120]. While the pheno- leads to the impairment of IL-12 production by APCs
type of increased T-cell immunity in DAF–/– mice seems [136, 137]. The measles virus is notorious for suppress-
clear and unquestionable, the underlying mechanism ing T-cell responses during the course of infection, and
that contributes to this phenotype remains to be deter- the suppression of IL-12 production by APCs through
mined. One hypothesis is that in the absence of DAF, AP subversion of CD46 may be one such mechanism for this
complement activation on APCs and T cells is increased pathogenic activity [137]. Cross-linking of CR1, which
leading to more local anaphylatoxin production. Subse- has regulatory properties discussed previously, on T cells
quent engagement of C3aR/C5aR within the immuno- has been shown to inhibit proliferation and reduce IL-2
logical synapse then provides a costimulatory signal for production [138]. DAF, in addition to those roles seen
T-cell survival and activation [125, 126]. AP-mediated previously in suppressing T-cell responses in vivo, may
production of C3a and engagement of C3aR have also also play a role in costimulation. It has been reported
been proposed to occur in normal (i.e., wild-type) mouse that the coengagement of DAF and CD3 results in the
APCs where DAF is intact [127]. Such C3aR-triggered proliferation of CD4 T cells, indicating that the role DAF
signaling in APCs was believed to involve cAMP as a plays in T-cell biology is, at best, multifaceted [139].
second messenger and contribute to the regulation of Overall, these results serve to illustrate a functional
APC maturation and antigen uptake [119, 121]. One is- role of complement activation with regard to T-cell biol-
sue that could potentially contradict these hypotheses, ogy. There seems to be sufficient evidence supporting a
and thus remains to be resolved by more careful studies, link between complement activation and enhanced T-cell
is whether anaphylatoxin receptors are actually expressed immune response at the organismal level. Although vari-
in T cells and professional APCs (i.e., dendritic cells), ous hypotheses have been proposed, there is yet to be a
as there are some contradictory reports on this issue [72, consensus regarding the precise mechanism by which
128-131]. complement regulates T-cell immunity. Ongoing studies
At the whole animal level, C5aR has been shown to in this field should provide an improved understanding of
be essential for the modulating effect of complement on this question and contribute to the development of com-
T-cell immunity in various models. For example, it has plement-based therapeutic strategies in human diseases
been demonstrated that mice treated with C5aR antago- relating to microbial infection, autoimmune disorders,
nists produced fewer antigen-specific CD8 T cells, fol- and organ transplantation.
lowing infection with influenza type A [118]. This agrees
with the finding that DAF-deficient mice present with Complement evasion/subversion strategies of mi-
an enhanced naїve and memory CD8+ T-cell response in croorganisms
reaction to infection with LCMV contingent on the pres-
ence of C3 or C5aR [120]. Adding further support is the Infectious diseases represent a major health, social,
observation that mice bearing a targeted C5aR deficiency and economic burden. The importance of complement
show reduced response to pulmonary infections with to host defense, and the control of infection, as a whole
Pseudomonas aeruginosa, characterized by impaired can be appreciated by the consequences observed when
pulmonary clearance, despite seemingly normal neutro- complement functions are compromised as a result of
philic infiltration [132]. C5aR has also been shown in genetic deficiency, pathogenic interference, or other
mice to mediate a synergistic effect with Toll-like recep- mechanisms. Given that complement has coevolved with
tor (TLR)-4 in eliciting a stronger inflammatory response pathogens for millions of years, it is perhaps not surpris-
with signaling from both innate immune receptors than ing to find that pathogens have developed mechanisms
with either alone [133]. This link is credible because, to inhibit complement activation and effector functions,
like complement, the TLR system recognizes conserved thereby subverting or avoiding this powerful component

44
of innate immunity and increasing their ability to survive is imperative from a pathogenic perspective. Bacteria
and replicate within the host. Given the disease burden can interfere with complement on nearly every level of
associated with infection with microorganisms and the complement activation [144]. Staphylococcus aureus
requirement of novel and effective antibiotics in order to produces a membrane protein, Staphylococcal protein
combat them, the study of complement and its roles in A (SpA), whose predominant biological function is the
defense has significant clinical implications. binding to the Fc region of IgG, which not only is effec-
As discussed throughout, animals deficient in various tive in inhibiting Fc-receptor-mediated phagocytosis but
complement components have a variety of phenotypes also is highly capable of limiting complement activation
related to host defense, including increased suscepti- via the classical pathway by interfering with the binding
bility to infection, impaired T- and B-cell responses, of C1q [145]. Similar immunoglobulin-binding proteins,
reduction in phagocytic activity, and ability to clear such as protein G and protein L can be found in an array
pathogens and other immune complexes, among many of other pathogens [144]. S. aureus also excretes a model
others. In humans, individuals deficient in one of the pathogenic complement inhibitor called the SCIN that
major complement effector pathways, most commonly blocks all complement pathways by efficient inhibition
opsonization and lytic pathways, present with increased of C3 convertases, preventing opsonization, phagocyto-
susceptibility to infection [1, 11, 140]. Deficiency or sis, and by killing human neutrophils through an interest-
defect in opsonization pathways, including the produc- ing interaction with C3 convertases [146]. Furthermore,
tion of antibody and phagocytic ability, results in early opsonization by C3 fragments can be inhibited. For
and recurrent infections with pyrogenic bacteria with instance, Pseudomonas aeruginosa secretes active pro-
the most common organisms being S. pneumoniae and teases that cleave C3b and prevent C3b deposition, and
Haemophilus influenzae [1]. Defect in the assembly or S. aureus cleaves surface-bound C3b, iC3b, and IgG
function of the MAC, or deficiency in the components through the conversion of plasminogen to the active pro-
needed for its generation, is associated with neisserial tease plasmin on its cell surface by staphylokinase [144,
disease, especially infection with Neisseria meningitidis 147]. Inhibition of MAC assembly and reduction of cy-
[141]. Due to the central role of C3 in the complement tolytic ability can be achieved simply by virtue of having
system, deficiency of C3 results in defects in both op- a thick cell wall, as is the case for Gram-positive bacteria
sonization and lysis, and thus is strongly associated with [148, 149]. In other cases, pathogens can inhibit the as-
recurrent infections by the organisms mentioned above sembly or function of the MAC as in the case of Borrelia
[140]. Deficiency of AP components properdin and Fac- burgdorferi, which encodes a 80 kDa surface protein that
tor D is rare, but is also a risk factor in some cases for in- shares functional similarities with human CD59, the in-
fection with the same organisms as C3 deficiency, while hibitor of MAC assembly [150].
deficiency in unique classical pathway components (e.g., Pathogens utilize other mechanisms to escape comple-
C1q, C2, C4) are more strongly associated with immune ment as well. They may interact with host regulators,
complex disease and the development of autoimmunity such as binding Factor H, which increases the degrada-
[140]. Interestingly, endemic meningococcal infection of C3b and reduces formation of C3 convertase,
tions are associated with deficiency of MAC proteins, thereby limiting complement activity [151]. This phe-
especially C6, in which prevalence of meningococcal nomenon is well characterized in the Nesseria family
infection is increased but mortality is decreased [142]. of pathogens, including N. meningitidis and N. gonor-
Finally, deficiency of MBL predisposes children to recur- rhoeae, both of which have been shown to bind to Factor
rent pyrogenic infection the ages of which (6 months to 2 H in an attempt to avoid destruction by the host comple-
years) suggest that the MBL is critical during the interval ment system [42, 152]. Interestingly, recent structural
between the loss of passively acquired maternal antibody determinations of the N. meningitidis: Factor H complex
and maturation of their personal immune system [1, 143]. have revealed that the pathogen subverts the host com-
Therefore, complement is indispensable for host defense plement system through the use of protein mimetics of
against certain pathogens and represents an effective in- host carbohydrate motifs, thereby recruiting Factor H to
nate defense against common infections. its surface and evading destruction [153]. In addition to
Many organisms, recognizing the potency of comple- Factor H binding, both viruses and bacteria may incorpo-
ment activity, have devised strategies to circumvent or rate or recruit other host complement regulatory proteins,
subvert complement to increase survival or enhance their encode structural mimics of complement regulatory pro-
virulence. A given pathogen may utilize multiple strate- teins, or simply encode unique regulatory proteins that
gies and molecules to evade host complement attack, as serve to inhibit complement activity and thereby render
overcoming the powerful, immediate role of complement the pathogen resistant to complement effectors [144,

45
154]. Alternatively, pathogens may inhibit chemotaxis defense against infection and provides a vital first-line
and recruitment of leukocytes by interfering with recep- barrier to invading pathogens. It is not surprising that the
tors that mediate these activities, most notably C5aR and most evolutionarily successful pathogens have developed
the related formyl peptide receptor [144]. The chemot- ways to circumvent or subvert complement in order to
axis inhibitory protein of S. aureus (CHIPS) is able to utilize host resources. The ways in which pathogens ma-
inhibit neutrophil chemotaxis and activation specifically, nipulate complement continue to be uncovered at a rapid
and represents an additional mechanism pathogens may rate and represent an exciting avenue of research. Fur-
utilize to escape complement [155, 156]. ther understanding of host-pathogen interactions and the
Some pathogens go further and subvert the comple- roles complement plays in these interactions may help to
ment system in order to enhance their virulence. This was develop more effective pharmacological agents against
alluded to previously when discussing the complement infection and reduce health-care burden.
regulatory protein CD46, which was first described as a On top of these important contributions to innate im-
receptor for the measles virus and may contribute to the munity, complement plays a vital role in shaping adap-
ability of measles to suppress the immune system [137, tive immune responses, functionally integrating it into
157]. CD46 may also act as a cellular receptor for major the ability of the host to combat invasion from a wide
bacterial strains, including N. gonorrhoeae and N. men- range of pathogens. Since complement represents such
ingitidis [158, 159]. DAF is a receptor for many picorna- an evolutionarily well-conserved mechanism of host de-
viruses, such as echoviruses and coxsakieviruses, which fense, it is not surprising to find that it has been integrat-
use different binding locations on DAF and require ac- ed into the relatively newer acquired immune responses.
cessory molecules such as ICAM-1 in order to internalize Complement has now been shown to play a role in both
[160, 161]. CR2, as discussed above, plays a crucial role B- and T-cell responses at the organismal level. However,
in B cells in the binding of C3 fragments. The Epstein- the exact mechanism(s) by which complement mediates
Barr virus has been shown to utilize CR2 as a cellular T-cell immunity has yet to be determined. A careful, inte-
receptor for its envelope glycoprotein gp350/220, which grated study of complement effects on B- and T-cell biol-
may help to explain the tropism of this virus, due to the ogy will provide valuable insight into the in vivo biology
cellular distribution of CR2, as well as the lymphoprolif- of complement and may have implications for infectious
erative aspects that may result in Burkitt’s lymphoma [1, disease as well as immunological disorders, such as in
162]. Human immunodeficiency virus exploits comple- the cases of multiple sclerosis and organ transplantation.
ment on multiple levels to increase its virulence [163]. It In conclusion, complement is a multifaceted and ro-
activates complement in the absence of antibody, which bust effector, which bridges the innate and adaptive im-
seems counterintuitive as this would normally result in mune systems. It is vital to host defense, and the extent
virolysis. However, this is avoided by complement regu- of its influence is becoming increasingly appreciated as
lators contained in the viral membrane including DAF, additional information regarding the far-reaching effects
which is subverted during the budding process from in- of its activation is uncovered. Further study should pro-
fected cells, and Factor H, which is attached secondarily duce significant dividends in our understanding of host
[163]. Furthermore, C3b deposition allows the virus to defense as an integrated process and the roles comple-
utilize CRs to enhance the efficiency of infection [163]. ment plays in bridging innate and adaptive immunity.
Conclusions Acknowledgments
The role of complement in the immune system, and We thank T Miwa and Y Kimura for critical evaluation of the
consequently on human health, has expanded dramati- figures. JRD is supported by a predoctoral fellowship from the
cally. It is a well-characterized and an evolutionarily American Heart Association (AHA). WCS is supported by grants
ancient component of host defense, impairment of which from the National Institutes of Health (NIH).
leads to susceptibility to infection. It has the ability to
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npg Complement in host immunity

Cell Research (2010) 20:34-50.

Complement and its role in innate and adaptive immune

Introduction nity is composed of those immunological effectors that

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CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY

Antigen: antibody PAMP recognition by Spontaneous hydrolysis/

C1r/C1s MASPs Factor B

C4a, C3a, C5a C3b

Inflammation Lysis Opsonization

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A Factor I cofactor activity stabilized by a bacterial immune-evasion protein staphy-

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Microbe lipid bilayer 10 nm

C Opsonization and phagocytosis

C1q MBL: Antibody: C3b/ C3b cleavage products

CR1 CR2 CR4 Fc

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