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Thus, these soluble molecular defenses are both pattern recognition receptors and effector molecules at the same time, representing the simplest form of innate immunity

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Complement is a collec- tion of soluble proteins present in blood and other body fluids. It was discov- ered in the 1890s by Jules Bordet as a heat-labile substance in normal plasma whose activity could ‘complement’ the bactericidal activity of immune sera. Part of the process is opsonization, which refers to coating a pathogen with antibodies and/or complement proteins so that it can be more readily taken up and destroyed by phagocytic cells

Although complement was first discov- ered as an effector arm of the antibody response, we now understand that it originally evolved as part of the innate immune system and that it still pro- vides protection early in infection, in the absence of antibodies, through more ancient pathways of complement activation

The complement system is composed of more than 30 different plasma pro- teins, which are produced mainly by the liver. In the absence of infection, these proteins circulate in an inactive form.

There are three pathways of complement activation. As the antibody-triggered pathway of complement activation was discovered first, this became known as the clas- sical pathway of complement activation. The next to be discovered was called the alternative pathway, which can be activated by the presence of the path- ogen alone; and the most recently discovered is the lectin pathway, which is activated by lectin-type proteins that recognize and bind to carbohydrates on pathogen surfaces

In the complement system, activation by proteolysis is inherent, with many of the complement proteins being proteases that suc- cessively cleave and activate one another.

The proteases of the complement system are synthesized as inactive pro-enzymes, or zymogens, which become enzymatically active only after proteolytic cleavage, usually by another com- plement protein

The complement pathways are triggered by proteins that act as pattern recognition receptors to detect the presence of pathogens. This detection activates an initial zymogen, triggering a cascade of proteolysis in which complement zymogens are activated sequentially, each becoming an active protease that cleaves and activates many molecules of the next zymogen in the pathway, amplifying the signal as the cascade proceeds. This results in activation of three distinct effector pathways—inflammation, phagocytosis, and membrane attack—that help eliminate the pathogen. In this way, the detection of even a small number of pathogens produces a rapid response that is greatly amplified at each step.

The first proteins discovered belong to the classical pathway, and they are designated by the letter C followed by a number. The native complement proteins—such as the inactive zymogens—have a simple number designation, for example, C1 and C2. Unfortunately, they were named in the order of their discovery rather than the sequence of reactions. The reac- tion sequence in the classical pathway, for example, is C1, C4, C2, C3, C5, C6, C7, C8, and C9 (note that not all of these are proteases)

Products of cleavage reactions are designated by adding a lowercase letter as a suffix. For example, cleavage of C3 produces a small protein fragment called C3a and the remain- ing larger fragment, C3b. By convention, the larger fragment for other factors is designated by the suffix b, with one exception. For C2, the larger fragment was named C2a by its discoverers, and this system has been maintained in the literature, so we preserve it here.

Another exception is the naming of C1q, C1r, and C1s: these are not cleavage products of C1 but are distinct proteins that together comprise C1

The proteins of the alternative pathway were discovered later and are designated by different capital letters, for example, factor B and factor D. Their cleavage products are also designated by the addition of lower- case a and b: thus, the large fragment of B is called Bb and the small fragment Ba.

Activated complement components are sometimes designated by a hori- zontal line, for example, C2a; however, we will not use this convention. All the components of the complement system are listed in Fig. 2.14

Besides acting in innate immunity, complement also influences adaptive immunity.

Opsonization of pathogens by complement facilitates their uptake by phagocytic antigen-presenting cells that express complement receptors; this enhances the presentation of pathogen antigens to T cells, which we dis- cuss in more detail in Chapter 6

B cells express receptors for complement proteins that enhance their responses to complement-coated antigens, as we describe later in Chapter 10

In addition, several of the complement fragments can act to influence cytokine production by antigen-presenting cells, thereby influencing the direction and extent of the subsequent adaptive immune response, as we describe in Chapter 11.

The lectin pathway is initiated by solu- ble carbohydrate-binding proteins—mannose-binding lectin (MBL) and the ficolins—that bind to particular carbohydrate structures on microbial surfaces. Specific proteases, called MBL-associated serine proteases (MASPs), that asso- ciate with these recognition proteins then trigger the cleavage of complement proteins and activation of the pathway.

The classical pathway is initiated when the complement component C1, which comprises a recognition protein (C1q) associated with proteases (C1r and C1s), either recognizes a microbial surface directly or binds to antibodies already bound to a pathogen.

Finally, the alter- native pathway can be initiated by spontaneous hydrolysis and activation of the complement component C3, which can then bind directly to microbial surfaces

These three pathways converge at the central and most important step in com- plement activation. When any of the pathways interacts with a pathogen sur- face, the enzymatic activity of a C3 convertase is generated

There are various types of C3 convertase, depending on the complement pathway activated, but each is a multisubunit protein with protease activity that cleaves complement component 3 (C3)

The C3 convertase is bound covalently to the pathogen sur- face, where it cleaves C3 to generate large amounts of C3b, the main effector molecule of the complement system; and C3a, a small peptide that binds to specific receptors and helps induce inflammation

The pathogen-recognition mechanisms of the three complement-activation pathways are shown in the top row, along with the complement components used in the proteolytic cascades leading to formation of a C3 convertase. This enzyme activity cleaves complement component C3 into the small soluble protein C3a and the larger component C3b, which becomes covalently bound to the pathogen surface (middle row). The components are listed by biochemical function in Fig, 2.14 and are described in detail in later figures. The lectin pathway of complement activation (top left) is triggered by the binding of mannose-binding lectin (MBL) or ficolins to carbohydrate residues in microbial cell walls and capsules. The classical pathway (top center) is triggered by binding of C1 either to the pathogen surface or to antibody bound to the pathogen. In the alternative pathway (top right), soluble C3 undergoes spontaneous hydrolysis in the fluid phase, generating C3(H2O), which is augmented by the action of factors B, D, and P (properdin). All pathways thus converge on the formation of C3b bound to a pathogen and lead to all of the effector activities of complement, which are shown in the bottom row. C3b bound to a pathogen acts as an opsonin, enabling phagocytes that express receptors for C3b to ingest the complement-coated microbe more easily (bottom center). C3b can also bind to C3 convertases to produce another activity, a C5 convertase (detail not shown here), which cleaves C5 to C5a and C5b. C5b triggers the late events of the complement pathway in which the terminal components of complement—C6 to C9—assemble into a membrane-attack complex (MAC) that can damage the membrane of certain pathogens (bottom right). C3a and C5a act as chemoattractants that recruit immune-system cells to the site of infection and cause inflammation (bottom left)

C3b can also bind to C3 convertases to produce another activity, a C5 convertase (detail not shown here), which cleaves C5 to C5a and C5b. C5b triggers the late events of the complement pathway in which the terminal components of complement—C6 to C9—assemble into a membrane-attack complex (MAC) that can damage the membrane of certain pathogens (bottom right)

C3a and C5a act as chemoattractants that recruit immune-system cells to the site of infection and cause inflammation (bottom left).

Cleavage of C3 is the critical step in complement activation and leads directly or indirectly to all the effector activities of the complement system (see Fig. 2.15)

Later in the chapter, we will describe the different complement receptors that bind C3b that are involved in this function of complement and how C3b is degraded by a serum protease into inactive smaller fragments called C3f and C3dg.

C3b can also bind to the C3 convertases produced by the classical and lectin pathways and form another multisubunit enzyme, the C5 convertase. This cleaves C5, liberating the highly inflammatory peptide C5a and gener- ating C5b. C5b initiates the ‘late’ events of complement activation, in which additional complement proteins interact with C5b to form a membrane- attack complex (MAC) on the pathogen surface, creating a pore in the cell membrane that leads to cell lysis (see Fig. 2.15, bottom right)

The key feature of C3b is its ability to form a covalent bond with microbial sur- faces, which allows the innate recognition of microbes to be translated into effector responses. Covalent bond formation is due to a highly reactive thioester bond that is hidden inside the folded C3 protein and cannot react until C3 is cleaved. When C3 convertase cleaves C3 and releases the C3a fragment, large conformational changes occur in C3b that allow the thioester bond to react with a hydroxyl or amino group on the nearby microbial surface (Fig. 2.16). If no bond is made, the thioester is rapidly hydrolyzed, inactivating C3b, which is one way the alternative pathway is inhibited in healthy individuals.

One important safeguard is that the key acti- vated complement components are rapidly inactivated unless they bind to the pathogen surface on which their activation was initiated

There are also several points in the pathway at which regulatory proteins act to prevent the activation of complement on the surfaces of healthy host cells, thereby protecting them from accidental damage, as we shall see later in the chapter.

Complement can, however, be activated by dying cells, such as those at sites of ischemic injury, and by cells undergoing apoptosis, or programmed cell death. In these cases, the complement coating helps phagocytes dispose of the dead and dying cells neatly, thus limiting the risk of cell contents being released and triggering an autoimmune response (discussed in Chapter 15)

Microorganisms typically bear on their surface repeating patterns of molec- ular structures, known generally as pathogen-associated molecular patterns (PAMPs)

The lipoteichoic acids of Gram-positive bacterial cell walls and the lipopolysaccharide of the outer membrane of Gram-negative bacteria are not present on animal cells and are important in the recognition of bacteria by the innate immune system. Similarly, the glycans of yeast surface proteins commonly terminate in mannose residues rather than the sialic acid residues (N-acetylneuraminic acid) that terminate the glycans of vertebrate cells (Fig. 2.18). The lectin pathway uses these features of microbial surfaces to detect and respond to pathogens.

Thus, multimeric MBL has high total binding strength, or avidity, for repetitive carbohydrate structures on a wide variety of microbial surfaces, including Gram-positive and Gram-negative bacteria, mycobacteria, yeasts, and some viruses and parasites, while not interacting with host cells

MBL is present at low concentrations in the plasma of most individuals, but in the presence of infection, its production is increased during the acute-phase response

The lectin pathway can be triggered by any of four different pattern recognition receptors that circulate in blood and extracellular fluids and recognize carbohydrates on microbial surfaces. The first such receptor to be discovered was mannose-binding lectin (MBL), which is shown in Fig. 2.19, and which is synthesized in the liver.

MBL is an oligomeric protein built up from a monomer that contains an amino-terminal collagen-like domain and a carboxy-terminal C-type lectin domain (see Section 2-4). Proteins of this type are called collectins.

A single carbohydrate-recognition domain of MBL has a low affinity for mannose, fucose, and N-acetylglucosamine (GlcNAc) residues, which are common on microbial glycans, but does not bind sialic acid residues, which terminate vertebrate glycans

The other three pathogen-recognition molecules used by the lectin pathway are known as ficolins. Although related in overall shape and function to MBL, they have a fibrinogen-like domain, rather than a lectin domain, attached to the collagen-like stalk (see Fig. 2.19)

The fibrinogen-like domain gives ficolins a general specificity for oligosaccharides containing acetylated sugars, but it does not bind mannose-containing carbohydrates

Humans have three ficol- ins: L-ficolin (ficolin-2), M-ficolin (ficolin-1), and H-ficolin (ficolin-3). L- and H-ficolin are synthesized by the liver and circulate in the blood; M-ficolin is synthesized and secreted by lung and blood cells

MBL in plasma forms complexes with the MBL-associated serine proteases MASP-1, MASP-2, and MASP-3, which bind MBL as inactive zymogens

When MBL binds to a pathogen surface, a conformational change occurs in MASP-1 that enables it to cleave and activate a MASP-2 molecule in the same MBL complex. Activated MASP-2 can then cleave complement components C4 and C2 (Fig. 2.20)

Like MBL, ficolins form oligomers that make a complex with MASP-1 and MASP-2, which similarly activate complement upon recognition of a microbial surface by the ficolin

C4, like C3, contains a buried thioester bond. When MASP-2 cleaves C4, it releases C4a, allowing a conformational change in C4b that exposes the reactive thioester as described for C3b (see Fig. 2.16). C4b bonds covalently via this thioester to the microbial surface nearby, where it then binds one molecule of C2 (see Fig. 2.20). C2 is cleaved by MASP-2, producing C2a, an active serine protease that remains bound to C4b to form C4b2a, which is the C3 convertase of the lectin pathway. (Remember, C2a is the exception in complement nomenclature.) C4b2a now cleaves many molecules of C3 into C3a and C3b. The C3b fragments bond covalently to the nearby pathogen surface, and the released C3a initiates a local inflammatory response.

The complement-activation pathway initiated by ficolins proceeds like the MBL lectin pathway (see Fig. 2.20)

Individuals deficient in MBL or MASP-2 experience substantially more res- piratory infections by common extracellular bacteria during early childhood, indicating the importance of the lectin pathway for host defense. This suscep- tibility illustrates the particular importance of innate defense mechanisms in early childhood, when adaptive immune responses are not yet fully developed but the maternal antibodies transferred across the placenta and present in the mother’s milk are gone.

One molecule of C4b2a can cleave up to 1000 molecules of C3 to C3b

Other members of the collectin family are the surfactant proteins A and D (SP-A and SP-D), which are present in the fluid that bathes the epithelial surfaces of the lung. There they coat the surfaces of pathogens, making them more susceptible to phagocytosis by macrophages that have left the subepithelial tissues to enter the alveoli.

Because SP-A and SP-D do not associate with MASPs, they do not activate complement

We have used MBL here as our prototype activator of the lectin pathway, but the ficolins are more abundant than MBL in plasma and so may be more important in practice

L-ficolin recognizes acetylated sugars such as GlcNAc and N-acetylgalactosamine (GalNAc), and particularly recognizes lipoteichoic acid, a component of the cell walls of Gram-positive bacteria that contains GalNAc. It can also activate complement after binding to a variety of capsu- lated bacteria.

M-ficolin also recognizes acetylated sugar residues; H-ficolin shows a more restricted binding specificity, for d-fucose and galactose, and has only been linked to activity against the Gram-positive bacterium Aerococcus viridans, a cause of bacterial endocarditis

In its overall scheme, the classical pathway is similar to the lectin pathway, except that it uses a pathogen sensor known as the C1 complex, or C1.

Because C1 interacts directly with some pathogens but can also interact with antibodies, C1 allows the classical pathway to function both in innate immu- nity, which we describe now, and in adaptive immunity, which we examine in more detail in Chapter 10.

Like the MBL–MASP complex, the C1 complex is composed of a large subunit (C1q), which acts as the pathogen sensor, and two serine proteases (C1r and C1s), which are initially in their inactive form (Fig. 2.21)

C1q is a hexamer of trimers, composed of monomers that contain an amino-terminal globular domain and a carboxy-terminal collagen-like domain. The trimers assem- ble through interactions of the collagen-like domains, bringing the globular domains together to form a globular head. Six of these trimers assemble to form a complete C1q molecule, which has six globular heads held together by their collagen-like tails.

C1r and C1s are closely related to MASP-2, and some- what more distantly related to MASP-1 and MASP-3; all five enzymes are likely to have evolved from the duplication of a gene for a common precursor.

C1r and C1s interact noncovalently and form tetramers that fold into the arms of C1q, with at least part of the C1r:C1s complex being external to C1q.

The activated C1s acts on the next two components of the classical pathway, C4 and C2. C1s cleaves C4 to produce C4b, which binds covalently to the pathogen surface as described earlier for the lectin pathway (see Fig. 2.20). C4b then also binds one molecule of C2, which is cleaved by C1s to produce the serine protease C2a. This pro- duces the active C3 convertase C4b2a, which is the C3 convertase of both the lectin and the classical pathways. However, because it was first discovered as part of the classical pathway, C4b2a is often known as the classical C3 conver- tase (see Fig. 2.17)

The recognition function of C1 resides in the six globular heads of C1q. When two or more of these heads interact with a ligand, this causes a conformational change in the C1r:C1s complex, which leads to the activation of an autocata- lytic enzymatic activity in C1r; the active form of C1r then cleaves its associ- ated C1s to generate an active serine protease.

C1q can attach itself to the surface of pathogens in several different ways. One is by binding directly to surface components on some bacteria, including certain proteins of bacterial cell walls and polyanionic structures such as the lipoteichoic acid on Gram-positive bacteria. A second is through binding to C-reactive protein, an acute-phase protein in human plasma that binds to phosphocholine residues in bacterial surface molecules such as pneumo- coccal C polysaccharide—hence the name C-reactive protein. We discuss the acute-phase proteins in detail in Chapter 3. However, a main function of C1q in an immune response is to bind to the constant, or Fc, regions of antibodies (see Section 1-9) that have bound pathogens via their antigen-binding sites. C1q thus links the effector functions of complement to recognition provided by adaptive immunity.

Most natural antibody is of the isotype, or class, known as IgM (see Sections 1-9 and 1-20) and represents a considerable amount of the total IgM circulating in humans. IgM is the class of antibody most efficient at binding C1q, making natural antibodies an effective means of activating complement on microbial surfaces immediately after infection and leading to the clearance of bacteria such as Streptococcus pneumoniae (the pneumococcus) before they become dangerous

This might seem to limit the usefulness of C1q in fight- ing the first stages of an infection, before the adaptive immune response has generated pathogen-specific antibodies. However, some antibodies, called natural antibodies, are produced by the immune system in the apparent absence of infection. These antibodies have a low affinity for many microbial pathogens and are highly cross-reactive, recognizing common membrane constituents such as phosphocholine and even recognizing some antigens of the body’s own cells (that is, self antigens). Natural antibodies may be pro- duced in response to commensal microbiota or to self antigens, but do not seem to be the consequence of an adaptive immune response to infection by pathogens

We have seen that both the lectin and the classical pathways of complement activation are initiated by proteins that bind to pathogen surfaces.

In innate immu- nity, C4 cleavage is catalyzed by a ficolin or MBL complex that is bound to the pathogen surface, and so the C4b cleavage product can bind adjacent proteins or carbohydrates on the pathogen surface. If C4b does not rapidly form this bond, the thioester bond is cleaved by reaction with water and C4b is irrevers- ibly inactivated. This helps to prevent C4b from diffusing from its site of acti- vation on the microbial surface and becoming attached to healthy host cells

C2 becomes susceptible to cleavage by C1s only when it is bound by C4b, and the active C2a serine protease is thereby also confined to the pathogen sur- face, where it remains associated with C4b, forming the C3 convertase C4b2a. Cleavage of C3 to C3a and C3b is thus also confined to the surface of the path- ogen.

Like C4b, C3b is inactivated by hydrolysis unless its exposed thioester rapidly makes a covalent bond (see Fig. 2.16), and it therefore opsonizes only the surface on which complement activation has taken place

Opsonization by C3b is more effective when antibodies are also bound to the pathogen sur- face, as phagocytes have receptors for both complement and Fc receptors that bind the Fc region of antibody (see Sections 1-20 and 10-20)

Because the reac- tive forms of C3b and C4b are able to form a covalent bond with any adjacent protein or carbohydrate, when complement is activated by bound antibody, a proportion of the reactive C3b or C4b will become linked to the antibody mol- ecules themselves. Antibody that is chemically cross-linked to complement is likely the most efficient trigger for phagocytosis

Although probably the most ancient of the complement pathways, the alter- native pathway is so named because it was discovered as a second, or ‘alter- native,’ pathway for complement activation after the classical pathway had been defined. Its key feature is its ability to be spontaneously activated

The alternative pathway C3 convertase is composed of C3b itself bound to Bb, which is a cleavage fragment of the plasma protein factor B. This C3 conver- tase, designated C3bBb, has a special place in complement activation because, by producing C3b, it can generate more of itself. This means that once some C3b has been formed, by whichever pathway, the alternative pathway can act as an amplification loop to increase C3b production rapidly.

C3b deposited by the classical or lectin pathway can bind factor B, making it susceptible to cleavage by factor D. The C3bBb complex is the C3 convertase of the alternative pathway of complement activation, and its action, like that of C4b2a, results in the deposition of many molecules of C3b on the pathogen surface

The alternative pathway can be activated in two different ways. The first is by the action of the lectin or classical pathway. C3b generated by either of these pathways and covalently linked to a microbial surface can bind factor B (Fig. 2.23). This alters the conformation of factor B, enabling a plasma protease called factor D to cleave it into Ba and Bb. Bb remains stably associated with C3b, forming the C3bBb C3 convertase.

The second way of activating the alter- native pathway involves the spontaneous hydrolysis (known as ‘tickover’) of the thioester bond in C3 to form C3(H2O), as shown in Fig. 2.24. C3 is abun- dant in plasma, and tickover causes a steady, low-level production of C3(H2O). This C3(H2O) can bind factor B, which is then cleaved by factor D, producing a short-lived fluid-phase C3 convertase, C3(H2O)Bb. Although formed in only small amounts by C3 tickover, fluid-phase C3(H2O)Bb can cleave many mole- cules of C3 to C3a and C3b. Much of this C3b is inactivated by hydrolysis, but some attaches covalently via its thioester bond to the surfaces of any microbes present.

On their own, the alternative pathway C3 convertases C3bBb and C3(H2O) Bb are very short-lived. They are, however, stabilized by binding the plasma protein properdin (factor P) (Fig. 2.25)

Properdin is made by neutrophils and stored in secondary granules. It is released when neutrophils are activated by the presence of pathogens.

Properdin may have some properties of a pattern recognition receptor, since it can bind to some microbial surfaces

Properdin- deficient patients are particularly susceptible to infections with Neisseria meningitidis, the main agent of bacterial meningitis

Properdin’s ability to bind to bacterial surfaces may direct the activity of the alternative complement pathway to these pathogens, thus aiding their removal by phagocytosis

Properdin can also bind to mammalian cells that are undergoing apoptosis or have been damaged or modified by ischemia, viral infection, or antibody binding, leading to the deposition of C3b on these cells and facilitating their removal by phagocytosis.

Bacterial surfaces do not express complement-regulatory proteins and favor the binding of properdin (factor P), which stabilizes the C3bBb convertase. This convertase activity is the equivalent of C4b2a of the classical pathway. C3bBb then cleaves many more molecules of C3, coating the pathogen surface with bound C3b

If C3bBb forms on the surface of host cells, it is rapidly inactivated by complement- regulatory proteins expressed by the host cell: complement receptor 1 (CR1), decay- accelerating factor (DAF), and membrane cofactor of proteolysis (MCP)

Several mechanisms ensure that complement activation will proceed only on the surface of a pathogen or on damaged host cells, and not on normal host cells and tissues.

After initial complement activation by any pathway, the extent of amplification via the alternative pathway is critically dependent on the stability of the C3 convertase C3bBb. This stability is controlled by both positive and negative regulatory proteins.

These complement-regulatory proteins interact with C3b and either prevent the convertase from forming or promote its rapid dissociation (Fig. 2.27)

For example, a membrane-attached protein known as decay-accelerating factor (DAF or CD55) competes with factor B for binding to C3b on the cell surface and can displace Bb from a con- vertase that has already formed

Convertase formation can also be prevented by cleaving C3b to an inactive derivative, iC3b. This is achieved by a plasma protease, factor I, in conjunction with C3b-binding proteins that act as cofac- tors, such as membrane cofactor of proteolysis (MCP or CD46), another host-cell membrane protein (see Fig. 2.27).

Cell-surface complement receptor type 1 (CR1, also known as CD35) behaves similarly to DAF and MCP in that it inhibits C3 convertase formation and promotes the catabolism of C3b to inac- tive products, but it has a more limited tissue distribution

Factor H is another complement-regulatory protein in plasma that binds C3b, and like CR1, it is able to compete with factor B to displace Bb from the convertase; in addition, it acts as a cofactor for factor I.

Factor H binds preferentially to C3b bound to vertebrate cells because it has an affinity for the sialic acid residues present on their cell surfaces (see Fig. 2.18). Thus, the amplification loop of the alternative pathway is allowed to proceed on the surface of a pathogen or on damaged host cells, but not on normal host cells or on tissues that express these negative regulatory proteins.

Only one component of the alternative pathway seems entirely unrelated to its functional equivalents in the classical and lectin pathways: the initiating serine protease, factor D.

Factor D can also be singled out as the only activat- ing protease of the complement system to circulate as an active enzyme rather than a zymogen. This is both necessary for the initiation of the alternative pathway (through the cleavage of factor B bound to spontaneously activated C3) and safe for the host, because factor D has no other substrate than factor B bound to C3b. This means that factor D finds its substrate only at pathogen surfaces and at a very low level in plasma, where the alternative pathway of complement activation can be allowed to proceed

Most of the factors are either identical or the homologous products of genes that have duplicated and then diverged in sequence.

The proteins C4 and C3 are homologous and contain the unstable thioester bond by which their large fragments, C4b and C3b, bind covalently to membranes. The genes encoding proteins C2 and factor B are adjacent in the MHC region of the genome and arose by gene duplication. The regulatory proteins factor H, CR1, and C4BP share a repeat sequence common to many complement-regulatory proteins. The greatest divergence between the pathways is in their initiation: in the classical pathway the C1 complex binds either to certain pathogens or to bound antibody, and in the latter circumstance it serves to convert antibody binding into enzyme activity on a specific surface; in the lectin pathway, mannose-binding lectin (MBL) associates with a serine protease, activating MBL-associated serine protease (MASP), to serve the same function as C1r:C1s; in the alternative pathway this enzyme activity is provided by factor D

After its initial appearance, the complement system seems to have evolved by the acquisition of new activation pathways that allow specific targeting of microbial surfaces

Evolutionarily, the ficolins may predate the collectins, which are also first seen in the urochordates

Homologs of MBL and of the classical pathway complement component C1q, both collectins, have been identified in the genome of the ascidian urochordate Ciona (sea squirt)

This also suggests that when adaptive immunity evolved, much later, the ancestral antibody molecule used an already diversified C1q-like collectin member to activate the complement pathway, and that the complement activation system evolved further by use of this collectin and its associated MASPs to become the initiating components of the classical complement pathway, namely, C1q, C1r, and C1s