Binding of mannose-binding lectin or ficolins to their carbohydrate cleaves many molecules of C3 to produce C3b, which binds to the ligands on microbial surfaces induces MASP-1 to cleave and activate pathogen surface, and C3a, an inflammatory mediator. The covalent the serine protease MASP-2. MASP-2 then cleaves C4, exposing attachment of C3b and C4b to the pathogen surface is important in the thioester bond in C4b that allows it to react covalently with the confining subsequent complement activity to pathogen surfaces. pathogen surface. C4b then binds C2, making C2 susceptible to Fig. 2.21 The first protein in the classical pathway of complement activation is C1, which is a complex of C1q, C1r, and C1s. As shown in the micrograph and drawing, C1q is composed of six identical subunits with globular heads (yellow) and long collagen-like tails (red); it has been described as looking like “a bunch of tulips.” The tails combine to bind to two molecules each of C1r and C1s, forming the C1 complex C1q:C1r2:C1s2. The heads can bind to the constant regions of immunoglobulin molecules or directly to the pathogen surface, causing a conformational change in C1r, which then cleaves and activates the C1s zymogen (proenzyme). The C1 complex is similar in overall structure to the MBL–MASP complex, and it has an identical function, cleaving C4 and C2 to form the C3 convertase C4b2a (see Fig. 2.20). Photograph (×500,000) courtesy of K.B.M. Reid.
but the maternal antibodies transferred across the placenta and present in the mother’s milk are gone. 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 capsulated 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.
2-7 The classical pathway is initiated by activation of the C1 complex and is homologous to the lectin pathway.
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 immunity, which we describe now, and in adaptive immunity, which we examine in more detail in Chapter 10.