C3b bound to pathogen surface C3b inactivated by hydrolysis ˜°Before cleavage by C3 convertase, the thioester bond within TED is protected from reacting Cleavage of C3 releases C3a, and a change in conformation of C3b allows the thioester bond to react with a chemical group on the pathogen surface C3b C3aTED TED 23 14 5 6 C3 convertase (C4b2a)pathogen surface thioester bond The reactive thioester group of C3b in TED Gly Glu GlnCys ˜°
Fig. 2.16 C3 convertase activates C3 for covalent bonding convertase C4b2a is shown here) and release of C3a from the amino to microbial surfaces by cleaving it into C3a and C3b and terminus of the α chain causes a conformational change in C3b exposing a highly reactive thioester bond in C3b. Top panel: that exposes the thioester bond. This can now react with hydroxyl C3 in blood plasma consists of an α chain and a β chain (formed by or amino groups on molecules on microbial surfaces, covalently proteolytic processing from the native C3 polypeptide) held together bonding C3b to the surface. Bottom right panels: schematic view by a disulfide bond. The thioester-containing domain (TED) of the α of the thioester reaction. If a bond is not made with a microbial chain contains a potentially highly reactive thioester bond (red spot). surface, the thioester is rapidly hydrolyzed (that is, cleaved by water), Bottom left panels: cleavage by C3 convertase (the lectin pathway rendering C3b inactive.
The complement system and innate immunity.
Pathways leading to such potent inflammatory and destructive effects—and which have a series of built-in amplification steps—are potentially dangerous and must be tightly regulated. One important safeguard is that the key activated 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).
Having introduced some of the main complement components, we are ready for a more detailed account of the three pathways. To help indicate the types of functions carried out by each of the complement components in the tables throughout the rest of the chapter, we will use the color code introduced in Fig. 2.13 and Fig. 2.14: yellow for recognition and activation, green for amplification, purple for inflammation, blue for phagocytosis, and pink for membrane attack.
2-6 The lectin pathway uses soluble receptors that recognize microbial surfaces to activate the complement cascade.
Microorganisms typically bear on their surface repeating patterns of molecular structures, known generally as pathogen-associated molecular patterns (PAMPs). The cell walls of Gram-positive and Gram-negative bacteria, for example, are composed of a matrix of proteins, carbohydrates, and lipids in a repetitive array (see Fig. 2.9). 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.