complex by up to ten-fold. Properdin is a soluble glycoprotein released by PMNs, monocytes, and adaptive immune cells in response to the presence of proinflammatory cytokines such as TNF-α.
Generation of large amounts of C3b has two functions. A portion of the C3b binds to the bacterial surface and acts as an opsonin to enhance uptake by phagocytes, while another portion binds to the existing C3 convertase complexes (C3bBb or C2aC4b) to form the C5 convertase complexes (C3bBbC3b or C4bC2aC3b), that then cleave C5 into C5a and C5b. C5a diffuses away from the site and acts as a chemokine to recruit phagocytes, whereas C5b binds to LPS on the surface of Gram-negative bacteria and recruits C6, C7, C8, and C9 to form the MAC. Some bacteria produce a polysaccharide surface coating, called a capsule, that preferentially binds serum factor H rather than factor B. As a result, C3b is eliminated as it deposits on the surface, effectively preventing opsonization of the bacterial surface, as well as MAC formation.
Controlling Complement Activation
In all three pathways, it is important to keep the accelerated production of C3a, C3b, C5a, and C5b under control so that overstimulation of the inflammatory response does not occur and host cells are not damaged. To this end, several mechanisms protect host cells from complement over-activation (Figure 3-15). Excess C3b molecules that bind to factor H when bound to sialic acid groups on the surface of host cells are proteolytically cleaved to produce iC3b. As mentioned previously, while iC3b is an effective opsonin (Figure 3-15A), it can no longer aid in the formation of a C3 convertase or C5 convertase. Likewise, when iC3b is bound to factor H on host cell surfaces, it is subject to further degradation by serum factor I.
Figure 3-15. Controlling complement. Multiple regulatory pathways help to dampen complement activation, returning the signaling pathways to the resting state. (A) Factor H and factor I work together to limit the amount of C3b present in the circulation. Factor H competes with factor B for binding to C3b. Formation of complex C3bH destabilizes C3b, exposing a site for the protease activity of factor I to then completely degrade C3b. C3b can also be clipped to form iC3b, which still acts as an opsonin but no longer stimulates complement. iC3b also is degraded by factor I. (B) CD35 (CR1) binds to complement component C3b (as well as C4b) and dissociates the C3 convertase complex, thereby preventing further cleavage of C3 to C3a and C3b. CD35 is also a cofactor for factor I, which clips C3b (as well as C4b) to generate iC3b (and iC4b) and further degradation products. (C) CD55 binds to C3b and C4b and causes dissociation of the C3 and C5 convertase complexes, thereby preventing further cleavage of C3 and C5 and limiting the formation of C3a, C3b, C5a, and C5b–C9 (MAC). (D) CD59 binds the C5b–C8 complex, which is inserted into the cell membrane, and thereby blocks the binding of C9 to the complex and the polymerization of C9 to form membrane pores.
Once the pathogen has been cleared from the system and the heightened immune responses are no longer needed, the host cell uses additional regulatory proteins to help inhibit the complement pathways and return them to basal levels of activity. Several proteins protect host cells from complement-mediated damage by rapidly inactivating components of the complement pathways (Figure 3-11). CD35 (complement receptor 1, CR1) is a membrane glycoprotein found on phagocytic cells that binds to opsonins on bacterial cells and mediates their phagocytosis (Figure 3-15B). CD35 thus serves as the primary pathway for processing and clearing complement-opsonized immune complexes and inhibits both classical and alternative pathways. C4b-binding protein (C4BP), a glycoprotein found in blood plasma that binds C4b (and, to a lesser extent, C3b), is an inhibitor of the classical and lectin complement pathways. C4BP serves as a cofactor of serum factor I, accelerating the degradation of C3 convertase by factor I-mediated cleavage of C4b and C3b. CD46 (membrane cofactor protein) is also a membrane protein receptor that binds factor I as a cofactor to cleave and inactivate C3b and C4b.
Several factors help protect the host cell from being damaged by complement activation by blocking MAC from forming on the host cell surface and thereby protecting the host cell membrane (Figure 3-15C and D). CD59 (MAC-inhibitory protein, MAC-IP) is a membrane-associated glycoprotein that blocks C9 polymerization and MAC formation. CD55 (complement decay-accelerating factor, DAF) is a membrane-associated glycoprotein found on the surface of many blood cells. CD55 binds to C4b and C3b and interferes with their ability to bind C2b and Bb to prevent formation of the C3 convertases (C4bC2b and C3bBb, respectively) on the host cell surface, thereby protecting the host cell membrane.
Cytokines and Chemokines—Mediators of Immune Responses
Roles of Cytokines and Chemokines in Directing Innate Immune Responses
Cytokines and chemokines play a central role in regulating the cellular activities of both the innate and adaptive defense systems (Table 3-2). These signaling molecules act as messengers by binding to receptors on the cells whose activities they direct. Cytokines are soluble glycoproteins (see Box 3-1) of 8 to 30 kDa produced by a variety of cells, including PMNs, DCs, NK cells, endothelial cells, and cells of the adaptive immune system, as well as other host cells when they are infected. Chemokines are small glycopeptides of 8 to 10 kDa that are produced by the same cells that produce cytokines. Their main function is to attract and activate phagocytes, a function similar to that of complement components C5a and C3a.
Box 3-1.
Glycoproteins
The surfaces of human cells are coated with glycoproteins that, as the name implies, contain proteins covalently linked to oligosaccharides. These glycoproteins play diverse roles in eukaryotic organisms. Shown are the structures of a typical N-glycosylation structure on human glycoproteins, that are capped with the nine-carbon monosaccharide sialic acid, called neuraminic acid. The predominant sialic acid found in mammalian cells is N-acetylneuraminic acid (core structure shown below). Not surprisingly, bacteria produce enzymes on their surfaces that can hydrolyze and release the sugars from host glycoproteins, such as the proteins NanA, BgaA, and StrH from S. pneumoniae, and provide food to the bacteria as well as opening up binding sites for bacteria to attach to the host cell surface.
Source:
King SJ, Hippe KR, Weiser JN. 2006. Deglycosylation of human glycoconjugates by the sequential activities of exoglycosidases expressed by Streptococcus pneumoniae. Mol Microbiol 59:961–974[PubMed][CrossRef].
Cytokines and chemokines recognize and bind to specific receptors on the surfaces of target immune cells, that set off signal transduction cascades that modify the functions of the immune cells. Just as complement can be activated by bacterial surfaces, cytokine release can be triggered by interaction between cytokine-producing cells and molecules on the surfaces of the invading bacterium. In the case of Gram-negative bacteria, the outer membrane LPS that activates complement is also a molecule that stimulates cytokine production. Although the surface molecules of other types of bacteria that activate complement and stimulate cytokine release have not been studied nearly as well, it appears likely that the same surface molecules on these bacteria that activate complement also stimulate cytokine production.
During
