The small complement fragments C3a and C5a act on specific receptors on endothelial cells and mast cells (see Fig. 2.30) to produce local inflammatory responses. Like C5a, C3a also signals through a G-protein-coupled receptor, discussed in more detail in Chapter 3. C4a, although generated during C4 cleavage, is not potent at inducing inflammation, is inactive at C3a and C5a receptors, and seems to lack a receptor of its own. When produced in large amounts or injected systemically, C3a and C5a induce a generalized circulatory collapse, producing a shocklike syndrome similar to that seen in a systemic allergic reaction involving antibodies of the IgE class, discussed in Chapter 14. Such a reaction is termed anaphylactic shock, and these small fragments of complement are therefore often referred to as anaphylatoxins. C5a has the highest specific biological activity, but both C3a and C5a induce the contraction of smooth muscle and increase vascular permeability and act on the endothelial cells lining blood vessels to induce the synthesis of adhesion molecules. In addition, C3a and C5a can activate the mast cells that populate submucosal tissues to release inflammatory molecules such as histamine and the cytokine tumor necrosis factor-α (TNF-α), which cause similar effects. The changes induced by C5a and C3a recruit antibody, complement, and phagocytic cells to the site of an infection (Fig. 2.33), and the increased fluid in the tissues hastens the movement of pathogen-bearing antigen-presenting cells to the local lymph nodes, contributing to the prompt initiation of the adaptive immune response.
Small complement-cleavage products act on blood vessels to increase vascular permeability and cell-adhesion molecules
Migration of macrophages, polymorphonuclear leukocytes (PMNs), and lymphocytes is increased. Microbicidal activity of macrophages and PMNs is also increased
Fig. 2.33 Local inflammatory responses can be induced by small complement fragments, especially C5a. The small complement fragments are differentially active: C5a is more active than C3a; C4a is weak or inactive. C5a and C3a cause local inflammatory responses by acting directly on local blood vessels, stimulating an increase in blood flow, increased vascular permeability, and increased binding of phagocytes to endothelial cells. C3a and C5a also activate mast cells (not shown) to release mediators, such as histamine and TNF-α, that contribute to the inflammatory response. The increase in vessel diameter and permeability leads to the accumulation of fluid and protein in the surrounding tissue. Fluid accumulation increases lymphatic drainage, bringing pathogens and their antigenic components to nearby lymph nodes. The antibodies, complement, and cells thus recruited participate in pathogen clearance by enhancing phagocytosis. The small complement fragments can also directly increase the activity of the phagocytes.
Deficiency of the C8 Complement Component
C5a also acts directly on neutrophils and monocytes to increase their adherence to vessel walls, their migration toward sites of antigen deposition, and their ability to ingest particles; it also increases the expression of CR1 and CR3 on the surfaces of these cells. In this way, C5a, and to a smaller extent C3a and C4a, act in concert with other complement components to hasten the destruction of pathogens by phagocytes.
2-15 The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens.
One of the important effects of complement activation is the assembly of the terminal components of complement (Fig. 2.34) to form a membrane-attack complex. The reactions leading to the formation of this complex are shown schematically in Fig. 2.35. The end result is a pore in the lipid bilayer membrane that destroys membrane integrity. This is thought to kill the pathogen by destroying the proton gradient across the pathogen’s cell membrane.