Immunology. Richard Coico
Part of B‐cell co‐receptor: lowers threshold for B‐cell activation by antigen
Complement plays a role in clearing these complexes (see Figure 4.7B). Deposition of C3b on a large antigen–antibody complex interferes with the bonds that keep the complex together. As a result, it breaks up into smaller pieces that can be cleared by macrophages. Deposition of C3b on the antigen–antibody complex also allows binding to erythrocytes, which express the receptor CR1 on their surface. Erythrocytes clear the complexes from the circulation by transporting them to the liver and spleen. In these organs, the complexes are transferred from the erythrocyte CR1 to macrophage CR3 and Fc receptors. Macrophages phagocytose the complexes and destroy them.
Removing Dead or Dying Cells.
Cells dying by necrosis can activate complement, leading to C4b and C3b deposition on the cell surface (see Figure 4.7C). The cell is then cleared by interacting with CR1 or CR3 on phagocytic cells. Subcellular membranes, from organelles such as mitochondria and endoplasmic reticulum, also directly activate both classical and alternative pathways and are cleared in a similar way. CRP, the acute‐phase protein and component of the inflammatory response, also binds to damaged and necrotic cells and activates the classical complement pathway. The same structure that CRP binds to on bacterial cell walls—the polysaccharide phosphocholine—is also exposed on damaged and necrotic mammalian cells. Recent evidence also indicates that cells dying as a result of apoptosis may trigger complement activation.
In all these situations, complement removes dead or dying cells from the tissues and contributes to homeostasis. In some conditions, however, complement activation by dead or dying cells may have clinical consequences. Notable examples include complement activation by ischemia and reperfusion. In ischemia, an area of tissue dies after blood and oxygen supplies have been cut (important examples include cardiac muscle after a myocardial infarction or brain tissue following a stroke). Reperfusion is the attempt to restore blood supply to the affected tissue. Complement activation is considered a major contributor to the inflammatory responses associated with both of these states, which damages healthy tissue. Complement‐based therapies are currently being tested to reduce the deleterious effects of the inflammatory response.
Responses to Viruses.
Complement plays a role in defense against viral infection (see Figure 4.7D). C1 can bind directly to and become activated by the surface of several viruses, including the type C retroviruses, lentiviruses, HIV‐1, and HTLV‐1. In addition, MBL of the lectin pathway binds to and is activated by mannose residues on the surfaces of HIV‐1, HIV‐2, and influenza virus. Antibodies generated in the response against these viruses mediate further binding and activation of the classical pathway on the surface of the virus. Repeating subunits on the viral capsid or membrane surfaces activate the alternative pathway. Binding of complement proteins leads to opsonization and lysis of the virus by phagocytic cells. Complement binding also interferes with the ability of the virus to interact with the membrane of its target cells and thus blocks viral entry into the cell.
Many viruses subvert the immune response by synthesizing proteins that bind to molecules in antigen‐processing pathways (see Chapter 8). Viruses also use mechanisms that undermine the action of complement proteins. For example, some viruses produce proteins that mimic complement inhibitor function: the herpes viruses make proteins that have DAF‐like and/or MCP‐like activities and others that block C5b‐9 formation. In addition, vaccinia virus produces a protein that binds to C3b and C4b and inhibits complement activation. The protein has both decay‐accelerating activity and acts as a co‐factor for factor I. HIV‐1, HTLV‐1, simian immunodeficiency virus (SIV), and cytomegalovirus (CMV) capture the complement control proteins DAF, MCP, and CD59 when the virions bud from host cell membranes. As a consequence of these strategies, the viruses are protected from complement‐mediated responses.
Some viruses even use complement components to promote infection, for example by binding to complement receptors and gaining entry into cells. One of the most studied interactions is the Epstein–Barr virus infection of human B lymphocytes. The virus’s membrane glycoprotein, gp350/220, binds to CR2 (CD21) expressed on the B‐cell surface, allowing the virus to be taken into the cell. Some viruses activate complement and use the C3b deposited on them to bind to host cell complement receptors; in this way, HIV‐1 uses CR1, CR2, and CR3 to infect T cells, B cells, and monocytes. Other viruses bind to membrane‐expressed complement regulators: paramyxovirus (measles virus) uses MCP and viruses of the picornavirus family use DAF to infect epithelial cells.
COMPLEMENT DEFICIENCIES
We described above how the complement system plays an important role in defending the host against microorganisms. It is particularly important in defending against pyogenic (pus‐forming) polysaccharide‐encapsulated bacteria, which include Neisseria species (the bacteria responsible for meningitis and some sexually transmitted diseases), S. pneumoniae, H. influenzae, and S. aureus. The major pathway of defense against these organisms appears to be the production of IgG antibody that binds to the bacteria, resulting in opsonization, complement activation, phagocytosis, and intracellular killing. Thus, genetic deficiencies or acquired conditions in which any one of these activities is diminished render a person particularly susceptible to these organisms. In addition, complement is important in removing immune complexes from the circulation; therefore, deficiencies of certain complement components can also result in immune complexes depositing in tissues, leading to inflammatory conditions. More information about complement deficiencies is provided in Chapter 16.
We now also recognize that some complement components show allelic variation—frequently the result of just a single nucleotide change or polymorphism—in their genes. These differences in allelic forms result not in outright deficiencies, but in variations in level and function of the component. The impact of these variations is also discussed below.
Table 4.3 summarizes the clinical conditions that develop from deficiencies of either specific complement components or regulators of