Thus, induction of inflammatory responses is a second key function resulting from complement activation.
As we describe in more detail below, in the alternative pathway the generation of C3b from C3 sets up an amplification loop that results in further triggering of the pathway.
After C3b has bound to the pathogen surface, the next component in the sequence, C5, is cleaved to produce C5b and C5a. C5b deposits on the surface of the pathogen, allowing the binding of components C6 through C9. These terminal components, C5b to C9, form a complex known as the membrane attack complex (MAC) on the surface of the pathogen that leads to the killing (lysis) of the pathogen. Thus, killing of pathogens is the third major function of complement activation. C5a, like C3a, is a small fluid‐phase anaphylatoxin.
Thus, all three pathways of complement activation result in three major biological activities: the production of opsonins on the pathogen surface, the synthesis of fluid‐phase anaphylatoxins that enhance inflammatory responses, and direct killing of the pathogen. All these activities lead to either rapid removal or direct destruction of the pathogen. We now describe each of the pathways and biological activities in more detail.
Classical Pathway
The classical pathway was so named because it was the first complement pathway to be worked out. The component proteins are C1, C2, and so on, up to C9; the numbers designate the order in which the components were discovered, rather than their position in the activation sequence. Cleavage products are given lower case letters, such as C3a or C4b. Large fragments such as C3b and C4b can be cleaved further to yield products such as C3c, C3d, and so on.
Activators.
Antigen–antibody complexes are the major activators of the classical pathway, with antibody bound to the surface of a pathogen being the predominant example. Antibody synthesis in response to pathogens is the key characteristic of the adaptive, humoral immune response. Thus, the classical complement pathway is a major effector mechanism of the adaptive immune response and leads to the elimination of pathogens.
Soluble antigen–antibody complexes also activate the classical pathway. Although they are normally removed by macrophages, they are found in autoimmune conditions such as systemic lupus erythematosus (SLE), which we discuss later in the chapter (see also Chapter 12). Other activators of the classical pathway include some viruses (including HIV‐1, discussed later in this chapter), necrotic cells and subcellular membranes (e.g., from mitochondria), aggregated immunoglobulins, and β‐amyloid, found in Alzheimer’s disease plaques. C‐reactive protein (CRP)—a component of the inflammatory response (an “acute‐phase reactant”)—also activates the classical pathway; CRP binds to the polysaccharide phosphocholine that is part of the cell wall of many bacteria, such as Streptococcus pneumoniae.
Early Steps in the Classical Complement Pathway That Lead to C3 Cleavage.
Figure 4.2A shows the predominant way in which the classical pathway is initiated: C1 binds to the Fc region of two closely spaced IgG molecules or one IgM molecule (IgM not shown in the figure) bound to an antigen expressed on the surface of a bacterium. Thus, IgM and IgG—the IgG3 subtype in particular—are effective activators of the classical complement pathway. IgM is synthesized early in the immune response, to both thymus‐dependent and thymus‐independent antigens. In addition, IgG3 is preferentially synthesized in antibody responses in which T cells synthesize interferon‐γ (see Chapter 10), generally responses triggered by bacteria and viruses. Thus, the synthesis of IgM or IgG3 in the adaptive humoral immune response results in the binding of these antibodies to the pathogen that elicited them, and via complement activation ultimately leads to the elimination of the pathogen.
Not all classes of immunoglobulins (Igs) are equally effective at activating the classical complement pathway. Among human Igs, the ability to bind and activate C1 is, in decreasing order, IgM > IgG3 > IgG1 >> IgG2. Other antibody subtypes—IgG4, IgA, IgE, and IgD—do not bind or activate C1 and thus do not activate the classical complement pathway.
C1 is a complex of three different proteins: C1q (comprising six identical subunits) combined with two molecules each of C1r and C1s (see Figure 4.2A). As a consequence of C1q binding to the Fc region of the IgM or IgG bound to the antigen, C1s becomes enzymatically active. This enzymatically active form, known as C1s esterase, cleaves the next component in the classical pathway, C4, into two pieces, C4a and C4b. C4a, the smaller piece, remains in the fluid phase, while C4b binds covalently to the surface of the pathogen. C4b bound to the cell surface then binds C2, which is cleaved by C1s. Cleavage of C2 generates the fragments C2b, which remains in the fluid phase, and C2a. C2a binds to C4b on the surface of the cell to form a complex, C4b2a. The C4b2a complex is known as the classical pathway C3 convertase; as we describe below, this enzyme cleaves the next component in the pathway, C3.
Lectin Pathway
Activators.
Terminal mannose residues expressed by Gram‐positive (Staphylococcus aureus) and Gram‐negative bacteria (Klebsiella, Escherichia coli, and Haemophilus influenzae type b), fungi (Candida and Aspergillus fumigatus), and yeast particles activate the lectin pathway by binding MBL. Many microbes, including the pathogen Streptococcus pneumoniae, express acetylated or neutral carbohydrate structures as part of extended polysaccharides, such as 1,3‐β‐D‐glucan; these are all bound by ficolin. Because the lectin pathway is activated by the molecular patterns expressed by pathogens (PAMPs, see Chapter 3) in the absence of antibody, it is part of the innate immune defenses and is involved in the rapid response to pathogens.
The terminal carbohydrate structures that activate the lectin pathway are generally not expressed on the surface of mammalian cells, so the lectin pathway of complement activation may be thought of as yet another way that the body discriminates between self and nonself. We referred to this critical concept earlier in the book, applicable in both innate immunity (pattern recognition receptors for pathogens expressed on cells of the innate immune system) and adaptive immunity (T and B cells respond to nonself antigens but do not respond to self‐antigens).
Figure 4.2. Early steps in activation of classical, lectin, and alternative complement pathways leading to formation of C3 convertase: C4aC2b in both classical and lectin pathways, and C3bBb in alternative pathway.
Early Steps in the Lectin Pathway That Lead to C3 Cleavage.
The lectin pathway is initiated when MBL binds to the terminal polysaccharide residues of a pathogen such as a bacterium (see Figure 4.2B). MBL is structurally homologous to C1q in the classical pathway. Ficolin (not shown in the figure) has a structure
