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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.