See also Fc receptors under signal transduction

The classical pathway is is a major effector of the humoral branch of the human immune response. the CP is typically triggered by immune complexes such as an antibody bound to a foreign particle, and thus requires prior exposure to that particle for the generation of specific antibody. 

The classical pathway is a calcium/magnesium dependent cascade (Fung, 2002/0081293). 

Activation of the Classical Pathway

Activation of the classical pathway occurs primarily during immunologic recognition of antigen by specific antibody that exposes a C1 binding site on the Fc portion of the antibody. (Figueroa, Clinical Microbiology Reviews, July 1991, p. 359-395)

There are four plasma proteins involved in the initial steps of the CP: C1, C2, C4 and C3.

C1: Activation of the CP is initiated by binding of C1, the first component in the complement cascase, to an antigen-antibody complex and the subsequent activation of the antibody bound C1. C1 can also be activated by certain pathogens including HIV. C1 is a complex of threee subcomponents, C1q, C1r and C1s, the latter two being homologous single chain zymogens of 85 kD each. The first proteins (i.e., C1r, C1s, C4, C2 and C3 in the complement cascade exist as inactive precursor molecules which when converted to active proteases by protolytic reactions participate in cleavage of the next protein in the sequence. Thus, the activation of C1r and C1s results in a complex protease that can cleave C4 and C2. Hourcade (US5,869,615). 

The interaction of C1 with Fc regions of IgG or IgM in immune complexes activates a C1 protease that can cleave plasma protein C4, resulting in the c4a and C4b fragments. With respect to binding of C1q to antigen-antibody complexes,  IgG or IgM isotypes bind antigen, resulting in increased affinity of the Fc domains for the first component of complement C1q. Binding of antibody to antigen exposes a site on the antibody which is a binding site for C1. Since IgM is a pentamer whereas IgG is a monomer, IgM is a better activator since there are more regions for the complement to bind. C4b can bind another plasma protein, C2. The resulting species, C4b2, is cleaved by the C1 protease to from the classical pathway C3 convertase, C4b2a. Addition of the C3 cleavage product, C3b, to the C3 convertase leads to the formation of the CP C5 convertase, C4b2a3b.

–C1q: 

The first step in the complement cascade is the binding of C1q to the antibody. Therea are six heads on C1q, connected by collagen-like stems to a central stalk and the isolated heads bind to the Fc portion of antibody rather weakly. Binding of antibody to multiple epitopes on an antigenic surface, aggregates the antibody and this facilitates the binding of several C1q heads, leading to an enhanced affinity. Within the Fc portion of the antibody, C1q binds to the CH2 domain. The interation is sensitive to ionic strengh, and appears to be highly conserved throughout evolution as C1q reacts with IgG form different speies. (Winter, The binding stie for C1q on IgG” Nature, 332(21), 1988). 

C2: has 39% sequence identity to Factor B, and is a 102 kD zyogen composed of three SCRs followed by a vWF repeat and a serine protease domain. In the Mg2+ dependent formation of the convertase C4bC2a, a weakly associated C4bC2 allows the clevage of the C2 subunit by activated C1, yielding two C2 fragmetns, C2a and C2b. The C2b fragment, derived form the amino terminus, dissociates while the remaining C2a fragment associates more tightly with C4b, to for the proteolytically active classical pathway C3 convertase, C4bC2a. Hourcade (US5,869,615)

C3: is cleavged to produce the important fragment C3b, an opsonin that binds covalently to nearby cells and macromolecules. When these reactions occur on a cell surface, they can direct the assembly of complemnt lytic components in the membrane. Hourcade (US5,869,615)

Classical pathway C3 convertase cleaves C3 into C3b which can work independent of the alternative pathway with full amplification of the classical pathway in 1% normal human serum in the presence of Ca2+/Mg2+ ions. Classical pathway C5 convertase can cleave C5 to generate C5a and C5b. The C5b molecule then inserts into the lipid bilayer of the cell to initiate the formation of C5b-9 or sC5b-9. Bansal (US 13/646286).

C5b: initiates the assembly of the membrane attack complex (MAC) by a series of protein-protein interactions that involve the components C6 to C9. Attachment of this C5b6789 complex to the membrane leads to formation of a channel that traverses the membrane. Hourcade (US5,869,615)

Classical Pathway Initatied Amplifcation of the Alternative Pathway

The classical pathway, like the AP, generates C3b. This C3b can feed into the AP which can couple to target pahtogens and serve as a substrate for the alternative pathway (Song, US2010/0263061).