1-12. THE CLASSIC COMPLEMENT PATHWAY
a. Activation of the classic pathway can be initiated by a number of substances,
the best known of these, and probably the most important, being the immunoglobulin
molecule. Only one molecule of lgM on the cell membrane is necessary to activate the
complement system (two subunits of the lgM molecule combining with adjacent
antigens on the membrane). In contrast, it is thought that lgG needs to form a "doublet";
that is to say, two separate lgG molecules have to combine with adjacent antigens on
the cell membrane as close together as 250 to 400 A, before they are able to activate
C1. Only certain subclasses of lgG are able to activate complement through this
pathway. IgG3 is the most efficient, followed by IgG1; IgG2 is the least efficient. IgG4
does not activate the complement; neither does IgA.
b. Appropriate interaction of antibody with antigen leads to sequential activation
of the complement system, often ending in cytolysis. This involves a series of
protein-protein interactions resulting in the generation of a series of cellular
intermediates bearing successively bound complement components. An
antibody-sensitized erythrocyte is designated EA, and successive complement
components are designated by numbers, for example, EACI, EAC1, 4. The protein
components of complement circulate in the plasma in an inactive state, and once
activated are designated by a bar over the component number, for example, C1. The
activation process usually is achieved by cleavage of the next complement molecule
into fragments, which are designated by lower case letters, for example, C3a, C3b. The
activated products usually have enzymatic properties; thus the whole pathway is an
enzymatic cascade similar to the coagulation cascade (see figure 1-4). The system is
held in check by the instability of the complexes formed and the naturally occurring
inhibitors and inactivators present in normal plasma (for example, C3b INA).
c. The pathway consists of three operationally defined functional units, the
recognition unit (C1), the activation unit (C4, C2, C3), and the membrane attack unit
(C5, C6, C7, C8, C9).
(1) Recognition unit. C1 is a complex of three proteins held together by
calcium. C1q is a collagen-like protein with binding sites for lgG and gM; C1r is the
activating enzyme of the critical catalytic site of the C1 complex, C1s is a proenzyme,
activated by C1r. When C1 collides with an antigen-antibody complex (EA), it is bound
to the Fc fragment of the immunoglobulin molecule through the C1q subunit. This
activates C1r and subsequently C1s by cleavage of a single polypeptide chain.
(2) Activation unit. This unit is assembled in two stages. Activated C1(C1s)
acts on native C4 by cleaving the molecule into C4a and C4b. The major fragment C4b
attaches to the cell membrane. A shower of fragments is produced by a single CIs
enzyme, so that many C4b molecules may cluster around the EAC1 site on the cell.
C1s also cleaves native C2 into two fragments; the major C2 fragment, C2a, combines
with C4b on the cell membrane to form an active complex C4b2a (C3 convertase), that