The Complement System: Classic Pathway
المؤلف:
Mary Louise Turgeon
المصدر:
Immunology & Serology in Laboratory Medicine
الجزء والصفحة:
5th E, P81-82
2025-07-02
607
The classic complement pathway is one of the major effector mechanisms of antibody-mediated immunity. The principal components of the classic pathway are C1 through C9. The sequence of component activation—C1, 4, 2, 3, 5, 6, 7, 8, and 9—does not follow the expected numeric order.
C3 is present in the plasma in the largest quantities; fixation of C3 is the major quantitative reaction of the complement cascade. Although the principal source of synthesis of complement in vivo is debatable, the majority of the plasma complement components are made in hepatic parenchymal cells, except for C1 (a calcium-dependent complex of the three glycoproteins C1q, C1r, and C1s), which is primarily synthesized in the epithelium of the gastrointestinal and urogenital tracts.
The classic pathway has three major stages:
1. Recognition
2. Amplification of proteolytic complement cascade
3. Membrane attack complex (MAC)
Recognition
The recognition unit of the complement system is the C1 complex—C1q, C1r, and C1s, an interlocking enzyme system. In the classic pathway, the first step is initiation of the pathway triggered by recognition by complement factor C1 of antigen antibody complexes on the cell surface. When C1 complex interacts with aggregates of immunoglobulin G (IgG) with antigen on a cell’s surface, two C1-associated proteases, C1r and C1s, are activated. A single IgM molecule is potentially able to f ix C1, but at least two IgG molecules are required for this purpose. The amount of C1 fixed is directly proportional to the concentration of IgM antibodies, although this is not true of IgG molecules. C1s is weakly proteolytic for free intact C2, but is highly active against C2 that has complexed with C4b molecules in the presence of magnesium (Mg2+) ions. This reaction will occur only if the C4bC2 complex forms close to the C1s.
The resultant C2a fragment joins with C4b to form the new C4bC2a enzyme, or classic pathway C3 convertase. The catalytic site of the C4bC2a complex is probably in the C2a peptide. A smaller C2b fragment from the C2 component is lost to the surrounding environment.
Amplification of Proteolytic Complement Cascade
Once C1s is activated, the proteolytic complement cascade is amplified on the cell membrane through sequential cleavage of complement factors and recruitment of new factors until a cell surface complex containing C5b, C6, C7, and C8 is formed.
The complement cascade reaches its full amplitude at the C3 stage, which represents the heart of the system. The C4bC2a complex, the classic pathway C3 convertase, activates C3 molecules by splitting the peptide, C3 anaphylatoxin, from the N-terminal end of the peptide of C3. This exposes a reactive binding site on the larger fragment, C3b. Consequently, clusters of C3b molecules are activated and bound near the C4bC2a complex. Each catalytic site can bind several hundred C3b molecules, even though the reaction is very efficient because C3 is present in high concentration. Only one C3b molecule combines with C4bC2a to form the final proteolytic complex of the complement cascade.
Membrane Attack Complex
The membrane attack complex (MAC) is a unique system that builds up a lipophilic complex in cell membranes from several plasma proteins. To initiate C5b fixation and the MAC, C3b splits C5a from the alpha chain of C5. No further proteinases are generated in the classic complement sequence. Other bound C3b molecules not involved in the C4b2a3b complex form an opsonic macromolecular coat on the erythrocyte or other target, which renders it susceptible to immune adherence by C3b receptors on phagocytic cells.
Fig1. Late steps of complement activation. A, The late steps of complement activation start after the formation of the C5 convertase and are identical in the alternative and classical pathways. Products generated in the late steps induce inflammation (C5a) and cell lysis (the membrane attack complex [MAC]). B, The properties of the proteins of the late steps of complement activation are listed. (From Abbas AK, Licht man AH: Basic immunology: functions and dis orders of the immune system, updated edition, ed 3, Philadelphia, 2011, Saunders.)
When fully assembled in the correct proportions, C7, C6, C5b, and C8 form the MAC (see Fig. 1, inset). The C5bC6 complex is hydrophilic but, with the addition of C7, it has additional detergent and phospholipid-binding properties as well. The presence of hydrophobic and hydrophilic groups within the same complex may account for its tendency to polymerize and form small protein micelles (a packet of chain molecules in parallel arrangement). It can attach to any lipid bilayer within its effective diffusion radius, which produces the phenomenon of reactive lysis on innocent so-called bystander cells. Once membrane bound, C5bC6C7 is relatively stable and can interact with C8 and C9.
The C5bC6C7C8 complex polymerizes C9 to form a tubule (pore), which spans the membrane of the cell being attacked, allowing ions to flow freely between the cellular interior and exterior. By complexing with C9, the osmotic cytolytic reaction is accelerated. This tubule is a hollow cylinder with one end inserted into the lipid bilayer and the other projecting from the membrane. A structure of this form can be assumed to disturb the lipid bilayer sufficiently to allow the free exchange of ions and water molecules across the membrane. Ions flow out, but large molecules stay in, causing water to flood into the cell. The consequence in a living cell is that the influx of sodium (Na+) ions and H2O leads to disruption of osmotic balance, which produces cell lysis.
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