Question
Classical pathway of complement activation.
Answer
The classical pathway of complement activation is triggered primarily by antigen-antibody (immune) complexes, providing a direct link between the adaptive (antibody-mediated) and innate (complement) immune systems.
Steps:
- Recognition: C1q (part of the C1 complex, along with C1r and C1s) binds to the Fc portion of antibody (IgM or, less efficiently, IgG) that has already bound its specific antigen — IgM, being pentameric, is a particularly efficient activator, since a single bound IgM molecule can provide the multiple closely-spaced Fc sites needed for C1q binding, whereas multiple separate IgG molecules bound in close proximity are usually required.
- Activation of C1: C1q binding activates C1r, which in turn cleaves and activates C1s (a serine protease).
- C4 and C2 cleavage: activated C1s cleaves C4 into C4a and C4b, and C2 into C2a and C2b; C4b and C2a combine on the target surface to form the C3 convertase (C4b2a).
- C3 cleavage: the C3 convertase cleaves C3 into C3a (an anaphylatoxin) and C3b, which deposits on the target surface (opsonization) and combines with C4b2a to form the C5 convertase (C4b2a3b).
- C5 cleavage and Membrane Attack Complex (MAC) formation: the C5 convertase cleaves C5 into C5a (a potent anaphylatoxin/chemotactic factor) and C5b; C5b sequentially recruits C6, C7, C8, and multiple C9 molecules to form the Membrane Attack Complex (C5b-9), which inserts into the target cell membrane, forming a pore that causes osmotic lysis.
Biological effects along the pathway: C3a and C5a act as anaphylatoxins, triggering mast cell degranulation and increasing vascular permeability, and C5a additionally acts as a potent neutrophil chemoattractant; C3b opsonizes the target for enhanced phagocytosis; the MAC directly lyses the target cell (particularly effective against Gram-negative bacteria and, notably, Neisseria species, explaining why terminal complement deficiencies predispose specifically to recurrent Neisserial infections).
Clinical relevance: deficiency of early classical pathway components (C1, C4, C2) impairs immune-complex clearance and is associated with SLE-like autoimmune disease; the classical pathway is the mechanistic basis of the Complement Fixation Test used in serodiagnosis.