Complement System Pathways
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Direct answer
The complement system is a set of serum and membrane proteins that amplify through proteolytic cleavage to opsonise, recruit and lyse microbes. It is activated by the classical, lectin and alternative pathways, which all converge on cleavage of C3. Its membrane attack complex forms pores in target membranes, so deficiency of the late components predisposes to Neisseria infection.
What you must remember
- Classical pathway: C1q binds antibody-antigen complexes, mainly IgM and IgG, and the activated C1 complex cleaves C4 and C2.
- Lectin pathway: mannose-binding lectin binds microbial mannose residues and activates MASP-1 and MASP-2, which cleave C4 and C2 without needing antibody.
- Alternative pathway: C3 hydrolyses spontaneously, and factors B and D with properdin stabilise the convertase on microbial surfaces, again without antibody.
- C3 convertase: C4b2a in the classical and lectin pathways, and C3bBb in the alternative pathway.
- C3b: an opsonin that binds phagocytes through complement receptor 1 and complement receptor 3.
- C3a and C5a: anaphylatoxins that release mast cell mediators and attract neutrophils, with C5a the stronger chemoattractant.
- Membrane attack complex: C5b with C6, C7, C8 and several C9 molecules forms a transmembrane pore that lyses target cells.
- Regulators: C1 inhibitor, factor H, factor I, CD55 and CD59 protect host cells from complement damage.
From C3 cleavage to membrane attack, step by step
Complement activation is a cascade in which each enzyme cleaves the next component. The sequence below follows the common pathway that all three activation routes share.
- Initiate: the classical, lectin or alternative pathway forms a C3 convertase on the microbial surface.
- Cleave C3: the convertase splits C3 into C3a, released as an anaphylatoxin, and C3b, which deposits on the target.
- Amplify: C3b binds factor B, which factor D cleaves to form the C3bBb amplification convertase, stabilised by properdin, generating many more C3b molecules.
- Form the C5 convertase: additional C3b attaches to the convertase, which then cleaves C5 into C5a and C5b.
- Assemble the MAC: C5b binds C6, C7, C8 and several C9 molecules to build a pore that lyses many Gram-negative bacteria.
- Regulate: factor H, factor I, C1 inhibitor and CD59 limit the cascade on host cells, so self tissue is spared.
Amplification explains how a small trigger produces a large response, while regulation explains why healthy host cells usually escape damage.
Where the exam tries to catch you
Complement questions often test which pathway needs antibody and which component is the convergence point.
- Trap: saying the alternative pathway needs antibody Correct: the alternative pathway is antibody-independent and is triggered directly by microbial surfaces, which is why it acts early.
- Trap: naming C1 as the initiator of the lectin pathway Correct: mannose-binding lectin with MASP enzymes starts the lectin pathway, whereas C1q starts the classical pathway.
- Trap: naming C4 as the convergence point of all three pathways Correct: C3 is the convergence point, because every route produces a C3 convertase that cleaves it.
Frequently asked questions
Which complement deficiency predisposes to recurrent Neisseria infection?
Deficiency of the terminal complement components, C5 to C9, predisposes to recurrent infection with Neisseria meningitidis and Neisseria gonorrhoeae. The membrane attack complex is the main killing mechanism against these organisms, so its absence leaves them largely unopposed.
Which complement pathway is activated without antibody?
The alternative pathway is activated without antibody, because spontaneous C3 hydrolysis and microbial surfaces can start it directly. The lectin pathway is also antibody-independent, since mannose-binding lectin recognises microbial sugars.
What are the anaphylatoxins of the complement system?
C3a and C5a are the anaphylatoxins of the complement system, and they release mast cell mediators and attract neutrophils. C5a is the stronger chemoattractant of the two, and both are released as fragments during complement activation.
What is the role of decay-accelerating factor in complement?
Decay-accelerating factor, also called CD55, is a host regulator that speeds the breakdown of C3 convertases on host cell surfaces. Its loss, together with CD59, causes paroxysmal nocturnal haemoglobinuria because host cells become exposed to complement attack.
Which complement component is the convergence point of all three pathways?
C3 is the convergence point, because the classical, lectin and alternative pathways each generate a C3 convertase that cleaves it. This central role is why C3 deficiency causes the most serious complement-related susceptibility to pyogenic infection.