Questions: Classical, Alternative, and Lectin Complement Pathways

Question 1

Which complement pathway(s) can provide defense against a pathogen encountered for the first time, before any antibody has been produced?

• A. The classical pathway only, because it is evolutionarily the most ancient
• B. Both the lectin and alternative pathways, because neither requires antibody for activation
• C. The alternative pathway only, because the lectin pathway requires prior MBL induction by infection
• D. None — complement activation always requires adaptive immune input to specify the target

Answer: (B)

Both the lectin and alternative pathways are fully operative before any adaptive immune response. The lectin pathway uses mannose-binding lectin (MBL), a constitutively present innate recognition molecule that binds carbohydrate patterns common on microbial surfaces. The alternative pathway relies on spontaneous C3 hydrolysis (tick-over) and continuous surface sampling. Both can activate against a novel pathogen on first encounter. The classical pathway is the only one that requires antibody-antigen complexes and therefore depends on a prior adaptive response.

Question 2

A patient has a genetic deficiency in factor B. Which complement functions would be most directly impaired?

• A. The classical pathway only, because factor B is a component of the C1 complex
• B. All three pathways equally, because factor B is required for C3 cleavage in every case
• C. The alternative pathway and its amplification of the other two pathways, because factor B is required to form the alternative C3 convertase C3bBb
• D. The lectin pathway only, because factor B associates with MASPs during lectin activation

Answer: (C)

Factor B is specific to the alternative pathway: it binds to surface-deposited C3b and is cleaved by factor D to form C3bBb, the alternative pathway C3 convertase. Critically, the alternative pathway serves as an amplification loop for all three pathways — once any pathway deposits C3b on a surface, factor B drives a positive feedback loop generating more C3b. A factor B deficiency therefore impairs not only primary alternative pathway activation but also the massive amplification that normally follows classical or lectin pathway initiation. The C1 complex is specific to the classical pathway and has no connection to factor B.

Question 3

The alternative complement pathway is constitutively active at low levels in plasma through spontaneous C3 hydrolysis, even in the absence of any infection.

• T. True
• F. False

Answer: True

This 'tick-over' is the defining feature distinguishing the alternative pathway from the other two. C3 undergoes continuous spontaneous hydrolysis in plasma to form C3(H₂O), which can associate with factor B and initiate convertase formation. The resulting C3b deposits randomly on all nearby surfaces. On host cells, regulatory proteins (factor H, DAF, MCP) rapidly inactivate deposited C3b. On pathogen surfaces lacking these regulators, C3b persists and triggers amplification. This means the alternative pathway is an ongoing surveillance mechanism, not a triggered response — making the 'backup pathway' label a misconception.

Question 4

The classical complement pathway is the most evolutionarily primitive of the three, having evolved first to provide innate defense before MBL and antibody-based recognition were available.

• T. True
• F. False

Answer: False

The naming is historically misleading. The alternative and lectin pathways are considered evolutionarily more ancient because they use innate pattern recognition that predates the adaptive immune system. The classical pathway — which requires IgG or IgM antibodies — is the most recently evolved, dependent on adaptive immune machinery. 'Classical' refers to historical discovery order (characterized in the early 20th century), not evolutionary precedence. The misconception that the classical pathway is evolutionarily first is explicitly flagged in the Common Misconceptions section: all three pathways coevolved.

Question 5

Explain why the alternative complement pathway is better described as an 'amplification loop' than as a 'backup pathway,' and what functional consequence this has for immune defense.

Model answer: The 'backup' label implies the alternative pathway activates only when the other two fail. In reality, the alternative pathway is constitutively active through spontaneous C3 hydrolysis (tick-over), continuously sampling all surfaces. More importantly, once any pathway — classical or lectin — deposits C3b on a pathogen surface, the alternative pathway immediately amplifies the response: C3b binds factor B, factor D cleaves it to form C3bBb, which generates more C3b, which recruits more factor B, creating a positive feedback loop. This amplification can expand a modest initial complement activation into a massive response. The functional consequence is that the alternative pathway multiplies the output of the other two pathways rather than substituting for them when they fail.

Key phrase: positive feedback amplification loop. The alternative pathway consumes its own output (C3b generates more C3b via C3bBb), so its activity grows exponentially once initiated by any of the three activation triggers.