# Complement System Physiology

> Complement system in MBBS Physiology: classical, alternative and lectin pathways, C3 and C5 convertases, membrane attack complex, deficiencies and CH50.

- Canonical URL: https://prepelephant.com/topics/mbbs/physiology/complement-system-physiology
- Exam / course: MBBS · Subject: Physiology
- Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team
- First published: 2026-10-02
- Last updated: 2026-10-02
- How to cite: "Complement System Physiology", PrepElephant, https://prepelephant.com/topics/mbbs/physiology/complement-system-physiology

## Direct answer

More than 30 serum proteins — roughly 10 per cent of the globulin fraction — cascade through three activating routes: the classical pathway (immune complexes binding C1qrs, calcium-dependent), the alternative pathway (spontaneous C3 hydrolysis amplified on microbial surfaces that lack regulatory proteins, magnesium-dependent), and the lectin pathway (mannose-binding lectin with MASP enzymes, an antibody-independent innate trigger). All converge on C3, whose convertases (C4b2a in the classical and lectin routes, C3bBb in the alternative) split C3 into C3b, the opsonin, and C3a, an anaphylatoxin; C5 convertases then launch C5b-9, the membrane attack complex — a polymer of up to 10-16 C9 molecules punching lytic pores in gram-negative envelopes. Deficiency patterns map cleanly: C3 loss invites recurrent pyogenic infection, C5-C9 loss recurrent meningococcal disease, C1-inhibitor loss hereditary angioedema.

## What you must remember

- **Ion dependence:** classical needs calcium, alternative needs magnesium — EDTA chelates both and is the standard tube that "kills" complement.
- **Convertases:** C4b2a (classical/lectin) and C3bBb stabilised by properdin (alternative); each C5 convertase is the C3 convertase plus an extra C3b.
- **Biological fragments:** C3b — opsonisation and immune adherence (CR1 on erythrocytes carts complexes to the spleen and liver); C5a — the most potent anaphylatoxin, chemotaxin and neutrophil activator; C3a — anaphylatoxin without chemotaxis; C5b-9 — the lytic pore.
- **Amplification:** one activated C3b molecule can generate hundreds more through the alternative loop — why regulation matters more than activation.
- **Regulators:** C1-inhibitor (blocks C1r/s and kallikrein), factor H and factor I (decay and degrade C3b), DAF/CD55 and CD59 on host cells; anaphylatoxins are trimmed by carboxypeptidase N to their inactive des-Arg forms.
- **C1-inhibitor deficiency:** hereditary angioedema — recurrent non-pitting swellings without urticaria or itch, C4 low with C3 normal (screening pair), bradykinin-mediated so antihistamines and steroids are useless; treat with C1-INH concentrate or icatibant.
- **CD59 (and DAF) loss by PIGA mutation:** paroxysmal nocturnal haemoglobinaemia — complement lysis of erythrocytes, haemoglobinuria mornings, diagnosed by flow cytometry for CD55/CD59, treated with eculizumab (anti-C5).
- **Deficiency rules:** early classical components (C1-C4) — immune-comclusive disease (SLE-like) plus encapsulated infection; C3 — severe recurrent pyogenic; terminal C5-C9 — recurrent Neisseria (meningococcus, gonococcus) with otherwise normal opsonisation.
- **Tests:** CH50 screens the classical pathway (zero with any single classical or terminal component missing), AH50 the alternative; both low means C3 or properdin involvement.

## A worked case: the teenager with second meningococcaemia

A 16-year-old is admitted with meningococcal septicaemia for the second time in three years; the first episode was at 13. Immunoglobulins are normal, HIV is negative, and the question is why the terminal defence keeps failing. The complement map answers: recurrent invasive Neisseria disease with normal antibodies and normal opsonisation (no particular problem with other bacteria) points to terminal pathway deficiency — C5, C6, C7, C8 or C9. CH50 will be near zero while AH50 may be normal and C3 normal; the specific component is then assayed. Management is physiology-led: vaccination with meningococcal ACWY and B conjugates (antibody can compensate via opsonisation where the MAC cannot), standing antibiotic prophylaxis consideration after episodes, and family screening since most are autosomal recessive. C8 deficiency clusters in Japanese and C9 in Japanese and Korean populations — a population fact examiners enjoy; the principle is universal: MAC deficiency equals Neisseria susceptibility.

## Where students slip

Two confusions dominate. First, hereditary angioedema looks like allergy but is bradykinin-driven complement dysregulation — no urticaria, no response to adrenaline or antihistamines, and a low C4 with normal C3 between attacks is the screening signature (acquired types with anti-C1-INH antibody occur in SLE and B-cell lymphoma). Second, students memorise "C3 deficiency — pyogenic, C5-C9 — Neisseria" without the mechanism: C3 is the opsonin everything else builds on, so its loss cripples phagocytosis of encapsulated bacteria broadly; the MAC is the only complement arm that directly kills, and only Neisseria rely on direct serum lysis for their control.

## Frequently asked questions

### What activates the three complement pathways?

Classical — immune complexes (IgG or IgM) binding C1q; lectin — mannose-binding lectin on microbial sugars; alternative — spontaneous C3 hydrolysis amplified on surfaces lacking regulatory proteins.

### Which fragments are the anaphylatoxins and what do they do?

C3a, C4a (weak) and C5a — degranulating mast cells and smooth muscle effects; C5a is the most potent and the only one that is also a powerful neutrophil chemotaxin.

### How does C1-inhibitor deficiency present and why?

Hereditary angioedema — recurrent non-itchy swellings of skin and mucosa from bradykinin accumulation, low C4 with normal C3, unresponsive to antihistamines, treated with C1-INH concentrate or bradykinin receptor blockade.

### Why does terminal complement deficiency cause recurrent meningococcal disease?

Neisseria with their thin walls and serum exposure are the organisms whose clearance depends on the membrane attack complex; without C5-C9 the complex cannot form, while antibody-mediated opsonisation of other bacteria remains intact.

### What does a CH50 of zero mean?

Complete absence of haemolytic complement activity through the classical pathway — any single missing classical or terminal component, localising the defect further with AH50 and individual levels.