Complement System
Microbiology · Immunology · lean revision notes
Complement System
The complement system is a cascade of ~30 plasma and membrane proteins that bridges innate and adaptive immunity. For NEET PG, the highest-yield areas are the three activation pathways, the central role of C3, the membrane attack complex (MAC), and the clinical deficiency syndromes that map onto very specific infection patterns. Master the "which protein, which pathway, which disease" triad and most questions become trivial.
Definition and overview
Complement is a group of heat-labile serum proteins (inactivated at 56°C for 30 minutes — a classic fact) synthesised mainly by the liver (hepatocytes), with additional production by macrophages and monocytes. They circulate as inactive proenzymes (zymogens) and are activated in a tightly regulated proteolytic cascade. Each component, once cleaved, generates a small fragment (usually "a", e.g. C3a) and a large fragment (usually "b", e.g. C3b). The historical exception worth memorising is C2, where the larger active enzymatic fragment is C2a (or C2b in some newer texts — know both conventions).
The three core biological effects of complement, useful as an exam framework:
- Opsonisation → C3b coats microbes for phagocytosis (binds CR1 on phagocytes).
- Inflammation / anaphylatoxins → C3a, C4a, C5a recruit and activate leukocytes; C5a is the most potent.
- Cytolysis → MAC (C5b–9) punches pores in the membrane.
High-yield: C3 is the central and most abundant complement protein and the point at which all three pathways converge. C3 deficiency is the single most clinically severe deficiency.
The three activation pathways
All pathways converge on cleavage of C3 by a C3 convertase, then C5 by a C5 convertase, leading to a common terminal (lytic) pathway.
| Feature | Classical pathway | Alternative pathway | Lectin (MBL) pathway |
|---|---|---|---|
| Trigger | Antigen–antibody complex (IgM, IgG1/3) | Microbial surfaces (LPS, polysaccharide), spontaneous C3 "tickover" | Mannose/mannan on microbes binding MBL |
| Initiating molecule | C1q (part of C1qrs) | C3, Factor B, Factor D, properdin | MBL + MASP-1/MASP-2 |
| First component activated | C1 | C3 | C4 (via MASP) |
| C3 convertase | C4b2a | C3bBb (stabilised by properdin) | C4b2a |
| C5 convertase | C4b2a3b | C3bBb3b (C3b2Bb) | C4b2a3b |
| Antibody needed? | Yes | No (innate) | No (innate) |
| Ca²⁺/Mg²⁺ | Both needed | Mg²⁺ only | Both needed |
| Earliest in evolution / phylogeny | Last | Oldest | Intermediate |
High-yield: Only the classical pathway needs antibody. The alternative and lectin pathways are antibody-independent (true innate immunity), making them critical defences in the neonate and in early infection before antibodies are made.
High-yield: IgM is the most efficient complement activator because a single pentameric IgM can fix C1q (needs two adjacent Fc). For IgG, two molecules are needed side by side. IgG3 > IgG1 > IgG2; IgG4, IgA, IgE, and IgD do NOT fix complement via the classical pathway.
Classical pathway flow
Antigen–antibody complex → C1q binds Fc → activates C1r → C1s → cleaves C4 → C4a + C4b and C2 → C2a + C2b → C4b2a (C3 convertase) → cleaves C3 → C3a + C3b → C4b2a3b (C5 convertase) → cleaves C5 → C5a + C5b → terminal pathway.
Alternative pathway flow
Spontaneous C3 tickover / microbial surface → C3b deposits → binds Factor B → Factor D cleaves bound B into Bb → C3bBb (C3 convertase) → stabilised by properdin (Factor P) → amplifies more C3b → C3bBb3b (C5 convertase) → C5 cleavage.
High-yield: Properdin (Factor P) is the only complement protein that stabilises (positively regulates) the cascade rather than inhibiting it. Properdin deficiency → recurrent Neisseria meningitidis infection, often X-linked. Factors B and D are unique to the alternative pathway.
Terminal (lytic) pathway
C5b + C6 + C7 + C8 + multiple C9 → Membrane Attack Complex (C5b6789ₙ) → transmembrane pore → osmotic lysis. C9 polymerises to form the actual pore; this is the killing step against Gram-negative bacteria, especially Neisseria.
High-yield: Gram-negative Neisseria (gonococcus, meningococcus) are uniquely dependent on MAC-mediated lysis because their thin cell wall is vulnerable. This is why terminal complement (C5–C9) deficiency selectively predisposes to Neisseria infection.
Anaphylatoxins and biological fragments — what each fragment does
| Fragment | Function | Memory hook |
|---|---|---|
| C3a | Anaphylatoxin (mast cell degranulation, histamine) | inflammation |
| C3b | Opsonin (binds CR1), forms convertases, immune complex clearance | the workhorse |
| C4a | Weak anaphylatoxin | weakest |
| C4b | Part of classical C3 convertase | |
| C5a | Most potent anaphylatoxin + chemotactic for neutrophils | strongest + chemotaxis |
| C5b | Initiates MAC assembly | nucleus of MAC |
| C2b (kinin) | Vasodilation (C2 kinin) — relevant in hereditary angioedema | swelling |
High-yield: C5a is the most potent anaphylatoxin AND the major chemotactic factor for neutrophils. C3b is the principal opsonin. iC3b (inactivated C3b) binds CR3 (Mac-1) and is also a strong opsonin.
Complement receptors: CR1 (CD35, binds C3b/C4b — immune complex clearance on RBCs), CR2 (CD21, binds C3d — also the EBV receptor on B cells, links innate to adaptive immunity), CR3 (CD11b/CD18, Mac-1, binds iC3b).
High-yield: CR2 (CD21) is the receptor for Epstein–Barr virus. Classic single-best-answer item.
Regulation of complement (the brakes)
Uncontrolled activation would damage host cells, so multiple regulators exist. These map directly to disease when deficient.
| Regulator | Action | Deficiency disease |
|---|---|---|
| C1 inhibitor (C1-INH) | Inactivates C1r/C1s, MASP, kallikrein → controls bradykinin | Hereditary angioedema (HAE) |
| DAF (CD55) | Accelerates decay of C3 convertases | PNH (with CD59) |
| CD59 (MIRL/protectin) | Blocks C9 insertion / MAC formation | PNH |
| Factor H | Cofactor for Factor I; regulates alternative pathway | aHUS, dense deposit disease (MPGN II) |
| Factor I | Cleaves C3b and C4b | Recurrent pyogenic infections (like C3 deficiency) |
| MCP (CD46) | Cofactor for Factor I | aHUS |
High-yield: DAF (CD55) and CD59 are GPI-anchored proteins. In Paroxysmal Nocturnal Haemoglobinuria (PNH), a PIGA gene mutation abolishes the GPI anchor → loss of CD55 and CD59 → unregulated complement attack on RBCs → intravascular haemolysis, haemoglobinuria, thrombosis. Treated with eculizumab (anti-C5 monoclonal antibody).
Clinical deficiency syndromes — the exam goldmine
This single grouping is the most heavily tested clinical aspect. Learn the pattern: early components → autoimmunity + pyogenic infection; terminal components → Neisseria.
| Deficiency | Clinical consequence |
|---|---|
| C1q/C1r/C1s, C4, C2 (early classical) | SLE-like autoimmunity (poor immune-complex clearance) + recurrent pyogenic infections. C2 deficiency is the commonest complement deficiency in humans. |
| C3 (central) | Severe recurrent pyogenic infections (encapsulated bugs: S. pneumoniae, H. influenzae) + immune-complex disease (glomerulonephritis). Most serious. |
| C5, C6, C7, C8, C9 (terminal/MAC) | Recurrent Neisseria (meningococcal, gonococcal) infections |
| Properdin (alternative) | Neisseria meningitidis — often fulminant, X-linked |
| Factor I / Factor H | Phenotype like C3 deficiency (uncontrolled C3 consumption) |
| C1-INH | Hereditary angioedema |
| DAF + CD59 (GPI anchor) | PNH |
High-yield: C2 deficiency = most common complement deficiency. C3 deficiency = most severe, with the worst infection burden. Terminal (C5–C9) and properdin deficiency = recurrent Neisseria. These three lines answer a large share of complement MCQs.
Hereditary angioedema (C1-INH deficiency) — know it cold
- Autosomal dominant; deficiency or dysfunction of C1 esterase inhibitor (C1-INH).
- Loss of C1-INH → unchecked activation of the classical pathway and the contact (kallikrein–kinin) system → excess bradykinin → increased vascular permeability.
- Clinical: recurrent, non-pruritic, non-pitting angioedema of skin, GI tract (abdominal pain mimicking acute abdomen), and dangerously the larynx (asphyxiation). No urticaria (distinguishes it from histaminergic/allergic angioedema).
- Lab: Low C4 (consumed) is the best screening test — low even between attacks; C4 falls further during attacks. C1-INH level/function low. C1q is normal in hereditary (helps differentiate from acquired C1-INH deficiency, where C1q is low).
- Triggers: trauma, dental procedures, stress, ACE inhibitors (block bradykinin breakdown — contraindicated).
- Management: Acute → C1-INH concentrate, icatibant (bradykinin B2-receptor antagonist), ecallantide (kallikrein inhibitor), or FFP. Prophylaxis → attenuated androgens (danazol/stanozolol) which increase hepatic C1-INH synthesis. Adrenaline, antihistamines, and steroids do NOT work (it is bradykinin-, not histamine-mediated) — a favourite distractor.
High-yield: In hereditary angioedema, C4 is persistently low and is the best screening test; C2 is also low during attacks. The C2 cleavage product (C2 kinin) and bradykinin drive the oedema.
Diagnosis and investigations of choice
A logical, stepwise complement workup:
- CH50 (total haemolytic complement) → screens the classical + terminal pathway (C1–C9). A CH50 of zero strongly suggests a complete deficiency of a single classical/terminal component.
- AH50 → screens the alternative pathway (Factor B, D, properdin + C3–C9).
- Pattern interpretation:
- Low CH50, normal AH50 → defect in classical-specific early components (C1, C4, C2).
- Normal CH50, low AH50 → defect in alternative-specific (Factor B, D, properdin).
- Both low → defect in shared components (C3, C5–C9).
- Then measure the individual component (e.g. C3, C4 levels) and functional assays.
High-yield: CH50 = classical + terminal pathway function. AH50 = alternative pathway. If both CH50 and AH50 are low, suspect a deficiency in a common component (C3 or terminal C5–C9).
C3 and C4 levels in disease (commonly examined):
| Condition | C3 | C4 |
|---|---|---|
| SLE (active, with nephritis) | Low | Low |
| Post-streptococcal GN | Low | Normal |
| MPGN type I | Low | Low |
| MPGN type II (dense deposit) | Very low (C3 nephritic factor) | Normal |
| Hereditary angioedema | Normal | Low |
Complement in disease beyond deficiencies
- C3 nephritic factor (C3NeF): an autoantibody that stabilises the alternative-pathway C3 convertase (C3bBb) → persistent C3 consumption → MPGN type II / dense deposit disease and partial lipodystrophy.
- Atypical HUS (aHUS): dysregulation of the alternative pathway (Factor H, Factor I, MCP mutations) → endothelial injury, microangiopathic haemolytic anaemia, AKI. Treated with eculizumab.
- PNH: as above (CD55/CD59 loss).
- Immune-complex diseases: consume complement (low levels reflect activity, e.g. lupus nephritis).
High-yield: Patients on eculizumab (anti-C5) are functionally terminal-complement deficient → must receive meningococcal vaccination before therapy (iatrogenic Neisseria risk mirrors C5–C9 deficiency).
Key differentials and discriminators
- Hereditary vs acquired angioedema: both have low C4; acquired (associated with lymphoproliferative disease/autoantibody) has low C1q, whereas hereditary has normal C1q.
- Bradykinin-mediated (HAE) vs histamine-mediated (allergic) angioedema: HAE has no urticaria/itch, no response to adrenaline/antihistamine; allergic angioedema has urticaria and responds to adrenaline.
- Pyogenic-infection deficiencies (C3, Factor I/H) vs Neisseria-only deficiencies (C5–C9, properdin): infection spectrum is the clincher.
- Early-classical deficiencies (C1, C4, C2) stand out by autoimmunity/SLE as the presenting feature.
Mnemonics
- "Naughty Pediatricians (Properdin) and Children (C5–C9) get Neisseria." → properdin + terminal complement deficiency → Neisseria.
- C2 = Common-est; C3 = Calamitous (most severe).
- Anaphylatoxins = "345a" (C3a, C4a, C5a); potency C5a > C3a > C4a.
- MAC = C5b6789, and C9 makes the hole.
- HAE: "Bradykinin Burns, not Histamine" → adrenaline/antihistamine useless; give C1-INH/icatibant.
Recently asked / exam angle
- Which complement protein is the receptor for EBV? → CR2 (CD21).
- Most potent anaphylatoxin / chemotactic factor? → C5a.
- Most common complement deficiency? → C2; most severe? → C3.
- Recurrent Neisseria infections point to deficiency of? → C5–C9 (terminal) or properdin.
- PNH mechanism → loss of GPI-anchored CD55 + CD59 due to PIGA mutation; treat with eculizumab.
- Best screening test in hereditary angioedema → low C4; treatment of acute attack → C1-INH concentrate / icatibant, NOT adrenaline.
- CH50 zero with normal AH50 → classical-specific early-component deficiency.
- Which Ig fixes complement best? → IgM (then IgG3 > IgG1).
- Low C3 with normal C4 in glomerulonephritis → post-streptococcal GN or MPGN II (C3 nephritic factor).
- Only positive regulator of complement? → properdin.
Rapid revision
- Complement proteins are heat-labile (destroyed at 56°C, 30 min) and made mainly by the liver.
- C3 is central; all three pathways converge on its cleavage.
- Classical pathway needs antibody (IgM best, then IgG3/IgG1); alternative and lectin are antibody-independent.
- Classical/lectin C3 convertase = C4b2a; alternative C3 convertase = C3bBb (stabilised by properdin).
- MAC = C5b–C9; C9 polymerises to form the lytic pore; kills Neisseria.
- C5a = most potent anaphylatoxin + neutrophil chemotaxin; C3b = chief opsonin.
- CR2 (CD21) is the EBV receptor; CR1 (CD35) clears immune complexes.
- C2 deficiency = commonest; C3 deficiency = most severe (pyogenic + immune-complex disease).
- Terminal (C5–C9) and properdin deficiency → recurrent Neisseria infections.
- Hereditary angioedema = AD C1-INH deficiency, bradykinin-mediated, low C4, normal C1q, no urticaria; treat with C1-INH/icatibant — adrenaline/antihistamines do not work.
- PNH = loss of GPI-anchored CD55 + CD59 (PIGA mutation) → intravascular haemolysis; treat with eculizumab (anti-C5).
- CH50 screens classical + terminal; AH50 screens alternative; both low → defect in a shared component (C3 or C5–C9).