SN5 SHORT NOTE 5M ★ High-yield

Describe the complement system with its pathways and biological functions.

Pathology · 2nd Professional — Para-Clinical

Definition

The complement system is a group of about 20 plasma proteins that, once activated in a cascade, mediate inflammation, opsonisation and cell lysis.

The Three Pathways

Pathway	Activated by	Key early components
Classical	Antigen–antibody complexes containing IgM or IgG	C1, C4, C2
Alternative	Microbial surfaces directly — endotoxin, polysaccharide; NO antibody needed	Factors B, D and properdin
Lectin	Mannose-binding lectin attaching to microbial mannose	MASP-1 and MASP-2, then C4 and C2

All three converge on the cleavage of C3 — the central step → C3a (released) and C3b (bound) → C3b joins the convertase to cleave C5 → C5a (released) and C5b (bound) → C5b assembles C6, C7, C8 and multiple C9 → membrane attack complex (C5b–9) — a pore that lyses the cell

Biological Functions

Function	Component	Effect
Inflammation	C3a and C5a — the anaphylatoxins	Trigger histamine release from mast cells → vasodilatation and increased permeability
Chemotaxis	C5a	The most potent chemotactic factor for neutrophils; also activates them
Opsonisation	C3b	Coats the organism; phagocytes bear C3b receptors — the most important function of complement
Cell lysis	C5b–9 (MAC)	Especially important against neisseria
Clearance of immune complexes	C3b	Binds complexes to red cell CR1 for removal by the spleen and liver

CLINICAL PEARL

The complement components were numbered in the order they were discovered, not the order they act — which is why the classical sequence runs C1, C4, C2, C3. C4 before C2 is not a misprint, and it is worth remembering because examiners test it.

Regulation

C1 inhibitor — blocks activated C1; its deficiency causes hereditary angio-oedema
Decay accelerating factor (CD55) and CD59 — membrane-bound, protect host cells; anchored by GPI. Their loss causes paroxysmal nocturnal haemoglobinuria
Factor H and factor I — inactivate C3b in the fluid phase
Regulation exists because the alternative pathway ticks over continuously; host cells are protected, microbial surfaces are not

Applied Aspects

C3 deficiency — the most serious; severe recurrent pyogenic infection, since opsonisation fails
Deficiency of C5–C9 (the terminal components) — recurrent neisseria infection specifically, because the MAC is the chief defence against it
Low C3 and C4 indicate consumption and are used to monitor activity in systemic lupus erythematosus and post-streptococcal glomerulonephritis
Eculizumab, a monoclonal antibody against C5, treats paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome — and its recipients require meningococcal vaccination, for exactly the reason above
Hereditary angio-oedema is not allergic, so it does not respond to antihistamines or adrenaline; C1 inhibitor concentrate or icatibant is needed

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