Q3 LONG ANSWER 10M ★ High-yield

Describe the complement system with its pathways, functions and the effects of its deficiencies.

Microbiology · 2nd Professional — Para-Clinical

Definition and Components

The complement system is a group of about 30 heat-labile serum proteins, mostly made in the liver, which act in a self-amplifying cascade to mediate inflammation, opsonisation and lysis.

Inactivated at 56°C for 30 minutes — the basis of "heat inactivation" of serum before certain serological tests
C3 is the most abundant and the central component, at which all three pathways converge

The Three Pathways

Pathway	Trigger	Early components	C3 convertase
Classical	Antigen-antibody complexes — IgM (most efficient, one molecule suffices) or IgG (needs two adjacent molecules)	C1q, C1r, C1s → C4 → C2	C4b2a
Alternative (properdin)	Microbial surfaces directly — LPS, teichoic acid, zymosan; NO antibody required, so it works from the first moment of infection	C3b with factors B and D, stabilised by properdin	C3bBb
Lectin	Mannose-binding lectin binds mannose residues on microbial surfaces; also antibody-independent	MBL with MASP-1 and MASP-2 → C4 → C2	C4b2a

All three pathways generate a C3 convertase → C3 → C3a + C3b → C3b binds the surface (opsonisation) and forms the C5 convertase → C5 → C5a + C5b → C5b binds C6, C7, C8 and multiple C9 molecules → membrane attack complex (MAC, C5b-9) forms a transmembrane pore → Osmotic lysis of the cell

CLINICAL PEARL

The alternative and lectin pathways matter because they work without antibody. The classical pathway requires a prior adaptive response, so it is useless on first encounter with a new organism. The other two recognise microbial surfaces directly and are active within minutes of infection, before any antibody exists — which is why complement belongs to innate immunity even though its classical arm is triggered by antibody.

Biological Functions

Function	Component	Effect
Opsonisation — the most important	C3b (and C4b)	Coats the organism; phagocytes carry C3b receptors, so ingestion is greatly enhanced. This is why C3 deficiency causes severe pyogenic infection
Chemotaxis	C5a (the most potent)	Attracts and activates neutrophils
Anaphylatoxins	C3a, C4a, C5a	Cause mast cell degranulation, histamine release, increased vascular permeability and smooth muscle contraction — an antibody-independent route to anaphylaxis-like reactions, as with radiocontrast
Cytolysis	MAC (C5b-9)	Lyses gram-negative bacteria; gram-positives are protected by their thick wall. Especially important against neisseria
Immune complex clearance	C3b	Complexes coated with C3b bind CR1 on erythrocytes and are carried to the liver and spleen for removal — failure of this causes immune complex disease
B-cell activation	C3d with CR2 (CD21)	Lowers the threshold for B-cell responses

Complement Deficiencies and Regulation

Deficiency	Consequence
C1 inhibitor	Hereditary angio-oedema — recurrent non-itchy, non-urticarial swelling of face, larynx and gut; mediated by bradykinin, so it does not respond to adrenaline, antihistamines or steroids. Treated with C1 inhibitor concentrate, icatibant or fresh frozen plasma. ACE inhibitors precipitate attacks
C3	Severe, recurrent pyogenic infections from infancy — the most serious complement deficiency, because opsonisation fails
C5–C9 (terminal components / MAC)	Characteristically recurrent neisserial infection — meningococcal and gonococcal — because these organisms are cleared chiefly by MAC lysis. Any patient with recurrent meningococcal disease should be tested
C1, C2, C4 (early classical)	SLE-like disease and immune complex disorders, from failure of complex clearance
DAF (CD55) and CD59	Paroxysmal nocturnal haemoglobinuria — an acquired defect of the GPI anchor; unregulated complement lyses the patient’s own red cells. Treated with eculizumab, an anti-C5 antibody
MBL	Increased infection in infancy

Regulatory proteins prevent damage to host cells — C1 inhibitor, factor H and factor I, DAF and CD59. Host cells are protected; microbial surfaces are not, which is what gives the alternative pathway its selectivity

Measurement and Clinical Interpretation

Test	What it assesses	Interpretation
CH50	Functional integrity of the whole classical pathway plus terminal components	A value of zero points to a complete deficiency of one component and is the screening test in recurrent neisserial infection
AH50	Alternative pathway	Abnormal in factor B, D or properdin deficiency
C3 and C4 levels	Individual components, measured by nephelometry	Both low — classical pathway consumption, as in active SLE and serum sickness. C3 low with normal C4 — alternative pathway activation, as in post-streptococcal glomerulonephritis. C4 low with normal C3 — suggests C1 inhibitor deficiency
C1 inhibitor level and function	Hereditary angio-oedema	Level may be normal in the type II variant, so function must also be measured
Complement in tissue	Immunofluorescence on renal biopsy	"Full house" staining with IgG, IgA, IgM, C3 and C1q is characteristic of lupus nephritis

Falling C3 and C4 indicate active consumption and are used to track disease activity, whereas a persistently low level with no illness suggests an inherited deficiency

Applied Aspects

Test complement in recurrent neisserial infection; terminal component deficiency is easily missed and the patient benefits from meningococcal vaccination and prophylaxis
Hereditary angio-oedema is repeatedly mistaken for anaphylaxis and treated with adrenaline, antihistamines and steroids, none of which work; the absence of urticaria and itch is the clue, and a low C4 supports the diagnosis
Low C3 and C4 indicate active consumption, and are used to monitor disease activity in SLE and post-streptococcal glomerulonephritis
Eculizumab blocks C5 and prevents MAC formation, transforming paroxysmal nocturnal haemoglobinuria and atypical haemolytic-uraemic syndrome — but it produces exactly the deficiency described above, so patients must be vaccinated against meningococcus before treatment
Anaphylatoxins explain "pseudo-allergic" reactions to radiocontrast, vancomycin and some drugs, which look like anaphylaxis but involve no IgE and may occur on first exposure
Heat serum at 56°C for 30 minutes to destroy complement before certain serological tests, or non-specific lysis confuses the result
C3 deficiency is the most dangerous, because opsonisation fails and both the classical and alternative pathways converge on it; such children present with severe pyogenic infection in infancy
Complement is consumed in disseminated intravascular coagulation and severe sepsis, and low levels there reflect consumption rather than deficiency
The alternative pathway is active from the first moment of infection, which is why complement is classed as innate immunity despite its classical arm needing antibody
Immune complexes are cleared on erythrocytes through CR1, so anaemia and splenectomy both impair clearance and predispose to immune complex deposition
C1 inhibitor also regulates the contact and kinin systems, which is why its deficiency causes bradykinin-mediated angio-oedema rather than a complement-mediated illness, and why ACE inhibitors precipitate attacks
Complement is heat-labile at 56°C but the antibody is not, which is the basis of inactivating serum without destroying the specific antibody being measured
The alternative pathway distinguishes self from non-self by regulation — host surfaces carry factor H and other inhibitors, microbial surfaces do not, so amplification proceeds only on the invader
Complement therapeutics are expanding — eculizumab and its successors block C5, and their cost and the meningococcal risk they create are both practical considerations
Vaccinate against meningococcus before starting a C5 inhibitor, and consider continuous penicillin prophylaxis; the drug creates precisely the deficiency that predisposes to neisserial disease
C-reactive protein and mannose-binding lectin are innate opsonins that activate complement without antibody, which is why CRP rises so early in bacterial infection
Do not confuse low complement with immunodeficiency in an acutely ill patient; consumption in active SLE or sepsis is far commoner than an inherited defect
Complement bridges innate and adaptive immunity — C3d binding CR2 lowers the threshold for B-cell activation, so the innate system amplifies the adaptive one it also instructs
Splenectomy impairs complement-mediated clearance as well as removing the site of response to blood-borne capsulated organisms, which is why these patients need vaccination and prophylaxis for life

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