Complement System

Basics

~30 plasma/cell-surface proteins. Liver-synthesized, circulate inactive. “Complements” antibody immunity but can act independently too. Sequential cascade, each step amplifies next.

3 Activation Pathways

Classical: triggered by Ag-Ab complex (IgM/IgG). C1(q,r,s) binds Fc → C1s cleaves C4+C2 → C4b2a (C3 convertase). Links complement to ACQUIRED immunity.

Alternative: triggered DIRECTLY by microbial surface (bacterial wall, endotoxin, fungal wall) — NO antibody needed. INNATE. Spontaneous C3 hydrolysis → C3b + Factor B → Factor D cleaves → C3bBb (C3 convertase), stabilized by Properdin.

Lectin: triggered by MBL (mannose-binding lectin) on microbial mannose residues — antibody-independent, INNATE. MASPs cleave C4+C2 → same C4b2a as classical.

ALL 3 converge at C3 CLEAVAGE = central, rate-limiting step.

Common (Terminal) Pathway

C3b + C3 convertase → C5 convertase → cleaves C5 → C5a + C5b. C5b + C6+C7+C8+multiple C9 → MAC (Membrane Attack Complex, C5b-9) → pore → osmotic lysis. SAME terminal pathway regardless of upstream trigger.

Biological Functions

C3b, C4b → OPSONIZATION (CR1 on phagocytes) — arguably MOST important function
C3a, C5a → ANAPHYLATOXINS — mast cell/basophil degranulation, ↑vascular permeability, smooth muscle contraction (contributes to inflammation + type III hypersensitivity)
C5a → CHEMOTAXIS — most potent complement chemoattractant, recruits neutrophils/monocytes
C5b-9 (MAC) → CYTOLYSIS — osmotic lysis
C3b → IMMUNE COMPLEX CLEARANCE — CR1 on RBC binds complex → carried to liver/spleen. Failure → type III hypersensitivity

Regulation

C1-INH (C1 inhibitor) — blocks C1r/C1s. Deficiency = HEREDITARY ANGIOEDEMA. Factor H + Factor I — degrade C3b, limit alternative pathway. DAF (CD55) + MCP (CD46) — host cell-surface, protect own cells from complement. CD59 — blocks MAC assembly on host cell.

PNH (Paroxysmal Nocturnal Hemoglobinuria): GPI anchor defect → ↓DAF + ↓CD59 → RBC vulnerable to complement lysis.

Complement Deficiencies

Early classical (C1, C2, C4) — COMMONEST deficiency. Lupus-like immune complex disease. C3 — MOST SEVERE (convergence point of all 3 pathways). Recurrent severe pyogenic bacterial infection. Late (C5, C6, C7, C8, C9) — ↓MAC formation. SPECIFIC: recurrent NEISSERIA infection (meningococcus, gonococcus). Regulatory: C1-INH def = hereditary angioedema. DAF/CD59 def (GPI anchor) = PNH.

Lab Assessment

CH50 (total hemolytic complement): overall classical pathway function. Dilution needed to lyse 50% Ab-sensitized sheep RBC. ↓ if any classical component missing OR cascade actively consumed (active SLE). Screening test.

Individual component levels (C3, C4 — nephelometry/ELISA): localizes deficiency, monitors disease activity. ↓C3/C4 in SLE = active consumption = disease flare correlation.

What Complement Is

The complement system is a group of roughly 30 plasma and cell-surface proteins — synthesized mainly by the liver, circulating normally in an inactive form — that “complements” antibody-mediated immunity (hence the name), while also being fully capable of acting independently of antibody altogether. Once triggered, the components activate each other in a strict sequential cascade, each step amplifying the next, converging on a common set of biological effects regardless of which pathway started the cascade.

The Three Activation Pathways

Three distinct routes converge on the same downstream cascade, differing only in what triggers them:

Classical pathway — triggered by antigen-antibody complexes (specifically IgM or IgG bound to antigen), making it the pathway that links complement to acquired, antibody-driven immunity. C1 (a complex of C1q, C1r, C1s) binds the Fc region of complexed antibody, activating C1s, which cleaves C4 and then C2 to form the classical pathway C3 convertase (C4b2a).
Alternative pathway — triggered directly by microbial surfaces (bacterial cell wall components, endotoxin, fungal cell walls) without any antibody involvement at all, making it part of innate immunity. Spontaneous low-level C3 hydrolysis generates C3b, which binds factor B; factor D cleaves the bound factor B to form the alternative pathway C3 convertase (C3bBb), stabilized by properdin.
Lectin pathway — triggered by mannose-binding lectin (MBL) recognizing mannose residues on microbial surfaces (again antibody-independent, innate). MBL-associated serine proteases (MASPs) then cleave C4 and C2, converging on the same C4b2a C3 convertase the classical pathway uses.

All three pathways converge at C3 cleavage, which is the central, rate-limiting event of the entire system — every pathway exists ultimately to generate C3 convertase and cleave C3 into C3a and C3b.

The Common (Terminal) Pathway

Once C3 is cleaved, C3b joins the existing C3 convertase to form a C5 convertase, which cleaves C5 into C5a and C5b. C5b then sequentially recruits C6, C7, C8, and multiple C9 molecules to assemble the membrane attack complex (MAC, C5b-9) — a literal pore punched through the target cell’s membrane, causing osmotic lysis. This terminal pathway is identical regardless of which of the three upstream pathways activated it.

Biological Functions of Complement Products

Complement’s effects come from its individual cleavage fragments, not just the final MAC:

C3b and C4b — opsonization: coating a microbe’s surface, recognized by complement receptors (CR1) on phagocytes, dramatically enhancing phagocytic uptake — arguably complement’s single most important physiological function.
C3a and C5a — anaphylatoxins: trigger mast cell/basophil degranulation (histamine release), increasing vascular permeability and causing smooth muscle contraction — a direct contributor to inflammation, and to the tissue damage of type III hypersensitivity.
C5a — chemotaxis: the most potent chemoattractant complement produces, recruiting neutrophils and monocytes to the site of complement activation.
C5b-9 (MAC) — cytolysis: direct osmotic lysis of the target cell, the endpoint most people associate with “complement” but functionally only one of several effects.
C3b — immune complex clearance: opsonized immune complexes are bound by CR1 on erythrocytes and carried to the liver and spleen for phagocytic clearance — a genuinely important housekeeping function, since its failure is directly implicated in type III hypersensitivity/immune-complex disease.

Regulation of Complement

Because complement activation is a self-amplifying cascade capable of causing real bystander damage to healthy host cells, tight regulation is essential, provided by several inhibitory proteins: C1 inhibitor (C1-INH) blocks C1r/C1s activity, preventing spontaneous classical pathway activation — its deficiency causes hereditary angioedema, since unchecked complement (and kinin) activation drives uncontrolled tissue oedema. Factor H and Factor I together degrade C3b, limiting alternative pathway amplification. Decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46) are host-cell-surface proteins that protect the host’s own cells from complement deposited nearby — their absence (as in paroxysmal nocturnal haemoglobinuria, from a defect in the GPI anchor that normally attaches DAF and a related protein, CD59, to the cell membrane) leaves red cells abnormally vulnerable to complement-mediated lysis. CD59 specifically blocks MAC assembly on the host cell membrane itself.

Complement Deficiencies

Deficiency of an individual complement component produces a fairly predictable clinical pattern depending on which step is missing:

Early classical pathway components (C1, C2, C4) — the commonest complement deficiency overall, strongly associated with immune-complex disease, particularly a lupus-like syndrome, since these components are what normally clear immune complexes efficiently.
C3 deficiency — the most severe deficiency, since C3 sits at the convergence point of all three pathways; produces recurrent severe pyogenic bacterial infection.
Late components (C5, C6, C7, C8, C9) — deficiency selectively impairs MAC formation, producing a strikingly specific susceptibility to recurrent Neisseria infection (meningococcus, gonococcus), since these organisms are otherwise cleared largely by complement-mediated lysis.
Regulatory protein deficiencies — C1-INH deficiency causes hereditary angioedema; DAF/CD59 deficiency (via the GPI-anchor defect) causes paroxysmal nocturnal haemoglobinuria.

Laboratory Assessment

CH50 (total haemolytic complement) assay measures the overall functional activity of the entire classical pathway cascade — the serum dilution required to lyse 50% of antibody-sensitized sheep red cells — and is reduced whenever any classical-pathway component is missing or when the whole cascade is being actively consumed (as in active SLE or immune-complex disease), making it a useful screening test before checking individual component levels. Individual complement component levels (C3, C4 by nephelometry or ELISA) further localize a suspected deficiency or monitor disease activity — a falling C3/C4 in a patient with SLE, for instance, signals active complement consumption and correlates with disease flare.