# Complement Pathways > Complement pathways for MBBS Microbiology: classical, lectin and alternative routes, MAC, regulators, CH50 and deficiency syndromes. - Canonical URL: https://prepelephant.com/topics/mbbs/microbiology/complement-pathways-micro - Exam / course: MBBS · Subject: Microbiology - 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 Pathways", PrepElephant, https://prepelephant.com/topics/mbbs/microbiology/complement-pathways-micro ## Direct answer Complement is a cascade of more than thirty heat-labile serum proteins that converts a small recognition event into massive amplification, ending in inflammation, opsonisation and lysis. Three routes converge on C3: the classical pathway triggered by antibody (IgG or IgM) bound to antigen through C1qrs generating C4b2a; the lectin pathway where mannose-binding lectin and its MASPs make the same convertase directly; and the alternative pathway, which ticks over continuously via spontaneous C3 hydrolysis and is stabilised by factor B, factor D and properdin on microbial surfaces. All three feed the terminal pathway: C5 cleavage assembles the membrane attack complex C5b-9 that lyses gram-negative bacteria and enveloped viruses, while C3b opsonises for phagocytes and C5a recruits and activates neutrophils. Regulators — C1 esterase inhibitor, factor H, factor I, DAF and CD59 — keep this artillery aimed away from self. ## What you must remember - **Classical:** antigen-antibody complex binds C1q (one IgM or two IgG molecules in proximity); C4 and C2 are cleaved to form C4b2a, the classical C3 convertase — the pathway exploited in complement fixation tests. - **Lectin:** mannose-binding lectin binds microbial carbohydrate patterns; MASP-1 and MASP-2 cleave C4 and C2 — antibody-free innate activation, important in childhood infections between waning maternal IgG and own antibody responses. - **Alternative:** spontaneous "tick-over" C3(H2O) binds factor B, cleaved by factor D to C3(H2O)Bb; on microbial surfaces lacking regulatory molecules, properdin stabilises the amplification C3bBb convertase — the reason the pathway distinguishes self from non-self biochemically. - **Terminal pathway:** C5 convertases (C4b2a3b or C3bBb3b) cleave C5; C5b recruits C6-C9 into the membrane attack complex that punches aqueous channels — gram-positive cocci are protected by thick peptidoglycan. - **Biological fragments:** C3b and iC3b are opsonins (CR1, CR3); C5a is the major chemotaxin and anaphylatoxin; C3a and C4a are weaker anaphylatoxins; C3b also clears immune complexes and antigen-antibody aggregates. - **Regulator diseases:** C1-INH deficiency causes hereditary angioedema (quantitative type I about 85 per cent); loss of DAF (CD55) and CD59 in PNH allows complement-mediated red cell lysis; factor H dysfunction causes atypical haemolytic uraemic syndrome. - **Deficiency patterns:** early classical component deficiency (C1-C4) predisposes to immune-complex disease including lupus-like syndromes; C3 deficiency means recurrent pyogenic infection with encapsulated bacteria; C5-C9 deficiency means recurrent Neisseria meningitidis and gonococcus infection with otherwise normal health — a viva classic. - **Laboratory read-out:** CH50 assays the classical and terminal pathways on antibody-sensitised sheep cells; AH50 assays the alternative; CH50 near zero with normal AH50 localises to classical components, both near zero to C3 or alternative defects. ## Why one teenager keeps returning with meningococcaemia Picture the recurring vignette: a seventeen-year-old with a second episode of meningococcal septicaemia in three years, fully recovered each time, no asplenia, normal immunoglobulins. The stepwise answer is complement. Order a CH50; a result near zero with normal immunoglobulins and a normal AH50 pattern points to terminal pathway deficiency, and individual C5-C9 assays then identify the missing component. The logic is elegant: the membrane attack complex is the only complement effector that matters for Neisseria, whose gonococcal and meningococcal species live on mucosal surfaces and in blood where antibody is present and opsonisation is adequate — so the patient handles most infections normally and fails only against meningococci. Management follows the mechanism: meningococcal ACWY and B vaccination, standing antibiotic readiness during outbreaks, and family testing since inheritance is usually autosomal recessive. In India, where complement component assays are confined to reference laboratories, the clinical pattern itself often has to carry the diagnosis. Contrast hereditary angioedema: C1-INH deficiency causes swelling without urticaria because unregulated bradykinin, not complement fragments, drives it — treated with C1-INH replacement or bradykinin-pathway blockers, not antihistamines. ## Where students slip Two fragment pairs get swapped every year: C5a is the chemotaxin and anaphylatoxin, while C3b is the opsonin — write them as a pair and they stay put. The second confusion is which pathway antibody needs: only the classical; the lectin and alternative pathways are antibody-independent innate routes, so a patient with agammaglobulinaemia still has a normal CH50 against a control antigen only if antibody is supplied — a subtlety examiners enjoy. Third, the alternative pathway's "specificity" lies not in recognition but in amplification permitted only on surfaces lacking factor H and sialic acid — human cells are spared, microbial surfaces are not. Finally, remember properdin deficiency is X-linked and selectively impairs the alternative pathway — the one deficiency pattern inherited from the mother's side. ## Frequently asked questions ### What is the CH50 test and what does a near-zero value mean? It titres the serum dilution lysing 50 per cent of antibody-sensitised sheep red cells; near-zero values indicate deficiency of any component from C1 through C9. ### Which complement deficiency predisposes specifically to recurrent meningococcal disease? Terminal component deficiencies (C5 through C9) impair membrane attack complex formation, leaving patients selectively vulnerable to Neisseria while handling other infections normally. ### Why does C1 esterase inhibitor deficiency cause angioedema? Uninhibited C1 and kallikrein activation generates bradykinin, raising vascular permeability and producing recurrent non-urticarial, non-pitting angioedema — treatable with C1-INH replacement or bradykinin-pathway blockers. ### How does the alternative pathway distinguish self from foreign surfaces? Amplification proceeds only where regulators like factor H and host sialic acid are absent; microbial surfaces lack these, so C3bBb escapes inactivation there and deposition escalates. ### Which immunoglobulin is the most efficient complement fixer? IgM, since a single pentameric molecule binding antigen presents C1q-compatible Fc pairs; IgG requires two molecules bound about 30-40 nanometres apart on the same surface.