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Multisystem Processes & Disorders

Complement pathways and deficiency syndromes

Core Principle of Complement System
🧷 The complement system is a cascade of plasma proteins that forms a critical bridge between innate and adaptive immunity, providing three main functions: opsonization of pathogens, direct lysis via membrane attack complex (MAC), and generation of inflammatory mediators.
🧷 Three pathways converge at C3: classical (antibody-mediated), lectin (mannose-binding), and alternative (spontaneous). All three ultimately generate C5 convertase → MAC formation.
🧷 Complement proteins are synthesized primarily in the liver and circulate as inactive zymogens that undergo sequential proteolytic activation.
🧷 Board pearl: The complement system is not just about pathogen killing — it's equally important for clearing immune complexes and apoptotic cells, explaining why deficiencies cause both infections AND autoimmunity.
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Classical Pathway Activation and Components
📍 Initiated by C1q binding to Fc regions of IgM (single pentameric molecule) or IgG (requires ≥2 IgG molecules in close proximity).
📍 C1q + C1r + C1s form the C1 complex → C1s cleaves C4 and C2 → C4b2a complex (C3 convertase) → cleaves hundreds of C3 molecules.
📍 C4b2a3b becomes C5 convertase → initiates MAC assembly.
📍 Board pearl: Classical pathway requires antibody-antigen complexes, making it part of adaptive immunity. IgM is more efficient than IgG because one pentameric IgM can activate C1q, while IgG needs multiple molecules.
📍 C1 inhibitor (C1-INH) regulates this pathway by inactivating C1r and C1s.
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Lectin Pathway: Antibody-Independent Recognition
🔹 Activated by mannose-binding lectin (MBL) or ficolins binding to carbohydrate patterns on microbial surfaces — no antibodies required.
🔹 MBL associates with MBL-associated serine proteases (MASPs), which are structurally similar to C1r and C1s.
🔹 Once activated, MASPs cleave C4 and C2, generating the same C3 convertase (C4b2a) as the classical pathway.
🔹 This represents innate immunity — recognizing pathogen-associated molecular patterns without prior exposure.
🔹 Board pearl: Lectin pathway deficiency (especially MBL deficiency) is common but usually asymptomatic unless combined with other immunodeficiencies.
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Alternative Pathway: Spontaneous Activation
⭐ Continuously active at low levels through spontaneous C3 hydrolysis (C3 tick-over), creating C3(H₂O) which binds factor B.
⭐ Factor D cleaves bound factor B → C3(H₂O)Bb acts as initial C3 convertase → generates C3b.
⭐ C3b binds factor B → factor D cleaves → C3bBb (alternative pathway C3 convertase).
⭐ Properdin stabilizes C3bBb, extending its half-life.
⭐ Board pearl: Alternative pathway serves as both an independent activation route AND an amplification loop for all pathways — even classical/lectin activation generates C3b that feeds into alternative pathway.
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Regulation and Host Protection
✅ Host cells express regulatory proteins that prevent complement-mediated damage: DAF (CD55), CD46 (MCP), and CD59.
✅ DAF and CD46 accelerate decay of C3 convertases; CD59 prevents MAC insertion.
✅ Soluble regulators include factor H (alternative pathway), C4-binding protein (classical/lectin), and C1-INH.
✅ Factor I cleaves C3b and C4b when bound to cofactors (factor H, CD46, C4BP).
✅ Board pearl: Deficiency of regulatory proteins → complement attacks host cells. Paroxysmal nocturnal hemoglobinuria (PNH) results from loss of GPI-anchored DAF and CD59 on RBCs.
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Membrane Attack Complex Formation
🧠 C5 convertase cleaves C5 → C5a (anaphylatoxin) + C5b (initiates MAC).
🧠 Sequential binding: C5b + C6 + C7 → membrane insertion → C8 binding → polymerization of 10-16 C9 molecules.
🧠 C9 polymerization forms the transmembrane pore causing osmotic lysis.
🧠 MAC is particularly effective against gram-negative bacteria (especially Neisseria) due to their outer membrane structure.
🧠 Board pearl: Terminal complement deficiencies (C5-C9) specifically predispose to recurrent Neisseria infections — meningococcal and gonococcal disease.
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Anaphylatoxins and Inflammation
⚡ C3a, C4a, and C5a are small peptides released during complement activation with potent inflammatory effects.
⚡ C5a > C3a >> C4a in biological potency.
⚡ Functions: mast cell/basophil degranulation, neutrophil chemotaxis and activation, increased vascular permeability, smooth muscle contraction.
⚡ C5a is the most powerful neutrophil chemoattractant in the body.
⚡ Board pearl: In septic shock, excessive C5a generation contributes to capillary leak, hypotension, and organ dysfunction. Anti-C5a therapies are under investigation.
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C3 Deficiency: The Central Defect
📌 C3 is the convergence point of all pathways — its deficiency causes the most severe phenotype.
📌 Presents in infancy with recurrent, severe pyogenic infections (especially encapsulated bacteria: S. pneumoniae, H. influenzae, N. meningitidis).
📌 Also develop immune complex disease (glomerulonephritis, vasculitis) due to impaired clearance.
📌 Absent CH50 AND AH50 (both pathways require C3).
📌 Board pearl: C3 deficiency combines features of both early (infections) and late (immune complex disease) complement defects because C3 is essential for both opsonization and immune complex solubilization.
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Early Classical Pathway Deficiencies (C1, C4, C2)
📣 C1q, C1r, C1s deficiencies: severe lupus-like syndrome with childhood onset, often with neurologic involvement.
📣 C4 deficiency: SLE-like disease, but C4 has two genes (C4A and C4B) so complete deficiency is rare.
📣 C2 deficiency: most common complement deficiency in Caucasians. Variable presentation — some asymptomatic, others develop SLE or recurrent infections.
📣 Mechanism: impaired immune complex clearance → tissue deposition → inflammation.
📣 Board pearl: Early classical pathway defects → lupus-like disease. The earlier the defect (C1q > C4 > C2), the more severe the lupus phenotype.
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Terminal Pathway Deficiencies (C5-C9)
🔸 Present with recurrent Neisseria infections (meningococcal meningitis, disseminated gonococcal infection).
🔸 First infection typically occurs in late childhood/adolescence, not infancy.
🔸 Infections may be less severe than in normal hosts (less inflammation), but more frequent.
🔸 Normal immune complex clearance — no increased autoimmunity.
🔸 Board pearl: Recurrent meningococcal disease or disseminated gonococcal infection in an otherwise healthy person → screen for terminal complement deficiency with CH50.
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Properdin and Factor D Deficiency
🧷 Only X-linked complement deficiency (all others are autosomal recessive).
🧷 Properdin stabilizes alternative pathway C3 convertase; deficiency → severe, often fatal meningococcal disease.
🧷 Factor D deficiency is extremely rare but causes similar susceptibility to Neisseria.
🧷 These deficiencies affect only the alternative pathway, so CH50 is normal but AH50 is absent.
🧷 Board pearl: Young male with severe meningococcal disease and normal CH50 → consider properdin deficiency (X-linked).
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Complement Regulatory Protein Deficiencies
📍 C1-INH deficiency → hereditary angioedema (HAE): episodic swelling without urticaria, triggered by trauma/stress.
📍 Factor H deficiency → uncontrolled alternative pathway activation → atypical hemolytic uremic syndrome (aHUS) and dense deposit disease.
📍 Factor I deficiency → consumption of C3 and factor B → secondary C3 deficiency phenotype.
📍 CD59 deficiency → chronic hemolysis (similar to PNH but inherited, not acquired).
📍 Board pearl: Angioedema without urticaria that doesn't respond to antihistamines/steroids → think HAE from C1-INH deficiency.
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Hereditary Angioedema: Mechanism and Features
🔹 C1-INH deficiency → uncontrolled activation of contact system (kallikrein-bradykinin) and complement.
🔹 Bradykinin is the primary mediator of swelling (not histamine).
🔹 Type I HAE (85%): low C1-INH level and function; Type II (15%): normal level but nonfunctional protein.
🔹 Episodic swelling of face, extremities, GI tract (abdominal pain), and potentially fatal laryngeal edema.
🔹 Board pearl: HAE shows low C4 even between attacks (diagnostic clue), while C1q is normal (distinguishes from acquired C1-INH deficiency).
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Atypical HUS and Complement
⭐ Caused by mutations in complement regulatory proteins (factor H, factor I, CD46) or activating mutations in C3 or factor B.
⭐ Uncontrolled complement activation on endothelial cells → microangiopathic hemolytic anemia, thrombocytopenia, acute kidney injury.
⭐ Distinguished from typical HUS (Shiga toxin-mediated) by absence of preceding diarrhea.
⭐ Often triggered by infection, pregnancy, or medications.
⭐ Board pearl: Microangiopathic hemolytic anemia + thrombocytopenia + AKI without diarrhea in an adult → consider complement-mediated aHUS.
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Laboratory Assessment of Complement
✅ CH50 (classical pathway): screens C1 through C9; absent in any classical or terminal pathway deficiency.
✅ AH50 (alternative pathway): screens factor B, D, properdin, C3, and C5-C9; specific for alternative pathway defects.
✅ Individual component levels: ordered based on CH50/AH50 results to identify specific deficiency.
✅ Low C3 with normal C4 suggests alternative pathway activation; low C4 with normal C3 suggests early classical pathway defect.
✅ Board pearl: CH50 = 0 means complete deficiency of at least one component; low but detectable CH50 suggests consumption.
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Complement in Glomerulonephritis
🧠 Low C3 + low C4: lupus nephritis, cryoglobulinemia, endocarditis-associated GN (classical pathway activation).
🧠 Low C3 + normal C4: post-streptococcal GN, C3 glomerulopathy, aHUS (alternative pathway activation).
🧠 Normal C3 + C4: IgA nephropathy, pauci-immune GN (ANCA-associated), anti-GBM disease.
🧠 C3 nephritic factor: autoantibody stabilizing C3 convertase → persistent alternative pathway activation → dense deposit disease.
🧠 Board pearl: Complement levels help narrow the differential in glomerulonephritis — low C3 alone suggests alternative pathway diseases.
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Complement and Infections
⚡ Encapsulated bacteria (especially Neisseria, S. pneumoniae, H. influenzae) are most problematic in complement deficiency.
⚡ Early component defects: broader susceptibility including S. aureus, Streptococcus.
⚡ Terminal defects: specifically Neisseria (need MAC for efficient killing).
⚡ Complement-deficient patients may not mount typical inflammatory responses → infections may present atypically.
⚡ Board pearl: Complement deficiency + encapsulated organism sepsis → give immediate antibiotics AND consider prophylaxis/vaccination after recovery.
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Clinical Management Principles
📌 Vaccination is critical: meningococcal (all serogroups), pneumococcal, H. influenzae type b, with boosters as recommended.
📌 Prophylactic antibiotics considered for some deficiencies (especially properdin deficiency).
📌 Immediate antibiotics for fever given impaired host defense.
📌 Screen family members (autosomal recessive inheritance for most).
📌 For HAE: avoid ACE inhibitors (increase bradykinin), trauma prevention, C1-INH replacement or kallikrein inhibitors for acute attacks.
📌 Board distinction: Complement deficiency → vaccinate aggressively but antibody responses may be suboptimal due to impaired B cell activation.
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Board Question Stem Patterns
📣 Recurrent meningococcal meningitis in a teenager → terminal complement deficiency.
📣 Severe childhood-onset SLE with low CH50 and normal AH50 → early classical pathway deficiency.
📣 Angioedema without urticaria, positive family history, low C4 → hereditary angioedema.
📣 Post-infectious glomerulonephritis with isolated low C3 → alternative pathway activation.
📣 Hemolytic anemia + thrombocytopenia + AKI without diarrhea → atypical HUS from complement dysregulation.
📣 X-linked inheritance pattern with severe meningococcal disease → properdin deficiency.
📣 Absent CH50 and AH50 → C3 deficiency.
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One-Line Recap
🔸 The complement cascade (classical/antibody-mediated, lectin/carbohydrate-recognition, alternative/spontaneous) converges at C3 to generate opsonins, inflammatory mediators, and MAC, with early deficiencies causing lupus-like disease from impaired immune complex clearance, terminal deficiencies causing Neisseria susceptibility from absent MAC, and regulatory defects causing angioedema or complement-mediated tissue injury.
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