Complement System – Clinical Immunology
Reviewer
I. Introduction to the Complement System
The complement system is a complex network of more than 50 soluble and cell-bound proteins that work
together to enhance host defense mechanisms. It bridges innate and adaptive immunity by promoting
inflammation, opsonization, and cell lysis. Most complement proteins are synthesized in the liver, with
exceptions such as C1 components (intestinal epithelial cells) and Factor D (adipose tissue). White blood
cells can also produce early components (C1, C2, C3, C4). Most components circulate as inactive zymogens
and are activated sequentially.
II. Functions of Complement
• Cell lysis of bacteria, viruses, and damaged host cells
• Opsonization (C3b, C4b, iC3b) to enhance phagocytosis
• Clearance of immune complexes
• Inflammation via anaphylatoxins (C3a, C5a)
• Chemotaxis of neutrophils and monocytes (C5a)
• Increased vascular permeability
• Amplification of immune responses through cytokine release
III. Pathways of Complement Activation
All pathways converge on C3 activation and end in formation of the membrane attack complex (MAC).
A. Classical Pathway
Trigger: Antigen–antibody complexes (IgG or IgM), CRP bound to ligand
Stages: 1. Recognition Unit – C1 complex (C1q, C1r, C1s) - C1q binds Fc regions of two adjacent IgG or one
IgM - Activates C1r → C1s 2. Activation Unit - C1s cleaves C4 → C4b and C2 → C2a - Forms C3 convertase
(C4b2a) - Addition of C3b forms C5 convertase (C4b2a3b) 3. Membrane Attack Unit - C5 → C5a + C5b -
C5b binds C6–C9 → MAC (C5b6789) → cell lysis
B. Lectin Pathway
Trigger: Carbohydrates (mannose) on microbial cell walls
Key Molecules: - Mannose-binding lectin (MBL) - Ficolins, CL-L1 - MASP-1, MASP-2, MASP-3
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Mechanism: - MBL binds mannose → activates MASP-2 - MASP-2 cleaves C4 and C2 - Pathway proceeds
identically to the classical pathway
C. Alternative Pathway
Trigger: Direct interaction with microbial surfaces (bacteria, fungi, viruses, parasites, tumor cells)
Key Components: - C3, Factors B, D, Properdin (P)
Role: - Acts mainly as an amplification loop - Forms C3 convertase (C3bBb) stabilized by Properdin - Leads
to MAC formation
IV. Regulation of the Complement System
A. Soluble (Plasma) Regulators
• C1-INH: Inhibits C1r and C1s (classical, lectin)
• Factor I: Cleaves C3b and C4b
• Factor H: Cofactor for Factor I; inhibits alternative pathway
• C4-binding protein (C4BP): Inactivates C4b
• S protein (Vitronectin): Prevents MAC insertion into host cells
B. Cell-Bound Regulators
• DAF (CD55): Prevents C3 convertase formation
• MIRL (CD59): Blocks C9 insertion → prevents MAC
• MCP (CD46): Cofactor for Factor I
V. Complement Receptors and Their Roles
• CR1 (CD35): Immune complex clearance; cofactor for Factor I
• CR2 (CD21): B-cell co-receptor; enhances antibody production
• CR3 (CD11b/CD18): Adhesion and phagocytosis
• CR4 (CD11c/CD18): Adhesion and increased phagocyte activity
VI. Biological Manifestations of Complement Activation
• Anaphylatoxins: C3a, C5a → inflammation, vascular permeability
• Chemotaxis: C5a attracts neutrophils and monocytes
• Opsonization: Enhanced phagocytosis
• Adaptive immunity support: Antigen presentation, B-cell activation
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• Neural development: Synaptic pruning
VII. Complement and Disease States
Complement can cause tissue damage when excessively activated, such as in: - Gram-negative septicemia
- Myocardial infarction - Autoimmune hemolytic anemia - Cold agglutinin disease
VIII. Complement Deficiencies and Associated Diseases
• C1, C2, C4: Lupus-like syndromes
• C3: Severe recurrent infections, glomerulonephritis
• C5–C8: Neisseria infections
• C1-INH: Hereditary angioedema
• DAF / MIRL: Paroxysmal nocturnal hemoglobinuria (PNH)
• MBL, MASP-2: Pneumococcal and Neisseria infections
Other abnormalities: - Atypical HUS: Complement dysregulation affecting kidneys - C3 glomerulopathy:
Persistent C3 activation
IX. Laboratory Detection of Complement Abnormalities
Quantitative Assays
• Nephelometry
• Immunoturbidimetry
• Radial immunodiffusion (RID)
Functional Assays
• CH50: Classical pathway activity
• AH50: Alternative pathway activity
• ELISA for complement activation products (C5a, soluble C5b-9)
X. Complement Therapeutics
• Recombinant C1-INH: Hereditary angioedema
• Eculizumab (anti-C5): aHUS, PNH
• Decreases MAC formation, CH50, and AH50
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XI. Key Takeaway Summary
The complement system is a tightly regulated cascade essential for host defense. It promotes inflammation,
opsonization, and cell lysis while supporting adaptive immunity. Dysregulation or deficiency can lead to
severe infections, autoimmune diseases, and renal pathology. Laboratory and therapeutic advances allow
targeted diagnosis and treatment of complement-related disorders.