What Are Complement Proteins C3 and C4?
Complement proteins C3 and C4 are essential components of the immune system's complement cascade, with C3 being the central protein in all complement pathways and C4 functioning specifically in the classical and lectin pathways to mark pathogens for destruction and facilitate immune complex clearance.
Basic Function and Role
C3 and C4 are serum proteins that serve as critical markers of complement system activity and immune function. 1
- C3 is the most abundant complement protein and serves as the convergence point for all three complement activation pathways (classical, alternative, and lectin). 2
- C4 functions specifically in the classical and lectin pathways, becoming covalently attached to pathogen surfaces as C4b, where it acts as an opsonin and provides a platform for convertase assembly. 2
- Both proteins are primarily synthesized by hepatocytes in the liver and secreted into circulation, though extra-hepatic sites produce moderate quantities for local defense. 3, 4
Clinical Significance
C3 and C4 levels are measured to help diagnose complement deficiencies, assess immune complex-mediated diseases, and evaluate inflammatory conditions. 1, 5
Interpretation of Abnormal Levels:
- Low C4 with normal C3 suggests hereditary angioedema (requires C1 inhibitor testing for confirmation). 1
- Low C3 and C4 together indicates complement consumption, typically from immune complex formation in conditions like lupus or other autoimmune diseases. 1
- Absent C4 (with zero CH50 but normal AH50) suggests C1, C2, or C4 deficiency. 1
- Absent C3 (with zero CH50 and zero AH50) indicates C3 or C5-C9 deficiency. 1
Important Testing Considerations
Complement components are unstable and degrade with time, especially if blood or plasma is warmed—specimens should be placed on ice or refrigerated immediately after drawing for accurate measurements. 1
- C3 and C4 behave as positive acute-phase proteins but respond sluggishly to cytokine drive, requiring several days rather than hours to show detectable elevation. 6
- Levels change little during life and between sexes, except for slight increases after age 20 in males and around age 45 in females. 6
- C4 is the most polymorphic protein of the complement system, with genetic variations affecting expression levels. 3
Genetic and Structural Features
- Human C4 exists as two isotypes (C4A and C4B) with different binding affinities: C4A preferentially forms amide bonds with protein antigens, while C4B forms ester bonds with carbohydrate antigens. 3
- C4 gene expression is inducible by gamma-interferon. 3
- Plasma levels are primarily determined by gene dosage, with partial deficiencies having a combined frequency of 31.6% in the population. 3