What are Complement C3 and Complement C4?
Complement C3 and C4 are serum proteins that are part of the complement cascade—a critical component of the innate immune system that defends against pathogens, clears immune complexes, and removes dying cells. 1, 2
Complement C3: The Central Component
C3 is the central and most critical protein in the complement system, positioned at the convergence point of all three complement activation pathways (classical, alternative, and lectin pathways). 1, 3
Key Functions of C3:
- Promotes phagocytosis of pathogens and cellular debris 1
- Supports local inflammatory responses against infectious organisms 1
- Instructs the adaptive immune response to select appropriate antigens for antibody production 1
- Essential for microbial defense—individuals with C3 deficiency are highly susceptible to infections and cannot properly handle immune complexes 2
Clinical Significance of C3:
- C3 levels remain relatively stable throughout life, with only slight variations by age and sex 4
- Low C3 levels indicate complement consumption, which occurs in immune complex-mediated diseases, certain infections, and autoimmune conditions 5
- C3d (a split product of C3) persists longer in tissues than C3 itself and indicates progression of complement activation—the combination of C4d and C3d predicts graft dysfunction and mortality better than C4d alone in transplant rejection 5, 6
Complement C4: Classical Pathway Indicator
C4 is activated primarily through the classical complement pathway, which is triggered by antibody-antigen immune complexes. 5
Key Functions of C4:
- Indicates classical pathway activation, typically in response to antibody-mediated immune responses 5
- C4d (a split product) binds covalently to endothelium at sites of complement activation and persists longer than native C4, making it useful for detecting antibody-mediated rejection 5
Clinical Significance of C4:
- Normal C4 with low C3 suggests alternative pathway activation (as seen in post-streptococcal glomerulonephritis or C3 glomerulopathy) 7, 5
- Low C4 with low C3 suggests classical pathway activation (as seen in lupus nephritis or cryoglobulinemia) 7, 5
- C4 levels are less predictive of poor outcomes compared to C3 in certain conditions like ANCA-associated vasculitis 8
Diagnostic Patterns in Clinical Practice
Immunofluorescence Patterns Guide Diagnosis:
- Immunoglobulin-positive with complement components indicates immune complex-mediated disease requiring evaluation for infections (hepatitis B/C, endocarditis), autoimmune diseases (SLE, Sjögren's), or monoclonal gammopathies 5
- Complement-dominant pattern (C3 or C4 positive without immunoglobulin) suggests C3 or C4 glomerulopathy with dysregulation of the alternative complement pathway 5
- Negative immunofluorescence should raise suspicion for thrombotic microangiopathy 5
Common Clinical Pitfalls
Avoid interpreting C3 and C4 levels in isolation—they must be contextualized with clinical presentation, other laboratory findings, and timing of disease process 5
C3 and C4 are acute-phase reactants that respond sluggishly (over days, not hours) to inflammatory stimuli, making serial measurements more informative than single values 4
In post-streptococcal glomerulonephritis, C3 typically normalizes within 8-12 weeks—persistently low C3 beyond this timeframe warrants kidney biopsy to exclude C3 glomerulonephritis 7
In transplant rejection, the combination of C4d+C3d positivity is more predictive of graft dysfunction (84% vs 5% with C4d alone) and mortality (37% mortality rate) than either marker alone 6