Immunology & Clinical Biology
C3 complement
Complement C3 is the central and most abundant protein in the complement system - a network of over 50 plasma and membrane proteins forming an essential arm of innate immunity, whose role is to identify, mark and destroy pathogens (bacteria, viruses, immune complexes) through a cascade of enzymatic chain activations. C3 occupies a pivotal position in this cascade: it is the point of convergence of the three complement activation pathways (classical pathway triggered by antigen-antibody complexes, alternative pathway activated directly by microbial surfaces, and lectin pathway activated by pathogen carbohydrate motifs), and its cleavage by C3 convertase generates two fragments with complementary roles - C3b (a powerful opsonin that binds to pathogen surfaces to facilitate phagocytosis) and C3a (a pro-inflammatory anaphylatoxin that recruits immune cells). Measurement of serum C3 levels by nephelometry or turbidimetry is a clinical biology test commonly prescribed for the assessment of autoimmune diseases, glomerulonephritis, vasculitis and chronic inflammatory conditions. Its interpretation requires distinguishing between two opposing mechanisms of variation: a decrease in C3, reflecting excessive consumption by pathological activation of complement (circulating immune complexes in lupus, glomerular deposits, severe infections) or a deficit in hepatic synthesis; and an increase in C3, reflecting an acute-phase inflammatory response, as C3 is an acute-phase protein synthesized in excess by the liver during inflammatory states. The C3 assay is almost always interpreted in conjunction with C4 and CH50 (hemolytic 50 % - global functional activity of complement) to identify the mechanism and activation pathway involved.
Role in the three complement activation pathways
| Activation pathway | Trigger | Impact on C3 and C4 |
|---|---|---|
| Classic route | C1q-binding antigen-antibody complexes (IgG or IgM); C1q-binding C-reactive protein (CRP); certain viruses and bacteria | Activation of C1 → C4 → C2 → C3 classical convertase (C4b2a) → C3 cleavage; consumption of C4 AND C3 — characteristic profile: low C3 + low C4; collapsed CH50; observed in active systemic lupus erythematosus with glomerulonephritis, cryoglobulinemia, infectious endocarditis |
| Alternate route | Microbial polysaccharide surfaces (Gram− LPS, Gram+ peptidoglycan); aggregated IgA; artificial surfaces; C3b spontaneously deposited on membranes (amplification loop) | Direct activation of C3 → alternative C3 convertase (C3bBb) → amplification; consumption of C3 with NORMAL C4 — characteristic profile: low C3 + normal C4; observed in type II membranoproliferative glomerulonephritis (Dense Deposit Disease), atypical hemolytic uremic syndrome (aHUS), severe bacterial infections |
| Lectin pathway (MBL) | Mannose-binding lectin (MBL) and ficolins recognize carbohydrate motifs on pathogens | Activation of C4 and C2 like the classical pathway (without C1) → C3 convertase → C3 cleavage; similar profile to the classical pathway (low C3 + low C4); frequent MBL deficiency (5–10 % population) — predisposes to recurrent childhood bacterial infections |
Reference values
- Adults: Normal serum C3 is between 0.90 and 1.80 g/L (90–180 mg/dL) depending on the laboratory; reference values vary slightly depending on the analytical method (nephelometry, turbidimetry) and the reference population — refer to the standards of the laboratory performing the analysis.
- Children: slightly lower values in infants (liver immaturity) — C3 between 0.57 and 1.16 g/L in newborns, reaching adult values around 6–12 months
- Pregnancy: slight physiological increase in C3 during normal pregnancy (gestational acute phase reaction) — to be interpreted with caution in case of associated pathology (lupus)
- Reference C4: 0.16–0.38 g/L (16–38 mg/dL); CH50: 75–160 U/mL (or expressed in % depending on the laboratory) — these two parameters always complement the interpretation of C3
Causes of C3 decrease
A decrease in C3 indicates either increased consumption (pathological activation of complement) or a deficit in hepatic synthesis:
| Cause | Mechanism | C3 / C4 / CH50 Profile |
|---|---|---|
| Active systemic lupus erythematosus (SLE) | Immune complex deposits (DNA/anti-DNA) activating the classical pathway via C1q; C3 and C4 consumption proportional to disease activity | C3 low + C4 low + CH50 down; normalization of C3 and C4 after treatment is a marker of therapeutic response; persistent low C3/C4 despite treatment = residual activity or active lupus nephritis |
| Membranoproliferative glomerulonephritis (MPGN) type I | Immune complexes (often HCV-associated or idiopathic) activating the classical pathway with glomerular deposits of C3 and C4 | C3 and C4 bases; often persistent hypocomplementemia; kidney biopsy necessary for diagnosis |
| Dense Deposit Disease (GNMP type II) | Auto-antibodies against alternate C3 convertase (C3 nephritic factor — C3NeF) that stabilize the alternate C3 convertase → massive and selective consumption of C3 via the alternate pathway | C3 very low (sometimes undetectable) + C4 NORMAL + CH50 collapsed; very suggestive profile; C3NeF positive; associated partial lipodystrophy (loss of facial adipose tissue) in 30 % of cases |
| Cryoglobulinemia (Types I, II, III) | Immune complexes containing cryoglobulins that activate the classical pathway; frequently associated with chronic hepatitis C | C3 low + C4 very low (C4 often more depressed than C3 in cryoglobulinemia); cutaneous vasculitis, purpura, glomerulonephritis; cryoglobulin level measurement on a tube kept at 37°C |
| Subacute infective endocarditis | Circulating immune complexes formed against bacterial antigens activating the classical pathway; glomerular deposits (Libman-Sacks glomerulonephritis) | C3 and C4 baseline; positive blood cultures; echocardiogram (vegetations); normalization after effective antibiotic therapy |
| Severe hepatocellular insufficiency (cirrhosis, fulminant hepatitis) | Reduced hepatic synthesis of C3 (and other complement proteins) due to hepatocyte insufficiency | C3 low + C4 low + CH50 decreased + hypoalbuminemia + prolonged PT; clinical context of obvious liver disease; to differentiate from immune activation based on clinical presentation and liver function tests |
| Genetic C3 deficiency (rare) | Homozygous or compound heterozygous mutation of the gene C3 Constitutional deficiency in C3 | C3 undetectable or very low permanently + C4 normal + CH50 zero; major susceptibility to repeated encapsulated bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidisfrom early childhood; complete immunological assessment and clinical immunology consultation |
| Atypical hemolytic uremic syndrome (aHUS) | Mutations in regulatory genes of the alternative pathway (factor H, factor I, MCP/CD46, C3, factor B, thrombomodulin) → uncontrolled activation of the alternative pathway → C3 consumption | C3 low + C4 normal; thrombotic microangiopathy (hemolytic anemia + thrombocytopenia + renal failure); treatment with eculizumab (anti-C5) |
Causes of elevated C3
- Acute or chronic inflammatory reaction: C3 is an acute-phase protein synthesized in excess by the liver in response to pro-inflammatory cytokines (IL-6, IL-1, TNF-α) — bacterial infections, chronic inflammatory diseases (rheumatoid arthritis, Crohn's disease, ankylosing spondylitis), trauma, surgery, neoplasms; elevated C3 in an inflammatory context can mask a decrease in underlying consumption in autoimmune diseases (low-activity lupus with associated inflammatory state)
- Obesity and metabolic syndrome: visceral adipose tissue is a source of C3 synthesis — positive correlation between BMI and C3 levels; high C3 is a marker of low-grade chronic inflammation in metabolic syndrome and an independent cardiovascular risk factor in some studies
- Type 2 diabetes: moderate elevation of C3 linked to chronic inflammatory state and insulin resistance
- Normal pregnancy: slight physiological increase in Cystatin C during the second and third trimesters
ℹ️
C3 should always be interpreted in conjunction with C4 and CH50. A low C3 + low C4 profile points towards the classical pathway (lupus, cryoglobulinemia, endocarditis). A low C3 + normal C4 profile points towards the alternative pathway (Dense Deposit Disease, aHUS, severe bacterial infections). A collapsed CH50 with normal C3 and C4 suggests a deficiency in terminal complement components (C5 to C9 — vulnerability to infections from NeisseriaThese profiles guide the diagnostic approach even before specialized assessments.
Clinical indications for C3 measurement
- Initial assessment and monitoring of systemic lupus erythematosus (SLE): C3 and C4 are markers of lupus activity. Their parallel decrease with an increase in anti-native DNA antibodies is one of the most reliable biological criteria for a lupus flare, particularly lupus nephritis. Measurement is recommended every 3 to 6 months in stable conditions, and whenever a flare is suspected.
- Assessment of glomerulonephritis or nephrotic syndrome: complement profile (C3, C4, CH50) guides etiological diagnosis before kidney biopsy—essential for any glomerular hematuria, significant proteinuria, or glomerular kidney failure.
- Assessment of cutaneous or systemic vasculitis: vascular purpura, immune complex vasculitis (IgA, cryoglobulins) — C3 and C4 are part of the etiological workup with ANCA, ANA, cryoglobulins, HBV/HCV serology
- Recurrent bacterial infections in children: primary immunodeficiency assessment if recurrent infections with encapsulated germs — complement component deficiency to consider (C3, C4, terminal pathway C5-C9, factor H); collapsed CH50 with normal C3 and C4 = terminal pathway deficiency
- Thrombotic microangiopathy workup (aHUS, TTP): C3 + C4 + ADAMTS13 activity + genetics of alternate pathway regulators; treatment with eculizumab (anti-C5) specifically targets the terminal complement pathway
- Monitoring of immunological chronic kidney diseases: MPGN, lupus nephritis, adult Henoch-Schönlein purpura (IgA vasculitis)
Pre-analytical sampling and conditions
- Sample type: venous blood in a plain tube (serum) or citrate tube depending on the laboratory; C3 is stable in serum for 24 to 48 hours at 4°C and for several months at -20°C
- Important storage conditions: C3 can be consumed in vitro by complement activation if the sample is stored improperly (delay before centrifugation, inappropriate temperatures) — artificially low results may result from improper storage; repeat the assay on a new sample if the result is inconsistent with the clinical picture
- Non-obligatory fasting: C3 levels are not significantly influenced by short-term nutritional status; a fasting blood draw is not necessary for this measurement.
- Analytical method: nephelometry or turbidimetry in immunochemistry — standardized quantitative methods; results expressed in g/L or mg/dL according to laboratories
Situations requiring immediate medical evaluation
A very low C3 level discovered in the context of purpura, gross hematuria, acute kidney injury, hemolytic anemia, or an edematous (nephrotic) syndrome necessitates urgent medical evaluation and a complete workup (C4, CH50, ANCA, ANA, anti-DNA, cryoglobulins, kidney function tests) to identify an autoimmune disease or active glomerulonephritis requiring early immunosuppressive treatment. In a patient followed for systemic lupus erythematosus, a significant drop in C3 and C4 associated with an elevation in anti-DNA should lead to an immediate rheumatological evaluation to adjust treatment before the onset of a visceral flare.
For a prescription of a complement test as part of monitoring autoimmune disease, renal abnormality, or immunological testing, Clinique Omicron offers consultations at our Quebec branches as well as via telemedicine. To make an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron physicians prescribe and interpret C3 complement levels as part of the workup for autoimmune diseases, glomerulonephritis, vasculitis, and immunodeficiency evaluations. They refer patients to rheumatologists, nephrologists, and immunologists based on the results and clinical context. Consultations are available at our Quebec branches and via telemedicine throughout the province. To make an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute the advice of a qualified healthcare professional. The interpretation of complement C3 should always be performed by a physician, considering the complete clinical context, other complement parameters (C4, CH50), and associated immunological test results.
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