Which complement pathway is activated in lupus?

Lupus Primarily Activates the Classical Complement Pathway

Systemic lupus erythematosus (SLE) primarily activates the classical complement pathway, which is evidenced by decreased levels of early classical pathway components (C1q, C4, and C3) during disease activity.

Complement Pathways and SLE

The complement system consists of three activation pathways:

1. Classical pathway - Activated by antigen-antibody complexes
2. Alternative pathway - Activated by microbial surfaces
3. Lectin pathway - Activated by mannose-containing carbohydrates

Classical Pathway Activation in SLE

In SLE, the classical pathway is predominantly activated through:

• Immune complex formation between autoantibodies and nuclear antigens 1
• Binding of these immune complexes to C1q, the recognition subunit of the C1 complex
• Sequential activation of C1r and C1s, leading to C4 and C2 cleavage
• Formation of C3 convertase (C4b2a), which cleaves C3 into C3a and C3b

Evidence for Classical Pathway Involvement

Complement Consumption in Active SLE

• During SLE flares, decreased serum levels of C3 and C4 are observed due to consumption through classical pathway activation 1
• Monitoring of these complement components is recommended for assessing disease activity 1
• European League Against Rheumatism (EULAR) guidelines recommend monitoring anti-dsDNA antibodies and C3/C4 levels to assess disease activity/remission 1

Complement-Related Autoantibodies

• Anti-C1q antibodies are found in approximately 15% of lupus nephritis patients 2
• These autoantibodies correlate with:
  • Disease activity
  • Renal histologic lesions
  • Histological activity index
  • Severity of renal involvement 2

Genetic Evidence

The strongest evidence for classical pathway involvement comes from genetic deficiencies:

• Homozygous deficiency of C1q carries a 93% risk of developing SLE 3
• C4 deficiency carries a 75% risk of SLE 3
• C2 deficiency is also associated with increased SLE risk 4

These genetic deficiencies paradoxically increase SLE risk because they impair:

• Clearance of immune complexes
• Removal of apoptotic cells
• Tolerance induction 5

Laboratory Assessment and Monitoring

According to EULAR guidelines, the following laboratory tests should be performed 1:

• At baseline: ANA, anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm, anti-phospholipid, C3, C4
• For monitoring: anti-dsDNA and C3/C4 levels to assess disease activity/remission

Complement Activation Markers

• Formation of C1 inactivator-C1r-C1s complexes indicates C1 activation 6
• Tetramer complexes (C1 IA-C1r-C1s-C1 IA) are associated with C2 and C3 cleavage in plasma 6
• Efficient recruitment of the classical pathway correlates with disease severity 6

Clinical Implications

Diagnostic Value

• Low C3 and C4 levels, along with elevated anti-dsDNA antibodies, support the diagnosis of active SLE
• Immunofluorescence patterns showing immunoglobulin-positive and C3-positive deposits suggest immune complex-mediated disease with classical pathway activation 1

Monitoring Disease Activity

• Decreasing C3 and C4 levels often precede clinical flares
• Persistently low complement levels despite treatment may indicate ongoing disease activity
• Normalization of complement levels typically indicates response to therapy

Treatment Considerations

• Treatments targeting complement activation may be beneficial in SLE
• Monitoring complement levels helps guide immunosuppressive therapy decisions
• Patients with genetic complement deficiencies may require more aggressive management

Complement Activation in Other Forms of Lupus

In lupus nephritis, immunofluorescence microscopy typically shows:

• Immunoglobulin-positive and C3-positive patterns
• Evidence of classical pathway activation 1
• Immune complex deposition in glomerular basement membranes

Common Pitfalls and Caveats

1. Not all SLE patients show complement consumption - Some patients may have normal complement levels despite active disease

2. Complement levels alone are insufficient - They should be interpreted alongside clinical features and other laboratory markers

3. Genetic complement deficiencies - Patients with inherited complement deficiencies may have persistently low levels even during disease remission

4. Complement consumption in other conditions - Low complement levels can occur in other diseases (infections, other autoimmune conditions)

5. Variability in assays - Different laboratories may use different reference ranges for complement levels

In conclusion, the classical pathway is the primary complement pathway activated in SLE, with substantial evidence from genetic, serological, and clinical studies supporting this association.