Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases.

Area of Science:

• Immunology
• Genetics

Background:

• The complement system is crucial for host defense but its dysregulation, especially the classical pathway (CP), is implicated in autoimmune diseases like systemic lupus erythematosus (SLE).
• Genetic and acquired deficiencies in early CP components are paradoxically linked to increased SLE risk, challenging previous understandings of CP's role in immune complex-mediated injury.

Purpose of the Study:

• To review current knowledge on genetic and acquired deficiencies of early CP components (C1q, C1r, C1s, C4A/C4B, C2) in the pathogenesis and prognosis of SLE.
• To explore the complement system as a therapeutic target in systemic autoimmune diseases.

Main Methods:

• Literature review of genetic deficiencies, gene copy-number variations, and acquired protein deficiencies related to early CP components.
• Analysis of associations between complement component levels/variations and SLE risk/protection in European and East-Asian cohorts.
• Summary of recent therapeutic developments targeting the CP in autoimmune diseases.

Main Results:

• Complete deficiencies of early CP components are strongly associated with SLE development.
• Low C4 gene copy numbers and C4A deficiencies are significant risk factors for SLE, while high C4 levels are protective.
• Acquired deficiencies of CP components are common in SLE patients.

Conclusions:

• Deficiencies in early classical pathway complement components are key factors in SLE pathogenesis and prognosis.
• The complement system, particularly the CP, represents a promising therapeutic target for SLE and other systemic autoimmune diseases.