Functional complement C1q abnormality leads to impaired immune complexes and apoptotic cell clearance

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Complement component C1q is crucial for clearing apoptotic cells and immune complexes, preventing autoimmunity.
• C1q deficiencies are rare, typically involving complete absence or non-functional fragments.
• Maintaining self-tolerance and immunity relies on proper complement system function.

Observation:

• A patient with lupus, neurological issues, and infections presented with a novel homozygous GlyB63Ser mutation in C1q.
• This mutated C1q molecule bound ligands like immune complexes and apoptotic cells normally.
• However, the mutation disrupted C1 complex formation with C1r/C1s, halting downstream complement activation.

Findings:

• The GlyB63Ser mutation impairs the interaction between C1q and its proteases C1r/C1s.
• This functional defect prevents the classical complement pathway activation, crucial for opsonization and pathogen clearance.
• The study identified a specific mutation site between LysB(61) and LysB(65) likely involved in C1r binding.

Implications:

• Normal C1q binding to apoptotic cells alone is insufficient for maintaining self-tolerance in humans.
• Intact opsonization via complement fragments C3 and C4 is essential for fighting infections and preventing autoimmune diseases.
• This case underscores the critical role of functional C1q in preventing autoimmunity and ensuring immune defense.