Combined Heterozygous Genetic Variations in Complement C2 and C8B: An Explanation for Multidimensional Immune...

Area of Science:

• Immunology
• Genetics
• Complement System Biology

Background:

• The complement system is vital for host defense, immunity, and tissue repair, linking innate and adaptive immune responses.
• Genetic variations in complement C2 and C8B are individually known, but their combined heterozygous effect is unexplored.

Observation:

• A patient with combined heterozygous C2 and C8B gene variations presented with poor health and diverse autoimmune diseases.
• Cellular and humoral innate immune investigations revealed impaired neutrophil and monocyte phagocytosis, reduced reactive oxygen species generation, and diminished C5aR1 expression.
• Complement analysis showed reduced activation potential in the alternative and classical pathways.

Findings:

• Reconstitution with purified C2 and C8 did not normalize the patient's serum dysfunction.
• Addition of C3 improved hemolytic activity, and in vitro supplementation with fresh frozen plasma fully restored complement function.
• The combined C2 and C8B heterozygous variations could not fully account for the observed complex immune dysfunctions.

Implications:

• This case highlights a novel combined heterozygous complement gene variation (C2 and C8B) with significant functional consequences.
• The findings underscore the complexity of complement-mediated autoimmune diseases and the potential of complement-based therapies.
• Further research into complement deficiencies and their therapeutic strategies is warranted.