Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from...

Area of Science:

• Immunology
• Metabolic Diseases

Background:

• Factor D (FD) is a serine protease essential for the alternative pathway (AP) of the complement system.
• Unlike most complement components, FD is predominantly produced by adipose tissue, making it a unique pharmaceutical target.

Purpose of the Study:

• To determine the contribution of adipose tissue to circulating Factor D levels.
• To ascertain the minimum quantity of FD required for a functional AP.

Main Methods:

• Studied lipodystrophy mouse models (complete and partial), FD-deficient mice, and lipodystrophic patient samples.
• Utilized serum mixing experiments, FD reconstitution, and adipose precursor transplantation.
• Assessed AP function in various experimental conditions.

Main Results:

• Complete lipodystrophy in mice led to undetectable FD and minimal AP activity.
• Low serum FD levels were sufficient for normal AP activity in mice.
• FD levels were reduced by approximately 50% in lipodystrophic patients.
• Significant AP activity was observed even with small amounts of FD in humans and mice.

Conclusions:

• Adipose tissue is the main source of serum FD in mice.
• A low concentration of FD is sufficient for maintaining AP function.
• Targeting FD for inhibition holds potential for treating autoimmune and inflammatory diseases driven by AP activation.