Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1

Area of Science:

• Immunology
• Complement System Biology

Background:

• Factor H (FH) and FH-like protein 1 (FHL-1) are key regulators of the complement alternative pathway.
• Host selectivity is crucial for complement regulators, but the mechanisms remain unclear.

Purpose of the Study:

• To investigate the discriminatory mechanisms of FH and FHL-1 in protecting host versus foreign cells.
• To determine the regulatory activity and selectivity principles of FH and FHL-1.

Main Methods:

• Analysis of human FH and FHL-1 protection on rabbit and yeast cells.
• Assays for C3b affinity, cofactor activity, decay acceleration, and serum activity.
• Evaluation of FHL-1 plasma clearance and concentration.

Main Results:

• FH demonstrates a 2-fold selectivity for self (sialylated host surfaces) over non-self (rabbit, yeast), with a selectivity factor of ~2.4.
• FHL-1 exhibits higher regulatory activity than previously known but is less selective.
• The complement regulatory site in FH extends beyond the first four domains to include domains 5-7.
• FHL-1 has rapid plasma clearance and low plasma concentration, suggesting a role in local compartments.

Conclusions:

• FH possesses a significant 2-fold discriminatory power, favoring self over foreign surfaces.
• FHL-1 is a potent regulator, more active than previously recognized, but specialized for local tissue regulation rather than systemic immunity.