Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera

Area of Science:

• Immunology
• Hematology
• Molecular Biology

Background:

• Mutations in complement regulator factor H (FH) cause atypical hemolytic uremic syndrome (aHUS), a severe disease characterized by hemolytic anemia, thrombocytopenia, and renal failure.
• Current treatments inhibiting the terminal complement pathway are effective but compromise pathogen defense.
• There is a need for therapies that restore complement regulation on human cells without impairing antimicrobial activity.

Purpose of the Study:

• To develop a therapeutic strategy that enhances FH function for improved complement regulation on human cells.
• To investigate an anti-FH monoclonal antibody (mAb) for its ability to potentiate FH activity.
• To assess whether this approach preserves complement-mediated protection against bacterial infections.

Main Methods:

• Identification and characterization of an anti-FH monoclonal antibody (mAb).
• Assessment of FH-mediated protection of primary human endothelial cells from complement activation.
• Evaluation of the mAb's effect on complement-mediated bacterial killing.
• Testing the mAb's ability to restore complement regulation in sera from aHUS patients with FH mutations.

Main Results:

• The anti-FH mAb significantly increased FH-mediated protection of endothelial cells from complement activation.
• The mAb preserved the complement-mediated killing of bacteria, indicating intact antimicrobial function.
• The FH-activating mAb restored normal complement regulation in sera from aHUS patients with various FH mutations.
• Data suggest FH circulates in a less active conformation, which can be potentiated by the mAb.

Conclusions:

• Antibody-mediated potentiation of FH offers a promising strategy to treat complement-mediated diseases like aHUS.
• This approach enhances complement regulation on human cells while preserving essential antimicrobial functions.
• Targeting FH conformation may be a novel therapeutic avenue for a range of hematological disorders involving complement dysregulation.