Understanding mechanistic relationships between IgG titers and Fc effector functions: a computational framework to...

Area of Science:

• Immunology
• Computational Biology
• Vaccinology

Background:

• Antibody-dependent cellular functions like ADCC and ADCP are crucial for vaccine and infectious disease immunity.
• These functions involve complex interactions between IgG antibodies, Fc gamma receptors (FcγRs), and antigens, making experimental deconvolution challenging.

Purpose of the Study:

• To develop a computational model predicting FcγRIIIa (ADCC) and FcγRIIa (ADCP) immune complexes.
• To dissect mechanisms of immune complex formation and Fc effector function activation.

Main Methods:

• Created an ordinary differential equation model to predict FcγRIIIa and FcγRIIa immune complexes.
• Simulated vaccine boosts (IgG1, IgG3) in HIV vaccine trial participants using the model.

Main Results:

• Model predicted maximum immune complex formation not at highest IgG titers; higher titers can decrease FcγRIIIa/FcγRIIa complexes due to competition.
• Simulated IgG1 and IgG3 combination boosts showed no significant change in ADCC/ADCP complexes.
• Simulated IgG3 boost alone significantly decreased ADCP (p<0.00001) but increased ADCC.

Conclusions:

• A computational framework provides quantitative insights into Fc effector function activation.
• This approach can guide the rational design of therapeutic and prophylactic interventions.