IgG antibodies are central mediators of human immunity that can both protect against infections and have the potential to mediate autoimmune diseases. While antibody-mediated immunity has been studied for decades, the heterogeneity that exists among people in IgG-mediated effector capabilities is only now being fully appreciated. This heterogeneity arises from differences in the structural determinants of IgG Fc domains; this, in turn, impacts Fc-Fc receptor interactions which mediate antibody effector functions. Our ongoing experiments have defined distinctions in immune functioning and susceptibility to diseases that arise from Fc domain diversity. Specifically, we have found that specific Fc domain repertoires can enhance vaccine responses and increase susceptibility to disease during dengue infection. Given these findings, a critical question emerges: how is the Fc domain repertoire regulated? Studies in this proposal are designed to identify regulators of the IgG Fc domain repertoire. We will define how heritable influences, age and sex influence the repertoire. In addition, we will study how basal Fc domain repertoires impact durable B and T cell responses to vaccination. Mechanisms regulating the Fc domain repertoire are of great interest since shifting the repertoire could potentially be done for therapeutic benefit in diseases responsive to IVIG treatment, to enhance the activity of anti-tumor antibodies, to prevent autoantibody-mediated tissue diseases, or to enhance the quality of antibodies generated during vaccination.

Public Health Relevance

IgG antibodies are fundamental agents in human immunity that can both protect against infections and mediate autoimmune diseases. Our studies have shown that differences among people in their IgG Fc domain repertoires drive heterogeneity in immune functioning, such as vaccine responses and susceptibility to infectious diseases. Studies proposed here will define regulators of the basal Fc repertoire and mechanisms by which basal Fc domain repertoires impact durable B and T cell responses to vaccination

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI139119-03
Application #
10082423
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2019-01-15
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305