As basic mediators of humoral immunity, immunoglobulins have evolved to clear microbes and toxic molecules through coupling of antigen specificity to Fc-mediated effector functions. Effector functions conferred through the Fc domain include positive regulatory mechanisms such as the activation of antibody-dependent cellular cytotoxicity, phagocytosis, or pro-inflammatory cytokine production, as well as negative regulatory functions, such as inhibition of inflammatory immune responses. Whether activity mediated by the Fc region is pro- or anti-Inflammatory in nature Is determined by Fc protein sequence and by the precise composition of an N-linked, complex, biantennary glycan that regulates interactions with members of the IgG Fc receptor family (FcyRs) the SIGN family of molecules (mouse SIGNRI/human DC-SIGN) and CD23. The composition of the core Fc glycan can be altered by addition of saccharide units (fucose, Nacetylglucosamine, galactose and sialic acid) and these modifications directly alter the biological activity of IgG molecules. Though the precise saccharide composition of Fc glycans is a known determinant of the biological activity of IgGs, little is known about regulation of Fc glycan composition. Interestingly, vaccination of mice and of humans has been observed to cause various modulations in IgG Fc glycan composition. That Fc glycan composition can be modulated by vaccination is Intriguing as it offers a system by which to study specific factors as they may or may not have a role In regulation; for example, glycan modifications might be determined by the nature/T cell dependence of the antigen, the route of antigen exposure, or host factors such as age. We propose to conduct the first systematic study of vaccine-elicited Fc glycan modifications in humans by Immunization of volunteers with a panel of FDA vaccines. The experiments proposed in this application are designed to investigate two basic hypotheses: 1) that the composition of Fc glycans is actively regulated, and 2) that Fc glycan composition, either In the pre-existing IgG pool or on newly elicited IgGs directs the maturation of a humoral immune response.
The proposed project is designed to Identify factors involved In the regulation of IgG Fc glycan composition and to Investigate a role for the Fc glycan in determining vaccine efficacy in humans. Data from these studies may contribute to our understanding of Inflammatory diseases and inform the design of new vaccines, adjuvants and enhanced monoclonal antibody therapies.
|Keeffe, Jennifer R; Van Rompay, Koen K A; Olsen, Priscilla C et al. (2018) A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep 25:1385-1394.e7|
|Wu, Xianfang; Dao Thi, Viet Loan; Huang, Yumin et al. (2018) Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell 172:423-438.e25|
|Hernandez, Nicholas; Melki, Isabelle; Jing, Huie et al. (2018) Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med 215:2567-2585|
|Rosenberg, Brad R; Freije, Catherine A; Imanaka, Naoko et al. (2018) Genetic Variation at IFNL4 Influences Extrahepatic Interferon-Stimulated Gene Expression in Chronic HCV Patients. J Infect Dis 217:650-655|
|Wang, Taia T; Bournazos, Stylianos; Ravetch, Jeffrey V (2018) Immunological responses to influenza vaccination: lessons for improving vaccine efficacy. Curr Opin Immunol 53:124-129|
|Bournazos, Stylianos; Wang, Taia T; Dahan, Rony et al. (2017) Signaling by Antibodies: Recent Progress. Annu Rev Immunol 35:285-311|
|Kenney, Adam D; Dowdle, James A; Bozzacco, Leonia et al. (2017) Human Genetic Determinants of Viral Diseases. Annu Rev Genet 51:241-263|
|Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Fc? Receptor Function and the Design of Vaccination Strategies. Immunity 47:224-233|
|Robbiani, Davide F; Bozzacco, Leonia; Keeffe, Jennifer R et al. (2017) Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico. Cell 169:597-609.e11|
|Wang, Taia T; Sewatanon, Jaturong; Memoli, Matthew J et al. (2017) IgG antibodies to dengue enhanced for Fc?RIIIA binding determine disease severity. Science 355:395-398|
Showing the most recent 10 out of 21 publications