Immunoglobulin A is the primary isotype secreted at mucosal surfaces and plays an important role in regulating gut microbiota composition and enforcing host-microbiota symbiosis. The long-term goal of the proposed research is to understand how IgA mediates these important effector functions, and to resolve the paradox of how IgA targeting can support the growth of certain gut microbes, while restricting the growth of others. We will explore the hypothesis that differential glycosylation of IgA can program unique antibody effector functions and imbue this important secretory isotype with divergent effects on gut microbiota composition. Although the role of glycosylation in regulating IgG function is now abundantly clear, almost nothing is known about how glycosylation regulates the effector function of secretory IgA in the intestine, which exhibits even more complex and extensive glycosylation patterns than IgG. Our proposal addresses this paradox by examining IgA glycosylation patterns under a variety of inflammatory versus immunoregulatory conditions, and attempting to connect changes in glycosylation to specific effects on microbial community structure.
In Aim 1 we will examine patterns of IgA glycosylation via lectin-based analyses, and through chromatography and mass-spectrometry. We will compare IgA glycosylation in mice with a `healthy' microbial community, as well as mice with a colitogenic `dysbiosis'; mice with and without T cells; and germ-free mice monocolonized with either Treg- inducing or Th17-inducing bacterial species.
In Aim 2 we will construct mice in which only B cells lack critical glycosyltranferase enzymes to examine the effects of aberrant glycosylation of IgA on shaping of the microbial community in the gut. The successful completion of these aims will result in the first full characterization of IgA glycosylation in the gut, and may resolve an apparent paradox regarding the divergent effects of IgA coating on colonization by and growth of specific gut microbes with inflammatory versus immunoregulatory capacities. Understanding the role of glycosylation in IgA effector function is necessary to empower potential therapeutic approaches that aim to use IgA to reshape microbial communities. Finally, these studies may lay the foundation for a broader program exploring the role of secretory IgA glycosylation in human health and disease.
The trillions of microbes that live in our guts (i.e., our microbiota) have dramatic impacts on human physiology. Maintenance of immune-microbiota symbiosis is essential to human health, and disruption of this delicate dialog can lead to the development of a variety of inflammatory diseases. This proposal aims to clarify the role of glycosylation of the secretory antibody IgA in regulating host-microbiota interactions; if successful, these studies may eventually lead to the development of novel therapies to optimize microbiota composition to promote health and prevent disease.