Phillip Domeier

The diversity of the antibody repertoire plays a critical role in the defense against pathogens, but without proper regulation, the processes that promote antibody diversification can also leave patients chronically susceptible to allergies and autoimmunity. Highly-specific antibodies are produced by B cells that mature in germinal centers (GCs), which optimize antibody affinity against pathogens through iterative rounds of proliferation, mutation and selection. The research program of the Domeier laboratory aims to determine how manipulation of signaling within germinal centers influences the generation of both protective and pathogenic antibody responses. We approach our study of germinal centers in transgenic mice and human tonsil organoid cultures with a combination of advanced spectral flow cytometry, fluorescent microscopy (2-dimensional sections and 3-dimensional whole-organ imaging), and multi-omics approaches. Collectively, our research goal is to identify and characterize novel and targetable molecular pathways that amplify protective B cell immunity, while preventing the production of pathogenic autoantibodies.

Project 1: Thymic Stromal Lymphopoietin Signaling in Germinal Centers, Plasma Cells, and Memory B cells.

We previously identified the alarmin cytokine, Thymic Stromal Lymphopoietin (TSLP), as a crucial regulator of germinal center responses in mice (PMID: 36608149), however several new studies in the Domeier laboratory will determine how this cytokine impacts the maintenance and function of memory B cells and plasma cells. A separate project will also use a novel tonsil organoid culture system to determine how TSLP-targeted therapeutics impact human germinal center responses.

Project 2: Germinal Center-mediated photosensitivity in autoimmunity.

We previously observed disrupted GC responses in a humanized mouse model of IPEX syndrome (PMID: 35749515), resulting in high circulating concentrations of skin-specific IgE autoantibodies. These mice also exhibit exaggerated inflammatory responses after sunburn (photosensitivity), mimicking similar disease phenotypes in several skin-related autoimmune diseases. Using this model, we will investigate the altered germinal center pathways in these mice to determine how skin-reactive IgE is generated in patients with autoimmune photosensitivity.

Project 3: Engineering Tonsil Organoids.

Several groups are now working with an innovative organoid culture system (called tonsil organoids), that allow for in-depth studies of human GC responses in vitro. Several projects are planned to optimize tonsil organoid performance through supplementation of cytokines and/or growth factors. Overall, the goal of this study will be to develop a high-throughput method for testing vaccine candidates and/or identifying novel therapeutic targets to selectively modify germinal center responses in vivo.