There is a growing appreciation of microenvironment-specific influences on B lymphocyte differentiation within the lymphoid tissue. An exciting new development in the field is the revelation of a novel chemotaxis axis involving the recognition of oxysterol compounds by the orphan G-protein-coupled receptor (GPCR), Epstein- Barr virus-induced gene 2 (EBI2). EBI2 (Epstein-Barr virus-induced gene 2) is a G-protein-coupled receptor (GPCR) expressed on B cells and is highly induced upon activation. Recent gene targeting experiments revealed that EBI2-/- B cells exhibited defective migration, resulting in strongly impaired T cell-dependent antibody responses. Most recently, two research teams made the unlikely discovery that oxysterol compounds, previously known to bind nuclear receptors, are the physiologic ligands for EBI2. This application seeks to develop tools to probe the in vivo biology and therapeutic potential of this exciting new component of immune cell chemotaxis. The proposed work enlists the MLPCN to screen for small molecule inhibitors of EBI2 that can function in vivo to blunt antibody production and, perhaps, have more broad reaching effects on inflammation. Prospectively, these probes could be used in mouse models of autoantibody-dependent inflammatory disease such as rheumatoid arthritis and lupus, or more broadly applied to examine effects on systemic inflammation.
We propose to use high-throughput screening to identify chemical compounds that antagonize EBI2 signaling. We will use the active compounds as probes (chemical tools) to investigate the pharmacology and B cell biology of EBI2 with the ultimate goal of developing these probes into drugs to treat antibody-dependent inflammatory diseases.