This proposal describes a 5-year training program to enable the applicant to expand her scientific knowledge, advance her technical skills, and establish independence from her primary mentor. In addition to the primary mentor, the applicant has 2 co-mentors and 1 collaborator to help her achieve the goals of this proposal. The overall scientific objectives are to elucidate the role of the transcription factor interferon regulatory factor-5 (IRF5) in B cell development and B cell function and to understand how this role might contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Human genetic studies have shown that IRF5 polymorphisms are strongly associated with an increased risk of developing SLE. In addition, we have found that IRF5 is absolutely required for disease development in a mouse model of SLE, although the underlying mechanism(s) through which IRF5 causes disease is not known In an attempt to begin to investigate possible mechanisms, I have performed preliminary studies which suggest that IRF5 is required for B cell development, especially in the transition from immature B cells to mature B cells. This is the case not only in autoimmune mice but also non-autoimmune mice C57BL/6 mice. Since this transition stage in B cell development is synergistically controlled by both B cell receptor (BCR) signaling and B lymphocyte stimulator (BLyS) receptor signaling, we hypothesize that IRF5 is involved in either B cell receptor signaling or BLyS receptor signaling or both. Another potential mechanism whereby IRF5 might contribute to lupus pathogenesis is through its role in Toll-like receptor-7 (TLR7) and TLR9 signaling cascades. We hypothesize that IRF5 plays a key role in mediating the TLR9-dependent activation of autoreactive B cells in response to DNA-containing autoantigens and that this will impact the type of CD4+ T cell response that is generated following antigen presentation by the autoreactive B cell to the T cell. Finally, we hypothesize that the effects of IRF5 on B cell development and B cell function are B cell intrinsic. To test our hypotheses, we will : 1a) Fully characterize the effects of IRF5 on B cell development;1b) Determine which IRF5-expressing cell type is responsible for the effects of IRF5 on B cell development;2) Determine whether IRF5 is involved in BCR or BLyS receptor signaling;3) Determine how IRF5 modulates autoreactive B cell activation and antigen presentation to T cells;4) Determine whether the effect of IRF5 on B cell function and development in vivo is B cell intrinsic. The proposed research will enhance our understanding not only of the role of IRF5 in the pathogenesis of SLE but also of the role of IRF5 in B cell biology more generally.
Increased levels or activity of a protein called interferon regulatory factor-5 (IRF5) in certain cells of the immune system may contribute to the development of a number of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis and scleroderma. In this proposal we will try and discover the mechanism by which IRF5 alters the function of B cells, one of the most important immune cell types responsible for causing lupus. Obtaining a better understanding of the effects of IRF5 in B cells may lead to new approaches to treat lupus and other autoimmune diseases.
