120 : Loss of IFN-gamma 3′untranslated region AU-rich element affects B220+ cell populations in novel murine lupus model

Interferon-gamma (IFN-g) is a key player in immunoregulation, inflammation and autoimmunity. We created a mouse with a 162 nt deletion of an AU-rich element (ARE) region in the 3’UTR of the IFN-g gene. The ARE-deleted (ARE-Del) mice have chronic circulating serum IFN-g levels and develop a lupus-like disease characterized by nuclear antigen-specific autoantibodies and glomerulonephritis. B cells and plasmacytoid dendritic cells (pDCs) play a prominent role is systemic lupus erythematosus (SLE) and we find alterations in both B220 + cell types in these mice. The percentage of CD11c + , pDCA1 + , B220 + , Siglec H + pDCs increases in bone marrow and spleens from ARE-Del mice. Furthermore, addition of IFN-g to flt-3 driven in vitro bone marrow cultures results in a dramatic increase in the pDC population with increases in IRF8, but not E2-2, mRNA expression that coincides with this expansion. In contrast, the total percentage of B220+, CD19+ B cells is reduced in spleens from ARE-Del mice. There is little impact on the CD23+ follicular B cell subset; however, CD21+ marginal zone (MZ) B cells are greatly reduced or absent. Crossing the ARE-Del mice with TLR7 or IFN-alpha receptor null mice restore MZ B cells to levels seen in WT mice indicating that interplay between type I and type II interferons plays a role in splenic B cell development. Current studies are underway to understand the molecular basis for how these interferons influence B cell maturation.