Evidence for an IFN-inducible gene, Ifi202, in the susceptibility to systemic lupus

The Nba2 locus is a major genetic contribution to disease susceptibility in the (NZB × NZW)F1 mouse model of systemic lupus. We generated C57BL/6 mice congenic for this NZB locus, and these mice produced antinuclear autoantibodies characteristic of lupus. F1 offspring of congenic and NZW mice developed high autoantibody levels and severe lupus nephritis similar to (NZB × NZW)F1 mice. Expression profiling with oligonucleotide microarrays revealed only two differentially expressed genes, IFN-inducible genes Ifi202 and Ifi203, in congenic mice versus control mice, and both were within the Nba2 interval. Quantitative PCR localized increased Ifi202 expression to splenic B cells and non-T cells/non-B cells. Moreover, recent results show Ifi202 shows inducible expression in NZB mice in response to both type I and type II IFNs, both in vivo and in vitro. Other experiments using mice with a targeted mutation of the type I IFN receptor show that this pathway is required for type I interferon-mediated responsiveness. Studies using splenic cells demonstrate that multiple subpopulations show enhanced Ifi202 expression in response to type I IFN, and indicate that dendritic cells show the greatest increased expression of Ifi202. These results together with analyses of promoter region polymorphisms, strain distribution of expression, effects on cell proliferation and apoptosis, in addition to recent results characterizing responsiveness to type I and type II IFNs, implicate Ifi202 as a candidate gene for lupus.