AbstractObjectiveSystemic lupus erythematosus (SLE) is diagnosed according to a spectrum of clinical manifestations and autoantibodies associated with abnormal expression of type I interferon (IFN‐I)–stimulated genes (ISGs). The role of IFN‐I in the pathogenesis of SLE remains uncertain, partly due to the lack of suitable animal models. The objective of this study was to examine the role of IFN‐I signaling in the pathogenesis of murine lupus induced by 2,6,10,14‐tetramethylpentadecane (TMPD).MethodsIFN‐I receptor–deficient (IFNAR−/−) 129Sv mice and wild‐type (WT) 129Sv control mice were treated intraperitoneally with TMPD. The expression of ISGs was measured by real‐time polymerase chain reaction. Autoantibody production was evaluated by immunofluorescence and enzyme‐linked immunosorbent assay. Proteinuria and renal glomerular cellularity were measured and renal immune complexes were examined by immunofluorescence.ResultsIncreased ISG expression was observed in the peripheral blood of TMPD‐treated WT mice, but not in the peripheral blood of TMPD‐treated IFNAR−/− mice. TMPD did not induce lupus‐specific autoantibodies (anti‐RNP, anti‐Sm, anti–double‐stranded DNA) in IFNAR−/− mice, whereas 129Sv controls developed these specificities. Although glomerular immune complexes were present in IFNAR−/− mice, proteinuria and glomerular hypercellularity did not develop, whereas these features of glomerulonephritis were found in the TMPD‐treated WT controls. The clinical and serologic manifestations observed in TMPD‐treated mice were strongly dependent on IFNAR signaling, which is consistent with the association of increased expression of ISGs with lupus‐specific autoantibodies and nephritis in humans.ConclusionSimilar to its proposed role in human SLE, signaling via the IFNAR is central to the pathogenesis of autoantibodies and glomerulonephritis in TMPD‐induced lupus. This lupus model is the first animal model shown to recapitulate the “interferon signature” in peripheral blood.