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A Novel Type I IFN-Producing Cell Subset in Murine Lupus¹

Pui Y. Lee^*, Jason S. Weinstein^*, Dina C. Nacionales^*, Philip O. Scumpia, Yi Li^*, Edward Butfiloski^*, Nico van Rooijen, Lyle Moldawer, Minoru Satoh^*, and Westley H. Reeves^2,*,

^* Division of Rheumatology & Clinical Immunology and Center for Autoimmune Disease, Department of Surgery, and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610-0221; and Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands

Excess type I IFNs (IFN-I) have been linked to the pathogenesis of systemic lupus erythematosus (SLE). Therapeutic use of IFN-I can trigger the onset of SLE and most lupus patients display up-regulation of a group of IFN-stimulated genes (ISGs). Although this "IFN signature" has been linked with disease activity, kidney involvement, and autoantibody production, the source of IFN-I production in SLE remains unclear. 2,6,10,14-Tetramethylpentadecane-induced lupus is at present the only model of SLE associated with excess IFN-I production and ISG expression. In this study, we demonstrate that tetramethylpentadecane treatment induces an accumulation of immature Ly6C^high monocytes, which are a major source of IFN-I in this lupus model. Importantly, they were distinct from IFN-producing dendritic cells (DCs). The expression of IFN-I and ISGs was rapidly abolished by monocyte depletion whereas systemic ablation of DCs had little effect. In addition, there was a striking correlation between the numbers of Ly6C^high monocytes and the production of lupus autoantibodies. Therefore, immature monocytes rather than DCs appear to be the primary source of IFN-I in this model of IFN-I-dependent lupus.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research Grant R01-AR44731 from the U.S. Public Health Service and by gifts from Lupus Link, Inc., Daytona Beach, FL, and from Mr. Lewis M. Schott to the University of Florida Center for Autoimmune Disease. P.Y.L. and J.S.W. are recipients of the National Institutes of Health T32 Trainee Grants DK07518 and AR007603. This work was also supported with resources and the use of facilities at the Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL.

² Address correspondence and reprint requests to Dr. Westley H. Reeves, Division of Rheumatology & Clinical Immunology, University of Florida, PO Box 100221, Gainesville, FL 32610-0221. E-mail address: whreeves{at}ufl.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; RNP, ribonucleoprotein; DC, dendritic cell; MDC, myeloid DC; PDC, plasmacytoid DC; ISG, IFN-stimulated gene; IFN-I, type I IFN; IFNAR, IFN-I receptor -chain; TMPD, tetramethylpentadecane; DTR, diphtheria toxin receptor; clo-liposome, clodronate-containing liposome; iNOS, inducible NO synthase.