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*Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104;
University of Southern California Keck School of Medicine, Los Angeles, CA 90033;
Albert Einstein College of Medicine, Bronx, NY 10461;
Department of Biostatistics and Epidemiology, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104; and
¶Service de Médecine Interne, Centre Hospitalier Universitaire de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR–/– mice. Numbers of activated CD40high plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR–/– mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR–/– spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR–/– DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR–/– DC produced less IL-12p40/70 and TNF-
than did NZM DC. The limited IFNAR–/– DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.
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 the Arthritis National Research Foundation (to S.K. and C.O.J.), the Arthritis Foundation OK Chapter (to S.K.), and National Institutes of Health Grants R01 AR050193 (to W.S.) and R01 AI057473 (to C.O.J.).
2 H.A., N.J., E.C., S.B., S.K., and C.O.J. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Susan Kovats, Arthritis and Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104. E-mail address: Susan-Kovats{at}omrf.org; or Dr. Chaim O. Jacob, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR 705, Los Angeles CA 90033. E-mail address: Jacob{at}usc.edu
4 Abbreviations used in this paper: IFNAR, type I IFN receptor; BM, bone marrow; cDC, conventional DC; DC, dendritic cell; FL, Flt3 ligand; IFNAR-KO mice, IFNAR knockout mice; LDC, lymphoid DC; MDC, myeloid DC; MFI, mean fluorescence intensity; NZB, New Zealand Black; NZM, New Zealand Mixed; NZW, New Zealand White; ODN, oligodeoxynucleotide; pDC, plasmacytoid DC; rLN, renal lymph node; SLE, systemic lupus erythematosus; WT, wild type.
5 The online version of this article contains supplemental material.
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