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Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion¹

Mileka R. Gilbert^2,*, Diane G. Carnathan^2,*, Patricia C. Cogswell, Li Lin, Albert S. Baldwin, Jr^, and Barbara J. Vilen^3,*,

^* Department of Microbiology/Immunology, Department of Biostatistics, Department of Biology, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

Autoimmunity results from a breakdown in tolerance mechanisms that regulate autoreactive lymphocytes. We recently showed that during innate immune responses, secretion of IL-6 by dendritic cells (DCs) maintained autoreactive B cells in an unresponsive state. In this study, we describe that TLR4-activated DCs from lupus-prone mice are defective in repressing autoantibody secretion, coincident with diminished IL-6 secretion. Reduced secretion of IL-6 by MRL/lpr DCs reflected diminished synthesis and failure to sustain IL-6 mRNA production. This occurred coincident with lack of NF-B and AP-1 DNA binding and failure to sustain IB phosphorylation. Analysis of individual mice showed that some animals partially repressed Ig secretion despite reduced levels of IL-6. This suggests that in addition to IL-6, DCs secrete other soluble factor(s) that regulate autoreactive B cells. Collectively, the data show that MRL/lpr mice are defective in DC/IL-6-mediated tolerance, but that some individuals maintain the ability to repress autoantibody secretion by an alternative mechanism.

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 M.G. was supported by a minority supplement to R01 AI53266 and F31 AI71292. This study was supported by the Lupus Research Institute and by U.S. Public Health Service Grant AI53266.

² M.R.G. and D.G.C. contributed equally.

³ Address correspondence and reprint requests to Dr. Barbara Vilen, CB 7290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. E-mail address: barb_vilen{at}med.unc.edu

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; M, macrophage; Tg, transgenic; Sm, Smith; 7-AAD, 7-aminoactinomycin D; AP, alkaline phosphatase; DRB, 5,6-dichloro-1--D-ribofuranosylbenzimidazole; ODN, oligodeoxynucleotides; DC, dendritic cell; BMDC, bone marrow-derived DC; CM, conditioned medium; lyDC, lymphoid DC; myDC, myeloid DC; pDC, plasmacytoid DC.

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