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Inducible Co-Stimulator Null MRL-Fas^lpr Mice: Uncoupling of Autoantibodies and T Cell Responses in Lupus

Geraldine C. Zeller^*, Junichi Hirahashi^*, Andreas Schwarting, Arlene H. Sharpe and Vicki R. Kelley^*

^* Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts; Department of Internal Medicine, Renal Division, Johannes-Gutenberg-University of Mainz, Mainz, Germany; and Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts

Address correspondence to: Dr. Vicki Rubin Kelley, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: 617-525-5915; Fax: 617-525-5830; E-mail: vkelley{at}rics.bwh.harvard.edu

MRL/MpJ-Tnfrsf6^lpr (MRL-Fas^lpr) mice develop a spontaneous T cell–dependent autoimmune disease that shares features with human lupus, including fatal nephritis, systemic pathology, and autoantibodies (autoAb). The inducible co-stimulator (ICOS) is upregulated on activated T cells and modulates T cell–mediated responses. To investigate whether ICOS has an essential role in regulating autoimmune lupus nephritis and the systemic illness in MRL-Fas^lpr mice, ICOS null (–/–) MRL Fas^lpr and ICOS intact (+/+) MRL-Fas^lpr strains (wild-type [WT]) were generated and compared. It was determined that in ICOS–/– MRL-Fas^lpr as compared with the WT strain, (1) there is a significant reduction in circulating IgG and double-stranded DNA autoantibody isotype titers, and (2) there is an amplification of the frequency of intrarenal T cells generating IFN- and TNF- in ICOS–/– versus WT mice. Of note, eliminating ICOS in the MRL-Fas^lpr strain does not alter renal pathology or function. Despite the reduction in circulating IgG and autoantibody isotypes (G1, G2a, and G2b), the amount of these IgG isotypes depositing in kidneys is similar. Furthermore, the systemic illness (skin, salivary and lacrimal glands, lungs, lymphadenopathy, and splenomegaly) is equivalent in ICOS–/– MRL-Fas^lpr and WT mice. These findings highlight the danger of relying on individual parameters, such as quantitative serum Ig levels and T cell functions, as prognostic indicators of lupus.

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				S. Datta and C Mauri Signalling defects and cellular interactions (2) Lupus, March 1, 2008; 17(3): 247 - 250. [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673