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T Cell-Independent Spontaneous Loss of Tolerance by Anti-Double-Stranded DNA B Cells in C57BL/6 Mice¹

Patricia Y. Tsao^*, Jing Jiao^*, Mei Qing Ji^*, Philip L. Cohen and Robert A. Eisenberg^2,*

^* Department of Medicine, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104; and Rheumatology Section, Temple University, School of Medicine, Philadelphia, PA 19140

Systemic lupus erythematosus is characterized by loss of tolerance to DNA and other nuclear Ags. To understand the role of T cells in the breaking of tolerance, an anti-DNA site-specific transgenic model of spontaneous lupus, B6.56R, was studied. T cells were eliminated by crossing B6.56R with CD4^–/– or TCRβ^{–/––/–} mice, and the effects on anti-dsDNA serum levels, numbers of anti-dsDNA Ab-secreting cells, and isotypes of anti-dsDNA were analyzed. In addition, the development and activation of B cells in these mice were examined. Surprisingly, the presence of T cells made little difference in the development and character of the serum anti-dsDNA Ab in B6.56R mice. At 1 mo of age, anti-dsDNA Abs were somewhat lower in mice deficient in β and T cells. Levels of Abs later were not affected by T cells, nor was autoantibody class switching. B cell activation was somewhat diminished in T cell-deficient mice. Thus, in the B6 background, the presence of an anti-dsDNA transgene led the production of autoantibodies with a specificity and isotype characteristic of murine systemic lupus erythematosus with little influence from T cells. TLR9 also did not appear to play a role. Although we do not yet understand the mechanism of this failure of immunoregulation, these results suggest that similar processes may influence autoimmunity associated with clinical 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 Foundation and the Alliance for Lupus Research, the Lupus Research Institute, the Lupus Foundation of South New Jersey, the Department of Veterans Affairs, and the National Institutes of Health (Grants R01-AR-34156, U19-AI-46358, R01-AI063626, and R01 DE017590).

² Address correspondence and reprint requests to Dr. Robert A. Eisenberg, Division of Rheumatology, University of Pennsylvania, 756 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6100. E-mail address: raemd{at}mail.med.upenn.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; KI, knock-in; cGVH, chronic graft-versus-host; MHC II, MHC class II; EDF, equivalent dilution factor; AFC, autoantibody-forming cell.

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