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© The Rockefeller University Press, 0022-1007/1998/9/909/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 5, September 7, 1998 909-917

Articles

Efficient Peripheral Clonal Elimination of B Lymphocytes in MRL/lpr Mice Bearing Autoantibody Transgenes

Jennifer A. Kench*,{ddagger}, David M. Russell*, and David Nemazee*,{ddagger}

From the * National Jewish Medical and Research Center, Division of Basic Sciences, Department of Pediatrics, Denver, Colorado 80206; and the {ddagger} Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80206

Peripheral B cell tolerance was studied in mice of the autoimmune-prone, Fas-deficient MRL/ lpr.H-2d genetic background by introducing a transgene that directs expression of membrane-bound H-2Kb antigen to liver and kidney (MT-Kb) and a second transgene encoding antibody reactive with this antigen (3-83µ{delta}, anti-Kk,b). Control immunoglobulin transgenic (Ig-Tg) MRL/lpr.H-2d mice lacking the Kb antigen had large numbers of splenic and lymph node B cells bearing the transgene-encoded specificity, whereas B cells of the double transgenic (Dbl-Tg) MRL/lpr.H-2d mice were deleted as efficiently as in Dbl-Tg mice of a nonautoimmune B10.D2 genetic background. In spite of the severely restricted peripheral B cell repertoire of the Ig-Tg MRL/lpr.H-2d mice, and notwithstanding deletion of the autospecific B cell population in the Dbl-Tg MRL/lpr.H-2d mice, both types of mice developed lymphoproliferation and exhibited elevated levels of IgG anti-chromatin autoantibodies. Interestingly, Dbl-Tg MRL/lpr.H-2d mice had a shorter lifespan than Ig-Tg MRL/lpr.H-2d mice, apparently as an indirect result of their relative B cell lymphopenia. These data suggest that in MRL/lpr mice peripheral B cell tolerance is not globally defective, but that certain B cells with receptors specific for nuclear antigens are regulated differently than are cells reactive to membrane autoantigens.

Key Words: B lymphocyte • tolerance • autoantibody • MRL/lpr • systemic lupus erythematosus

Address correspondence to David Nemazee, Rm. K1023, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Phone: 303-398-1623; Fax: 303-398-1225; E-mail address: nemazeed{at}njc.org

Abbreviations used: ALT, alanine aminotransferase; AST, asparate aminotransferase; BCR, B cell receptor; BGG, bovine {gamma} globulin; Dbl-Tg, double transgenic; FasL, Fas ligand; HRP, horseradish peroxidase; Ig-Tg, immunoglobulin transgenic; MT-Kb, metallothionein-Kb; Tg, transgenic.


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