The Journal of Experimental Medicine
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Published 16 December 2002. doi:10.1084/jem.20021560
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© Rockefeller University Press, 0022-1007/2002/12/1543/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 12, December 16, 2002 1543-1552

Anti–DNA B Cells in MRL/lpr Mice Show Altered Differentiation and Editing Pattern

Yijin Li, Hui Li, Dongyao Ni and Martin Weigert

Department of Molecular Biology, Princeton University, Princeton, NJ 08544

Address correspondence to Dr. Martin Weigert, Dept. of Molecular Biology, Princeton University, Princeton, NJ 08544. Phone: (609) 258-4698; Fax: (609) 258-2205; E-mail: mweigert{at}molbio.princeton.edu

We have studied the regulation of anti–DNA B cells in transgenic mice with a heavy chain transgene (3H9H/56R). This transgene codes for a heavy chain that forms anti–double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous V{kappa} repertoire, but certain L chains, referred to as V{kappa} editors, do not sustain dsDNA binding in combination with 3H9H/56R. In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is associated with a V{kappa} editor. A minor population of B cells (30%) bind dsDNA and express the {lambda}1 light chain (known to sustain 3H9H/56R DNA binding). These 3H9/56R/{lambda}1 B cells coexpress a {kappa} editor, and we propose that the down-regulation of the anti-DNA BCR caused by the dual L chain expression may prevent activation of this {kappa}/{lambda} population. These {kappa}/{lambda} B cells are sequestered in the marginal zone. Here, we studied the influence of autoimmunity on expression and regulation of 3H9H/56R. In 3H9H/56R MRL/lpr mice, the expression of anti-dsDNA is vastly accelerated. Anti–dsDNA B cells use noneditor {kappa}s but, in addition, most anti–dsDNA B cells have edited the heavy chain transgene. {lambda}1 B cells (without the coexpression of a {kappa} editor) are found and the {kappa}/{lambda}1 MZ population is absent. Our results suggest that improper editing and failure to sequester autoreactive B cells may contribute to the breakdown of tolerance in MRL/lpr mice.

Key Words: lupus • autoimmunity • isotype switch • tolerance • marginal zone


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