Somatic Mutation and Light Chain Rearrangement Generate Autoimmunity in Anti–single-stranded DNA Transgenic MRL/lpr Mice

doi:10.1084/jem.190.5.691

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© The Rockefeller University Press, 0022-1007/1999/9/691/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 5, September 6, 1999 691-704

Somatic Mutation and Light Chain Rearrangement Generate Autoimmunity in Anti–single-stranded DNA Transgenic MRL/lpr Mice

Frederic Brard^a, Michele Shannon^a, Eline Luning Prak^b, Samuel Litwin^c, and Martin Weigert^a
^a From the Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544
^b Department of Pathology and Laboratory Medicine and the Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
^c Fox Chase Cancer Center, Institute for Cancer Research, Philadelphia, Pennsylvania 19111

Correspondence to: Martin Weigert, Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544. Tel:609-258-2683 Fax:609-258-2205 E-mail:mweigert{at}molbio.princeton.edu.

Antibodies to single-stranded (ss)DNA are expressed in patientswith systemic lupus erythematosus and in lupus-prone mouse modelssuch as the MRL/Mp-lpr/lpr (MRL/lpr) strain. In nonautoimmunemice, B cells bearing immunoglobulin site-directed transgenes(sd-tgs) that code for anti-ssDNA are functionally silenced.In MRL/lpr autoimmune mice, the same sd-tgs are expressed inperipheral B cells and these autoantibodies gain the abilityto bind other autoantigens such as double-stranded DNA and cellnuclei. These new specificities arise by somatic mutation ofthe anti-ssDNA sd-tgs and by secondary light chain rearrangement.Thus, B cells that in normal mice are anergic can be activatedin MRL/lpr mice, which can lead to the generation of pathologicautoantibodies. In this paper, we provide the first direct evidencefor peripheral rearrangement in vivo.

Key Words: anti-DNA, B cell tolerance, receptor editing, systemic lupuserythematosus, V_H replacement

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