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

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 patients with systemic lupus erythematosus and in lupus-prone mouse models such as the MRL/Mp-lpr/lpr (MRL/lpr) strain. In nonautoimmune mice, 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 in peripheral B cells and these autoantibodies gain the ability to bind other autoantigens such as double-stranded DNA and cell nuclei. These new specificities arise by somatic mutation of the anti-ssDNA sd-tgs and by secondary light chain rearrangement. Thus, B cells that in normal mice are anergic can be activated in MRL/lpr mice, which can lead to the generation of pathologic autoantibodies. In this paper, we provide the first direct evidence for peripheral rearrangement in vivo.

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

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