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Secondary Heavy Chain Rearrangement : A Mechanism for Generating Anti–double-stranded DNA B Cells

Debora R. Sekiguchi¹, Robert A. Eisenberg¹ and Martin Weigert²

¹ Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
² Department of Molecular Biology, Princeton University, Princeton, NJ 08544

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

The chronic graft-versus-host (cGVH) reaction results in a syndrome that closely resembles systemic lupus erythematosus (SLE). It is induced in nonautoimmune mice by the transfer of alloreactive T cells. The availability of anti-DNA transgenes allows us to study the genetic origins of autoantibodies in this model. We induced cGVH in two anti-DNA H chain site-directed transgenic mouse strains. This resulted in clonal expansion and selection of specific mutations in the anti–double-stranded (ds) DNA B cell population. These data, together with a high frequency of anti-dsDNA B cell clones recovered as hybridomas, suggested that anti-dsDNAs are the product of an antigen-driven immune response. Genetic analysis associated this response with the generation of anti-dsDNA B cells through secondary rearrangements that replaced the site-directed transgene (sd-tg) with endogenous VH genes.

Key Words: SLE • autoimmunity • anti-dsDNA • B lymphocytes • graft vs. host

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