Silmmal'y Anti-DNA antibodies, specifically those that stain nuclei in a homogenous nuclear (HN) fashion, are diagnostic of systemic lupus erythematosus (SLE) and the MRL-Ipr/Ipr SLE murine model.We have used a heavy chain transgene that increases the frequency of anti-HN antibodies to address whether their production in SLE is the consequence of a defect in B cell tolerance. Anti-HN B cells were undetectable in nonautoimmune-prone transgenic mice, but in MRL-Ipr/Ipr transgenic mice their Ig was evident in the sera and they were readily retrievable as hybridomas. We conclude that nonautoimmune animals actively delete anti-HN-specific B cells, and that mRL-1pr/Ipr mice are defective in this process possibly because of the lpr defect in theJ~s gene. SLE is a complex disease that has a spectrum of clinical manifestations thought to be the consequence of a dysfunctional immune system. Autoantibodies, specifically anti-DNA antibodies, are the serological hallmark of SLE (1). Although the etiology of serum autoantibodies is unknown, their presence has been attributed to a defect in the regulation of self-reactive B and/or T cells (2-6). Studies using selfreactive Ig transgenic (tg) 1 mice have demonstrated that B cells are normally subject to tolerance induction either by deletion or functional inactivation (7,8). It is not clear, however, how the rules that have been established for B cell tolerance to exogenous antigens or neo-self antigens apply to antigens targeted in autoimmunity.Anti-DNA antibodies from both SLE patients and animal models of SLE are heterogeneous in terms of their specificity for DNA and DNA/protein complexes (1,(9)(10)(11)(12). Antibodies that stain nuclei and mitotic figures in a homogeneous fashion in the anti-nuclear antibody (ANA) assay are designated as anti-homogeneous nuclear (anti-HN). The presence of this subset of anti-DNA antibodies is one of the diagnostic criteria for SLE (13). Here we address the regulation of various anti-DNA antibodies in nonautoimmune mice and how this may be disrupted in autoimmune animals. Our approach has been to generate anti-DNA Ig tg mice and cross the anti-DNA Ig tg onto both nonautoimmune (BALB/c) and autoimmune (MRL-Ipr/lpr) Materials and MethodsMice. The generation of VH3H9 tg mice using a construct consisting of the MRL.lpr/lpr-derived 3H9 V region combined with the BALB/c/z constant region has been described previously (26).The tg has been backcrossed onto the nonautoimmune BALB/c and the SLE-prone MRLlpr/Ipr backgrounds: homozygosity for the Ipr mutation infas was determined for mice on the MRL background by scoring for development of lymphadenopathy and the presence of (CD4-, CDS-, CD3 +) double negative T cells that characterize Ipr/lpr mice (12). In addition, the earliest backcross mouse (MRL1 at backcross 2) was verified as Ipr/lpr by PCR amplification which distinguishes the Ipr allele from the wild-type allele (data not shown). Each VH3H9 tg mouse is at least backcross 2, which corresponds to three matings onto and *88% of a given genetic ...

We have used an Ig transgene (VH3H9) that increases the frequency of anti-DNA autoantibodies to address whether the production of antinuclear Abs in systemic lupus erythematosus is the consequence of a breakdown of B cell tolerance. We have shown that nonautoimmune mice regulate anti-DNA B cells, and that lupus-prone MRL-lpr/lpr mice are defective in this regulation. Here we show that a subset of anti-DNA B cells, namely those that stain nuclei in a homogeneous fashion, not only fail to be deleted in MRL-lpr/lpr mice, but undergo preferential clonal expansion. In addition, we describe a surprising finding: the VH3H9 transgene is less efficient at inhibiting endogenous heavy chain gene rearrangement on the autoimmune-prone MRL-lpr/lpr genetic background than on the nonautoimmune BALB/c background.