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 ...

These data corroborate the fact that the rate of detection of truly contaminated PLT apheresis products in the United States is approximately 1 in 5000 (0.02%); this is lower than the 0.03 to 0.05 percent rates that were generally quoted in the literature before the implementation of prospective bacterial culturing programs.

The goal of this study was to examine the in vivo site of autoantibody production in normal and autoimmune-prone mice. B cells were identified in tissue sections with IgM- and IgG2a-specific riboprobes that readily distinguished resting cells from antibody-forming cells (AFC). In normal mice, the few identifiable IgG2a-secreting cells were found in the red pulp. By contrast, in Ipr mice exceedingly high numbers of IgG2a and autoantibody-producing cells were found deep within the T cell-rich periarteriolar lymphoid sheaths (PALS). This unusual anatomic location of autoantibody-secreting B cells is unique to Fas dysregulated strains, since IgG2-producing cells in MRL/+ and (SWR x NZB)F1 mice were found predominantly in the red pulp or outer PALS, similar to normal mice. Furthermore, analysis of spleens from Ipr and non-Ipr anti-DNA immunoglobulin transgenic mice revealed dramatic accumulation of Tg+ cells in the inner PALS only in Ipr mice. These data suggest that in the absence of Fas, autoreactive B cells accumulate in T cell-rich zones, and this anatomic feature may contribute to autoantibody production.