An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

Abstract

Introgression of a New Zealand Black (NZB) chromosome 13 interval onto a C57BL/6 (B6) background (B6.NZBc13) is sufficient to produce many hallmarks of lupus, including hightitre anti-chromatin antibody production, abnormal B-and T-cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these abnormalities. By generating hematopoietic chimeras and BCR transgenic mice, we show that the congenic autoimmune phenotype can be transferred by BM cells and requires the presence of autoreactive B cells. Using the hen egg white lysozyme immunoglobulin transgenic mouse model, we demonstrate that B-cell anergy, deletion, and receptor editing are intact. Nevertheless, congenic B cells exhibit altered peripheral B-cell selection, as demonstrated by enhanced survival and activation of endogenous B cells with autoreactivity to chromatin and Sm/ribonucleoprotein. Given the autoantibody specificities to nuclear antigens, TLR signalling was assessed. B6.NZBc13 B cells were hyper-responsive to poly(I:C), a TLR3 ligand, demonstrating enhanced proliferation and survival as compared to B6 B cells. Our findings indicate the presence of an intrinsic B-cell defect on NZB chromosome 13 that results in hyper-responsiveness to a dsRNA analogue and implicates its potential supporting role in the generation of autoimmunity in B6.NZBc13 mice. Keywords: Autoimmunity . B cells . TLRs Supporting Information available online IntroductionSystemic lupus erythematosus is a chronic autoimmune disorder characterized by the production of antibodies directed against nuclear antigens (ANAs). Similar to human lupus, the New Zealand Black (NZB) mouse produces antibodies directed against nuclear antigens, develops Coomb's positive hemolytic anaemia, and exhibits a number of phenotypic and functional B-cell abnormalities (reviewed in [1]). Although glomerulonephritis is mild in these mice, severe nephritis develops when the NZB background is crossed onto a permissive MHC haplotype (H-2 bm12 ), indicating that this mouse possesses a full complement of non-MHC lupus susceptibility genes [2].Generation of congenic mice, by introgression of homozygous chromosomal intervals from the NZB mouse strain onto a normal mouse C57BL/6 (B6) background, has been a particularly useful technique for characterizing susceptibility loci and their role in disease genesis [3]. In our mapping study of (B6 Â NZB) F 2 mice, we identified a locus on NZB chromosome (c) 13 that was linked to increased B-cell activation and abnormal IgM production [4]. To further characterize this locus, we generated congenic mice with an NZB c13 interval (denoted B6.NZBc13). B6.NZBc13 mice spontaneously developed autoimmunity characterized by hightitre IgM and IgG anti-chromatin antibody production, increased 527T-cell activation, expansion of DCs, and the development of mild glomerulonephritis [5]. Moreover, as predicted from our mapping study, B6.NZBc13 mice closely recapitulated the abnormal polyclonal B-cell activation and B-cell subset distribution...

The transcription factor Bright plays a role in marginal zone B lymphocyte development and autoantibody production

“…Other studies also suggest that MZ B cells are enriched for autoreactive clones compared to FO B cells (Cyster et al , 1994;Martin and Kearney, 2000). Chromosome 13 transgenic mice show skewing of splenic B cell subpopulations similar to our BrTg mice and also produce autoantibodies (Loh et al , 2011). However, the BrTg mice did not show altered surface activation markers as was found in the congenic mice.…”

Activation of Autoreactive B Cells by Endogenous TLR7 and TLR3 RNA Ligands

“…The only model that has been closely examined for TLR3 is the MRL.lpr, where TLR3 deficiency did not ameliorate disease, but this model is dominated by DNA autoantibodies (52). On the other hand, B cells containing a genetic susceptibility locus from the New Zealand Black autoimmune prone strain are hyperresponsive to TLR3 ligands (53). A better understanding of the role played by TLR7 and TLR3 in murine models and in patients will be useful when paired with autoantibody profiles to identify which TLR pathways are most relevant as therapeutic targets.…”

Suppression of autoimmunity by CD5+ IL-10-producing B cells in lupus-prone mice

“…Although studies of congenic mouse strains with introgressed homozygous intervals derived from lupus-prone mouse strains have provided considerable insight into how susceptibility loci promote disease development, less is known regarding the mechanisms involved in inhibition of autoimmunity by suppressor loci. Our laboratory has previously shown that introgression of a New Zealand Black (NZB) homozygous chromosome (c) 4 interval (B6.NZBc4), spanning 32-150 Mb, onto a C57BL/6 (B6) congenic mouse strain with a homozygous NZB c1 interval (B6.NZBc1) significantly attenuated the fatal autoimmunity observed in this mouse strain (B6.NZBc1c4), 1,2 indicating the presence of a suppressor locus on NZB c4. 3 Examination of the immune system in B6.NZBc4 mice revealed expansion of two innate-like lymphocyte populations, invariant Natural Killer T (NKT) cells and CD5 + B cells, leading us to hypothesize that one or both of these populations inhibit autoimmunity in B6.NZBc1c4 bicongenic mice.…”