Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice

Goodnow, Christopher C.; Crosbie, Jack; Adelstein, Stephen; Lavoie, Thomas B.; Smith‐Gill, Sandra J.; Brink, Robert; Pritchard-Briscoe, H; Wotherspoon, John S.; Loblay, Robert H.; Raphael, Kathy; Trent, Ronald J.; Basten, Antony

doi:10.1038/334676a0

Cited by 1,465 publications

(1,471 citation statements)

References 45 publications

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“…In this well-characterized model of B-cell tolerance, anti-HEL IgTg B cells develop in the presence of soluble self-antigen and are rendered functionally anergic [11]. As shown in Fig.…”

Section: Congenic B6nzbc13 Mice Have An Intrinsic B-cell Defectmentioning

confidence: 99%

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

et al. 2010

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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...

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“…In this well-characterized model of B-cell tolerance, anti-HEL IgTg B cells develop in the presence of soluble self-antigen and are rendered functionally anergic [11]. As shown in Fig.…”

Section: Congenic B6nzbc13 Mice Have An Intrinsic B-cell Defectmentioning

confidence: 99%

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

et al. 2010

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“…with 4 Â 10 6 splenocytes or 2 Â 10 6 B lymphocytes from IgHEL-Tg mice admixed with 2 Â 10 8 HEL-SRBC conjugates. HEL was covalently conjugated to SRBC with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (Sigma-Aldrich) as described previously [31]. Sera or tissues from recipients were harvested for analysis 1-21 days post-transfer.…”

Section: Adoptive Transfersmentioning

confidence: 99%

“…NOD and B6 mice carrying IgHEL or sHEL Tg, as well as B6.insHEL and NOD.H2 k .insHEL mice, have been described previously [3,8,12,13,31]. NOD.H2 k .insHEL mice were backcrossed to NOD/Lt mice to replace the H2 k congenic region with the H2 g7 haplotype.…”

Section: Micementioning

confidence: 99%

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Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

et al. 2010

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Self-reactive B lymphocytes contribute to type 1 diabetes pathogenesis as APC and auto-Ab producers in NOD mice and humans. To shed light on the mechanisms responsible for the breakdown in B-lymphocyte self-tolerance to b-cell Ag, we utilised a model whereby hen-egg lysozyme (HEL)-specific Ig Tg (IgHEL-Tg)-Tg B lymphocytes were allowed to develop in or were transferred into mice expressing the HEL Tg under an insulin promoter (insHEL-Tg). IgHEL-Tg B lymphocytes enhanced type 1 diabetes susceptibility of insHEL-Tg NOD mice. A comparison of the tolerogenic activity of IgHEL-Tg B lymphocytes with NOD and non-autoimmune-prone C57BL/6 genetic backgrounds showed that both were rendered anergic in the presence of insHEL when competing with polyclonal B lymphocytes. Nevertheless, NOD IgHEL-Tg B lymphocytes transferred into insHEL-Tg mice were more readily susceptible to rescue from anergy than their C57BL/6 counterparts, following provision of in vivo T-cell help. The different tolerogenic outcomes were an intrinsic property of B lymphocytes rather than being related to the quality of T-cell help, with the defective response being at least partially controlled by genes mapping to insulin-dependent diabetes (Idd) susceptibility loci on Chromosome 1 (Idd5) and 4 (Idd9/11).Key words: Anergy . B lymphocytes . Self-tolerance . Transgenic mice . Type 1 diabetes Supporting Information available online Introduction B lymphocytes make important contributions to pancreatic b-cell pathogenesis in the NOD mouse model of type 1 diabetes (T1D): first, through secretion of auto-Ab which enhance capture of auto-Ag by DC and NK cells; second, and more importantly, through their action as efficient APC capable of activating and expanding b-cell-reactive CD4 1 T cells [1]. Both pathogenic functions depend on the production of self-reactive Ig by B lymphocytes [2,3], indicating that defective B-lymphocyte self-tolerance is a mechanism that contributes to susceptibility to this disease. Several lines of evidence also point to a pathogenic role for B lymphocytes in human T1D. For example, a recently completed clinical trial has demonstrated that treatment of newly diagnosed T1D patients with the B lymphocyte depleting Ab Rituximab resulted in markedly improved preservation of b-cell function [4]. Furthermore, the fact that the presence and spectrum of b-cell-specific auto-Ab have predictive value in determining T1D susceptibility is consistent with the impairment of B-lymphocyte tolerance in patients developing disease [5]. Studies of models in which BCR Tg specific for natural or neo-self-Ag are expressed in the germ-line of non-autoimmune prone mouse strains have revealed a range of self-tolerance mechanisms in the B-lymphocyte compartment [6]. Which of these mechanisms operate in particular situations is determined by the avidity of the Tg BCR for its cognate self-Ag, i.e. a combination of Ag valency, concentration and receptor affinity [7]. Self-reactive B lymphocytes that encounter cognate Ag with high avidity modify their specificity b...

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“…LK35.2 transfectants expressing the HEL-specific BCR D1.3 and HyHEL-10 [3] were a kind gift from F. Batista. BCR expression on the transfected LK35.2 HyHEL-10 cells was compared to that seen on splenocytes from MD4 BCR-transgenic mice [31] (expressing the same BCR) using biotinylated IgHa allotypic specific monoclonal antibody RS3.1 [32] followed by streptavidin-FITC (Southern Biotech). Ten-thousand events were collected on a Becton Dickinson FACSCalibur and analyzed using FlowJo (Tree Star Inc.).…”

Section: Cell Culture and Facs Analysismentioning

confidence: 99%

Lowering the affinity between antigen and the B cell receptor can enhance antigen presentation

Brooks

Knight

2004

Eur J Immunol

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The B cell receptor (BCR) enables antigen-specific B cells to bind, internalize and target antigens for processing into small peptide fragments. These epitopes are then expressed on the plasma membrane in association with MHC class II molecules for recognition by CD4 + T cells. The affinity of the interaction between the BCR and antigen plays an important part in determining T cell epitope generation. In this report we provide evidence that the efficiency of antigen presentation by specific B cells does not need to be directly proportional to antigen/BCR affinity. We show that increased presentation can result from lowering the affinity of the antigen/BCR interaction. This finding suggests a novel mechanism by which B cells can recruit T cell help and obtain survival signals. Activation of these cells may have consequences for the generation of the B cell repertoire.

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Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice

Cited by 1,465 publications

References 45 publications

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

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

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

Lowering the affinity between antigen and the B cell receptor can enhance antigen presentation

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