Genes within the <i>Idd5</i> and <i>Idd9/11</i> Diabetes Susceptibility Loci Affect the Pathogenic Activity of B Cells in Nonobese Diabetic Mice

Silveira, Pablo A.; Chapman, Harold D.; Stolp, Jessica; Johnson, Emory R.; Cox, Selwyn L.; Hunter, Kara; Wicker, Linda S.; Serreze, David

doi:10.4049/jimmunol.177.10.7033

Cited by 26 publications

(40 citation statements)

References 53 publications

(72 reference statements)

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“…6B). Idd5 and Idd9/11 loci contribute to the T-cell-mediated breakdown of tolerance in NOD B lymphocytes A previous study from our laboratories indicated that introgression of Idd5 or Idd9/11 T1D-resistance loci into the NOD genetic background restored the anergic state of self-reactive B lymphocytes from the IgHEL Â sHEL Dbl-Tg model [9]. We therefore set out to confirm whether these particular Idd loci were involved in the T-cell-mediated breakdown of B-lymphocyte tolerance to the b-cell neo-self-Ag in NOD.insHEL recipients.…”

mentioning

confidence: 78%

“…NOD.H2 k .insHEL mice were backcrossed to NOD/Lt mice to replace the H2 k congenic region with the H2 g7 haplotype. NOD.IgHEL mice containing B10-derived Idd5 (R444 line) or the NOR-derived Idd9/11 congenic region have also been characterised [9] and were intercrossed to produce a Dbl congenic strain. All experiments were performed on female mice and were approved by the Garvan Institute/St.…”

Section: Micementioning

confidence: 99%

“…Second, the anergic state of NOD compared with B6 IgHEL-Tg B lymphocytes escaping deletion was more readily reversed following in vitro stimulation through BCR and CD40. The greater predisposition of NOD B lymphocytes to loss of self-tolerance was subsequently shown to be controlled by genes mapping to insulindependent diabetes (Idd) susceptibility loci on Chromosomes 1(Idd5) and 4 (Idd9/11), respectively [9].To determine whether such defects in tolerance were responsible for the production of diabetogenic B lymphocytes specific for b-cell proteins per se in NOD mice, Thomas and colleagues generated a BCR Tg model (termed 125-Tg) where the majority of B lymphocytes were rendered specific for insulin [10]. Surprisingly, 125-Tg B lymphocytes seemed to be effectively tolerised in mice on both NOD and B6 backgrounds, as demonstrated by their failure to secrete anti-insulin Ab or to respond to a range of potent stimuli.…”

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confidence: 99%

“…This experiment also demonstrated that differences in activation of anergic NOD B lymphocytes were not necessarily due to the presentation of distinct peptides by the unique H2-A g7 MHC class II molecule, since B lymphocytes from NOD and Dbl congenic mice express the same haplotype. Interestingly, both Idd5 and Idd9/11 resistance loci were required to maintain in vivo tolerance of NOD B lymphocytes to insHEL upon provision of T-cell help, whereas either resistance locus was sufficient to restore anergy in the IgHEL Â sHEL Dbl-Tg model when B lymphocytes were activated in vitro through BCR and CD40 [9]. The need for both genetic loci to maintain tolerance in the in vivo model may result from the more stringent demands faced by self-reactive B lymphocytes when competing with non-autoreactive cells for T-cell help, survival factors and niches within lymphoid microenvironments.…”

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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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confidence: 78%

Section: Micementioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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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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B‐cell anergy induces a Th17 shift in a novel B lymphocyte transgenic NOD mouse model, the 116C‐NOD mouse

et al. 2016

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Autoreactive B lymphocytes play a key role as APCs in diaebetogenesis. However, it remains unclear whether B-cell tolerance is compromised in NOD mice. Here, we describe a new B lymphocyte transgenic NOD mouse model, the 116C-NOD mouse, where the transgenes derive from an islet-infiltrating B lymphocyte of a (8.3-NODxNOR) F1 mouse. The 116C-NOD mouse produces clonal B lymphocytes with pancreatic islet beta cell specificity. The incidence of T1D in 116C-NOD mice is decreased in both genders when compared with NOD mice. Moreover, several immune selection mechanisms (including clonal deletion and anergy) acting on the development, phenotype, and function of autoreactive B lymphocytes during T1D development have been identified in the 116C-NOD mouse. Surprisingly, a more accurate analysis revealed that, despite their anergic phenotype, 116C B cells express some costimulatory molecules after activation, and induce a T-cell shift toward a Th17 phenotype. Furthermore, this shift on T lymphocytes seems to occur not only when both T and B cells contact, but also when helper T (Th) lineage is established. The 116C-NOD mouse model could be useful to elucidate the mechanisms involved in the generation of Th-cell lineages.Keywords: B lymphocyte r Immune tolerance r NOD mouse r Th17 r Transgenic r Type 1 diabetes Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Joan Verdaguer e-mail: joan.verdaguer@mex.udl.cat * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 594Jorge Carrascal et al. Eur. J. Immunol. 2016. 46: 593-608 Introduction Type 1 diabetes (T1D) is an autoimmune disease characterized by selective destruction of pancreatic beta cells [1]. In both humans and mice, the disease begins with insulitis, which consists of a mononuclear infiltrate that progressively destroys islet beta cells and eventually results in diabetes onset. Although T lymphocytes are the major effectors of beta cell damage, over the last decades it has become clear that B lymphocytes also play an important role in the pathogenesis of T1D. In this regard, NOD.IgM null or wild-type NOD mice depleted of this cell population do not develop T1D and/or show a delay in the age of disease onset [2][3][4]. Although the mechanisms by which B lymphocytes contribute to diabetes remain poorly understood, it has been proposed that they act as APCs, capturing beta cell autoantigens via cell surface autoreactive immunoglobulins and presenting them to autoreactive T lymphocytes in regional lymph nodes [5][6][7]. Moreover, B lymphocytes migrate to pancreatic islets during the development of T1D [8], thus suggesting a key function in the progression of the disease in situ.To elucidate the antigen specificity of islet-infiltrating B lymphocytes during disease progression, hybridoma cell lines of infiltrating B lymphocytes from NOD mice and other related strains developing insulitis were generated [9]. Only a small per...

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Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice

et al. 2017

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Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β cells. Therapies need to incorporate strategies to overcome the genetic defects that impair induction or maintenance of peripheral T-cell tolerance and contribute to disease development. We tested whether the enforced expression of an islet autoantigen in antigen-presenting cells (APC) counteracted peripheral T-cell tolerance defects in autoimmune-prone NOD mice. We observed that insulin-specific CD8 T cells transferred to mice in which proinsulin was transgenically expressed in APCs underwent several rounds of division and the majority were deleted. Residual insulin-specific CD8 T cells were rendered unresponsive and this was associated with TCR downregulation, loss of tetramer binding and expression of a range of co-inhibitory molecules. Notably, accumulation and effector differentiation of insulin-specific CD8 T cells in pancreatic lymph nodes was prominent in non-transgenic recipients but blocked by transgenic proinsulin expression. This shift from T-cell priming to T-cell tolerance exemplifies the tolerogenic capacity of autoantigen expression by APC and the capacity to overcome genetic tolerance defects.

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Genes within the Idd5 and Idd9/11 Diabetes Susceptibility Loci Affect the Pathogenic Activity of B Cells in Nonobese Diabetic Mice

Cited by 26 publications

References 53 publications

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

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

B‐cell anergy induces a Th17 shift in a novel B lymphocyte transgenic NOD mouse model, the 116C‐NOD mouse

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice

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Genes within the Idd5 and Idd9/11 Diabetes Susceptibility Loci Affect the Pathogenic Activity of B Cells in Nonobese Diabetic Mice

Cited by 26 publications

References 53 publications

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

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

B‐cell anergy induces a Th17 shift in a novel B lymphocyte transgenic NOD mouse model, the 116C‐NOD mouse

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8+ T‐cell priming to tolerance in autoimmune‐prone NOD mice

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Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice