Anergy and not Clonal Ignorance Determines the Fate of B Cells that Recognize a Physiological Autoantigen

Rojas, Mauricio; Hulbert, Chrys; Thomas, James W.

doi:10.4049/jimmunol.166.5.3194

Cited by 63 publications

(126 citation statements)

References 42 publications

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“…2), as had been demonstrated previously when the expression of HEL was confined to another tissue specific site, the thyroid [23]. Ignorance in our model could not be explained simply in terms of Ag concentration since soluble cleaved HEL was present in the circulation at similar levels to insulin, which normally confers tolerance [24]. Moreover, insufficient affinity for self-Ag was an equally unlikely explanation given that the BCR on IgHEL-Tg B lymphocytes has an exceptionally high affinity for HEL (2 Â 10 10 M À1 , [25]).…”

supporting

confidence: 72%

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: 72%

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 cells in 125Tg mice show no signs of allelic inclusion (25) and maintain high levels of allelic exclusion for long periods of time (Ͼ30 wk); Ն 95% of B220 ϩ lymphocytes express only IgM a as revealed by staining with anti-IgM a vs anti-IgM b (27,28). Nontransgenic (non-Tg) C57BL/6 mice (Taconic Farms) were used as controls.…”

Section: Micementioning

confidence: 99%

“…Anti-insulin 125Tg B cells mature normally but are maintained in an anergic state by autologous insulin occupying their BCR (25,27). To examine the BCR-derived responses of B lymphocytes that have been rendered tolerant by exposure to physiologic concentrations of insulin in vivo, protein p-Tyr was examined following stimulation with 10 g/ml anti-IgM.…”

Section: Protein P-tyr Is Highly Active In Tolerant Anti-insulin B Cementioning

confidence: 99%

“…The 125Tg mice used in this study harbor conventional anti-insulin Ig transgenes (Ig only) derived from mAb 125 on a C57BL/6 background (backcross Ͼ27) and were generated and maintained as described previously (27,28). B cells in 125Tg mice show no signs of allelic inclusion (25) and maintain high levels of allelic exclusion for long periods of time (Ͼ30 wk); Ն 95% of B220 ϩ lymphocytes express only IgM a as revealed by staining with anti-IgM a vs anti-IgM b (27,28).…”

Section: Micementioning

confidence: 99%

“…Purified B cells were suspended in complete medium as described previously (25,27) and stimulated (where specified) with 10 g/ml F(abЈ) 2 goat anti-mouse -chain (Jackson ImmunoResearch Laboratories) or 1 M ionomycin (Sigma-Aldrich) for the indicated times. Total cell lysates were prepared in lysis buffer containing 50 mM HEPES (pH 7.5) (Invitrogen Life Technologies), 5% glycerol (Invitrogen Life Technologies), 1% Triton X-100 (Sigma-Aldrich), 1 mM sodium orthovanadate (Sigma-Aldrich), 100 mM sodium chloride (Sigma-Aldrich), and protease inhibitors (Roche Applied Science).…”

Section: Immunoblottingmentioning

confidence: 99%

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Impaired Intracellular Calcium Mobilization and NFATc1 Availability in Tolerant Anti-Insulin B Cells

Acevedo-Suárez

Kilkenny

Reich³

et al. 2006

The Journal of Immunology

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B lymphocytes that recognize soluble self-Ags are routinely found in normal individuals in a functionally inactive or anergic state. Current models indicate that this tolerant state is maintained by interactions with self-Ags that uncouple the BCR from downstream signaling pathways and increase levels of free calcium. Contrary to this expectation, B cells that harbor anti-insulin Ig transgenes (125Tg) are maintained in a tolerant state even though free calcium levels remain normal and tyrosine kinase substrate phosphorylation is preserved following BCR stimulation. Under basal conditions, intracellular levels of inositol 1,4,5-trisphosphate are increased and NFATc1 levels are reduced in 125Tg B cells. The 125Tg B cells are markedly impaired in their ability to mobilize calcium upon stimulation with ionomycin, and BCR-induced calcium mobilization from internal stores is decreased. In contrast, poisoning intracellular calcium pumps with thapsigargin increases calcium mobilization in 125Tg B cells. Changes in calcium signaling are accompanied by a failure of 125Tg B cells to translocate NFATc1 into the nucleus following stimulation with either anti-IgM or ionomycin. Thus, disassociation of BCR from multiple signaling pathways is not essential for maintaining tolerance in anti-insulin 125Tg B cells. Rather, BCRs that are occupied by autologous insulin deliver signals that induce changes in intracellular calcium mobilization and maintain tolerance by preventing activation of key transcription factors such as NFAT.

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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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Anergy and not Clonal Ignorance Determines the Fate of B Cells that Recognize a Physiological Autoantigen

Cited by 63 publications

References 42 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

Impaired Intracellular Calcium Mobilization and NFATc1 Availability in Tolerant Anti-Insulin B Cells

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

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