High Rate of Antibody Secretion Is not Integral to Plasma Cell Differentiation as Revealed by XBP-1 Deficiency

Taubenheim, Nadine; Tarlinton, David M.; Crawford, Simon; Corcoran, Lynn M.; Hodgkin, Philip D.; Nutt, Stephen L.

doi:10.4049/jimmunol.1201042

Cited by 117 publications

(130 citation statements)

References 39 publications

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“…In accordance with such a double hit model, IgM titers upon immunization were negligible in mice with B cells lacking XBP-1, as had been shown before [34], but ameliorated when the endonuclease domain of IRE1α, rather than XBP-1, was floxed out.…”

Section: See Accompanying Article By Benhamron Et Alsupporting

confidence: 50%

A RIDDle solved: Why an intact IRE1α/XBP‐1 signaling relay is key for humoral immune responses

2014

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To cope with changing environmental conditions, eukaryotic cells employ various stress pathways designed to maintain or restore homeostasis in a given compartment or in response to a particular need. Stress pathways may also be invoked during development, when cells adapt their machineries and reset their homeostatic balances to befit the novel physiological role(s) they are bound to assume. A striking example of this is the differentiation of B cells into antibody-secreting plasma cells. When suitably activated, B cells abandon their quiescent state and undergo an extensive metamorphosis to become -in a matter of few days -one of the most prolific secretory cells [1]. A profound "makeover" is required, that most notably results in a massively expanded endoplasmic reticulum (ER), the organelle where antibodies fold, assemble and are subjected to stringent quality control before proceeding along the exocytic pathway for eventual secretion [1,2].That a signaling pathway is responsible for adjusting the folding capacity of the ER according to necessity was first hypothesized in the late 1980s/early 1990s [3,4], and then proven to indeed exist through genetic screens in yeast [5,6]. Using drugs that perturb productive protein folding specifically in the ER Correspondence: Dr. Eelco van Anken e-mail: eelco.vananken@hsr.it by targeting N-linked glycosylation or disulfide bond formation, the key components of the so-called unfolded protein response (UPR) were identified. Biochemical analyses demonstrated that Ire1 is a transmembrane protein with a stress-sensing domain in the ER and a bifunctional kinase/endonuclease effector domain in the cytosol [7,8]. Intriguingly, the endonuclease domain of Ire1 is dedicated to the excision of an intron from the HAC1 mRNA [7,8]. Upon spliceosome-independent intron removal and religation of the severed exons by Rlg1 [9], the processed HAC1 mRNA encodes a transcription factor that drives the expression of a vast repertoire of chaperones, folding assistants, and other factors needed for the expansion of a functional ER [10].A major breakthrough came when XBP-1 was identified as the mammalian equivalent of yeast HAC1 mRNA, likewise undergoing IRE1α-mediated nonconventional splicing [11][12][13]. Thus, the Ire1/IRE1α-HAC1/XBP-1 axis of the UPR is conserved from yeast to human. These findings, combined with the seminal discovery that XBP-1 is essential for plasma cell differentiation [14], revealed that the IRE1α/XBP-1 relay is central to the development of cells that commit to a professional secretory phenotype [14,15]. Moreover, B-cell activation entails the induction of the transcription factor Blimp-1 [16], which represses BSAP/Pax5 [17,18]. Since BSAP/Pax5 represses XBP-1 [19], the net result is that XBP-1 transcription is enhanced in activated B cells [20]. Altogether,www.eji-journal.eu 642Eelco van Anken et al. Eur. J. Immunol. 2014. 44: 641-645 connecting the dots between the requirements for high antibody production and UPR signaling highlights how findings from fields as di...

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Section: See Accompanying Article By Benhamron Et Alsupporting

confidence: 50%

A RIDDle solved: Why an intact IRE1α/XBP‐1 signaling relay is key for humoral immune responses

2014

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“…Of these transcription factor genes, only Xbp1 and Prdm1 (Blimp1) are directly activated by E2A and E2-2. As XBP1 is required for antibody secretion, but not for plasmablast differentiation (Taubenheim et al, 2012), its loss cannot account for the E-protein-dependent block of plasma cell development. In contrast, loss of Blimp1 stringently arrests plasmablast differentiation at an early stage (Shapiro-Shelef et al, 2003;Kallies et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Wöhner¹,

Tagoh²,

Bilić³

et al. 2016

J. Cell Biol.

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1201B cell immunity provides acute and long-term protection of the host against infections through the generation and secretion of high-affinity antibodies that recognize a shear unlimited number of pathogens. This enormous adaptive potential of B cells is brought about by V(D)J recombination of the immunoglobulin heavy chain (Igh) and light chain (Igk and Igl) genes in early B cell development, and by subsequent affinity maturation of the Ig heavy chain in late B cell differentiation (Victora and Nussenzweig, 2012). Somatic hypermutation alters the antigen-binding V H sequences of the Ig heavy-chain, whereas class switch recombination (CSR) exchanges the C H exons to generate Ig isotypes with distinct effector functions (Chaudhuri and Alt, 2004). Whereas the activation-induced deaminase (AID) is an essential regulator of both processes (Muramatsu et al., 2000), somatic hypermutation only takes place in germinal centers (GCs), which are formed upon antigen exposure by the interplay of T follicular helper (Tfh) cells and follicular (FO) B cells in secondary lymphoid organs (Victora and Nussenzweig, 2012). Affinity-based selection in this specialized compartment leads to clonal expansion of B cells expressing high-affinity B cell receptors, which subsequently differentiate to proliferating, antibody-secreting plasmablasts (Victora and Nussenzweig, 2012). Upon migration to specialized bone marrow niches, plasmablasts differentiate into long-lived quiescent plasma cells secreting high amounts of antibodies (Nutt et al., 2015). While many transcription factors are involved in coordinating these B cell responses, we have here studied the role of E-proteins in the regulation of these processes.Basic helix-loop-helix (bHLH) transcription factors can be subdivided into different classes based on biochemical and functional properties (Murre, 2005). Class I bHLH proteins, also known as E-proteins, consist of the three members, E2A (Tcf3), E2-2 (Tcf4), and HEB (Tcf12; Murre, 2005), which bind the E-box (CAN NTG) motif with similar sequence specificity (Fig. S1 A). E-proteins are broadly expressed and heterodimerize with class II bHLH proteins in nonlymphoid cell types. Within the lymphoid system, E-proteins function as homodimers or heterodimers with a different E-protein (Bain et al., 1993;Shen and Kadesch, 1995). E-proteins are thought to mainly function as transcriptional activators, as they interact with the co-activators p300 and CBP (Bradney et al., 2003;Bayly et al., 2004), as well as the promoter recognition factor TFI ID (Chen et al., 2013). The activity of E-proteins is controlled by the inhibitor of DNA binding proteins, which are HLH proteins lacking the basic DNA-binding domain, and are thus capable of sequestering E-proteins into DNA-bindingincompetent heterodimers (Kee, 2009).E-proteins control different aspects of B cell development (Murre, 2005). E2A is required for the commitment of lymphoid progenitors to the B cell lineage (Bain et al.,

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“…34 A key transcription factor is XBP1 (X-box-binding protein-1), and previous studies have characterized in detail that mice with B cell-specific Xbp1 genetic deletion display a specific defect in antibody production. [35][36][37] Using this model under the atherosclerotic Ldlr −/− background, we demonstrate that Xbp1-dependent plasma cell responses have a prominent antiatherosclerotic influence.…”

Section: Novelty and Significancementioning

confidence: 99%

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

Sage

Nus

Chakraborty

et al. 2017

Circulation Research

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Rationale: Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies, and their importance in both humans and mouse models is still unclear.Objective: To specifically target antibody production by plasma cells and determine the impact on atherosclerotic plaque development in mice with and without CD4+ T cells. Methods and Results:We combined a model of specific antibody deficiency, B cell-specific CD79a-Cre x XBP1 (X-box binding protein-1) floxed mice (XBP1-conditional knockout), with antibody-mediated depletion of CD4+ T cells. Ldlr knockout mice transplanted with XBP1-conditional knockout (or wild-type control littermate) bone marrow were fed western diet for 8 weeks with or without anti-CD4 depletion. All groups had similar levels of serum cholesterol. In Ldlr/ XBP1-conditional knockout mice, serum levels of IgG, IgE, and IgM were significantly attenuated, and local antibody deposition in atherosclerotic plaque was absent. Antibody deficiency significantly accelerated atherosclerosis at both the aortic root and aortic arch. T cell and monocyte responses were not modulated, but necrotic core size was greater, even when adjusting for plaque size, and collagen deposition significantly lower. Anti-CD4 depletion in Ldlr/wild-type mice led to a decrease of serum IgG1 and IgG2c but not IgG3, as well as decreased IgM, associated with increased atherosclerosis and necrotic cores, and a decrease in plaque collagen. The combination of antibody deficiency and anti-CD4 depletion has no additive effects on aortic root atherosclerosis. Conclusions:

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High Rate of Antibody Secretion Is not Integral to Plasma Cell Differentiation as Revealed by XBP-1 Deficiency

Cited by 117 publications

References 39 publications

A RIDDle solved: Why an intact IRE1α/XBP‐1 signaling relay is key for humoral immune responses

A RIDDle solved: Why an intact IRE1α/XBP‐1 signaling relay is key for humoral immune responses

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

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