B cells expressing the transcription factor T-bet drive lupus-like autoimmunity

Rubtsova, Kira; Rubtsov, Anatoly V.; Thurman, Joshua M.; Mennona, Johanna M.; Kappler, John W.; Marrack, Philippa

doi:10.1172/jci91250

Cited by 219 publications

(301 citation statements)

References 47 publications

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“…These cells secrete autoantibodies upon in vitro stimulation, pointing towards a role in autoimmune pathology [22,26]. B cell-specific conditional deletion of T-bet in a spontaneous murine model of SLE resulted in reduced kidney damage, mortality and lowered serum levels of anti-chromatin autoantibodies [39]. Interestingly, the authors report that the difference in serum autoantibody levels between conditional knockout mice, and their T-bet − sufficient littermates decreased over time, suggesting that T-bet may not be the only factor regulating development of autoimmune phenotype.…”

Section: Outcome Of T-bet Driven Signaling In B Cellsmentioning

confidence: 99%

Signals that drive T-bet expression in B cells

Myles

Gearhart

Cancro

2017

Cellular Immunology

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Transcription factors regulate various developmental and functional aspects of B cells. T-bet is a recently appreciated transcription factor associated with “Age-associated B cells” or ABCs, the development of autoimmunity, and viral infections. T-bet expression is favored by nucleic acid-containing antigens and immune complexes and is regulated by interplay between various cytokines, notably, the TFH cytokines IL-21, IL-4 and IFNγ. Adaptive signals by themselves cannot upregulate T-bet; however, they have a synergistic effect on induction of T-bet by innate receptors. The functional role of T-bet + B cells is unclear, although it is known that T-bet promotes class switching to IgG2a/c. It is likely T-bet serves dichotomous roles in B cells, promoting pathogenic autoreactive antibodies on one hand but mediating microbial immunity on the other, making it a target of interest in both therapeutic and prophylactic settings.

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Section: Outcome Of T-bet Driven Signaling In B Cellsmentioning

confidence: 99%

Signals that drive T-bet expression in B cells

Myles

Gearhart

Cancro

2017

Cellular Immunology

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“…As reviewed in this volume, T-bet + , CD11c + B cells that express unique phenotypic and functional characteristics, termed age-associated B cells (ABCs), appear in mice with age, autoimmunity and viral infections (67–69). T-bet expression in this context was shown to be driven by IFN-γ (70, 71).…”

Section: Introductionmentioning

confidence: 99%

“…T-bet expression in this context was shown to be driven by IFN-γ (70, 71). ABCs are generated through the interplay of IL-4, IL-21, and IFN-γ in concert with Toll-like receptor engagement (72), and have been shown to play a role in the pathogenesis of lupus-like autoimmunity (69) and anti-viral immunity (73, 74). Although mouse ABCs are similar to human aMBCs in that they upregulate T-bet and CD11c, and downregulate CD21, unlike aMBCs (26), murine ABCs proliferate in response to TLR agonists, produce IL-10 and IFN-γ and differentiate into ASCs—distinct functional profiles that call into question the relatedness of mouse ABCs and human aMBCs that are associated with chronic infections.…”

Section: Introductionmentioning

confidence: 99%

Atypical memory B cells in human chronic infectious diseases: An interim report

Portugal

Obeng-Adjei

Moir

et al. 2017

Cellular Immunology

161

177

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Immunological memory is a remarkable phenomenon in which survival of an initial infection by a pathogen leads to life-long protection from disease upon subsequent exposure to that same pathogen. For many infectious diseases, long-lived protective humoral immunity is induced after only a single infection in a process that depends on the generation of memory B cells (MBCs) and long-lived plasma cells. However, over the past decade it has become increasingly evident that many chronic human infectious diseases to which immunity is not readily established, including HIV-AIDS, malaria and TB, are associated with fundamental alterations in the composition and functionality of MBC compartments. A common feature of these diseases appears to be a large expansion of what have been termed exhausted B cells, tissue-like memory B cells or atypical memory B cells (aMBCs) that, for simplicity’s sake, we refer to here as aMBCs. It has been suggested that chronic immune activation and inflammation drive the expansion of aMBCs and that in some way aMBCs contribute to deficiencies in the acquisition of immunity in chronic infectious diseases. Although aMBCs are heterogeneous both within individuals and between diseases, they have several features in common including low expression of the cell surface markers that define classical MBCs in humans including CD21 and CD27 and high expression of genes not usually expressed by classical MBCs including T-bet, CD11c and a variety of inhibitory receptors, notably members of the FcRL family. Another distinguishing feature is their greatly diminished ability to be stimulated through their B cell receptors to proliferate, secrete cytokines or produce antibodies. In this review, we describe our current understanding of the phenotypic markers of aMBCs, their specificity in relation to the disease-causing pathogen, their functionality, the drivers of their expansion in chronic infections and their life span. We briefly summarize the features of aMBCs in healthy individuals and in autoimmune disease. We also comment on the possible relationship of human aMBCs and T-bet+, CD11c+ age/autoimmune-associated B cells, also a topic of this review volume.

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“…ixed cryoglobulinemia is one of several B-cell proliferative disorders that may result from chronic hepatitis C infection, and it is thought to be driven by expansion of HCV envelope-specific B cells that preferentially use immunoglobulin gene segments V H 1-69 and V k [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]3 and to evolve rheumatoid factor activity through somatic hypermutation.…”

mentioning

confidence: 99%

“…B-cell anergy, an adaptive response to chronic antigen exposure for autoreactive B cells, has been postulated to be a vulnerability exploited by pathogens to evade humoral sterilization and enhance permissiveness for chronic bloodborne infections. Recent data suggest that the T-box expressed in T cells (T-bet) transcription factor, critical for inducing sterilizing humoral immunity in acute infections, 6 may also regulate the exhausted state in both autoreactive 7 and antigeninduced anergic B cells. 8,9 No data to date specifically link the anergy properties observed in cryoglobulin-producing B cells and T-bet, but there are phenotypic similarities (CD11c 1 /CD21 low ) that suggest a possible relationship that should be explored; rapid upregulation of T-bet in convalescent CD21 low B cells upon reexposure to autologous HCV strains ex vivo has been observed, 8 suggesting a link between B-cell receptor ligation, T-bet, and the CD21 low exhaustion phenotype.…”

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confidence: 99%

Persistence of exhaustion in cured hep C

Kaplan

2017

Blood

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In this issue of Blood, Del Padre et al 1 evaluated the impact of eliminating chronic antigen exposure on B-cell exhaustion in the human therapeutic setting of directacting antiviral therapy for chronic hepatitis C virus infection (HCV) complicated by mixed cryoglobulinemia (MC). The phenotype of hepatitis C-related MC B cells has been previously demonstrated by this group and others 2 to include low-level CD21 expression (CD21 low ) and hypoproliferation in response to stimulation either through the B-cell receptor or Toll-like receptor 9, imperfectly termed "exhausted" or "anergic." At baseline, CD21 low B cells from HCVinfected patients expressed markers of chronic activation, with elevated and nearmaximal basal levels of phosphorylated extracellular signal-regulated kinase, and were also predisposed to apoptosis. During oral direct-acting antiviral therapy, the authors observed that by 4 weeks (at which point, most patients have no circulating HCV RNA), these basal abnormalities at least partially normalized. During longitudinal follow-up after patients were documented as cured, the overall frequency of CD21 low cells progressively declined from 50% to 30% of circulating B cells. However, the frequency of V H 1-69 1 B cells specific for HCVrelated MC generally remained stable, although some regained CD21 expression. Despite partial resolution of the exhaustion phenotype, surviving V H 1-69 1 B cells remained hypoproliferative upon Toll-like receptor 9 ligation, suggesting that the B-cell exhaustion phenotype is durably programmed into antigen-specific B cells during long-term extracellular antigen exposure. Mixed cryoglobulinemia is one of several B-cell proliferative disorders that may result from chronic hepatitis C infection, and it is thought to be driven by expansion of HCV envelope-specific B cells that preferentially use immunoglobulin gene segments V H 1-69 and V k [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]3 and to evolve rheumatoid factor activity through somatic hypermutation. 4Although MC is an infrequent complication of chronic hepatitis C infection, the technological ability to identify and isolate HCV-specific B cells via an anti-idiotype V H 1-69-specific antibody (G6) has made this condition an important model for studying humoral immune dysfunction during human chronic viral infection. Prior studies have identified that V H 1-69 1 B cells manifest genetic signatures of enhanced interferon-mediated responsiveness, apoptosis, and B-cell anergy; are phenotypically most commonly CD27

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B cells expressing the transcription factor T-bet drive lupus-like autoimmunity

Cited by 219 publications

References 47 publications

Signals that drive T-bet expression in B cells

Signals that drive T-bet expression in B cells

Atypical memory B cells in human chronic infectious diseases: An interim report

Persistence of exhaustion in cured hep C

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