The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus

Kim, Chan Johng; Lee, Choong-Gu; Jung, Ju‐Yang; Ghosh, Ambarnil; Hasan, Syed Nurul; Hwang, Sung Min; Kang, Hye-Ji; Lee, Changhon; Kim, Gi-Cheon; Rudra, Dipayan; Suh, Chang‐Hee; Im, Sungbin

doi:10.1016/j.immuni.2018.10.012

Cited by 95 publications

(96 citation statements)

References 56 publications

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“…Studies on influenza vaccines showed that an increase of activated Tfh1 cells in the blood correlated with the emergence of CD27 + CD38 + PBs in the blood as well as a precursor of ASCs sharing properties with CD11c + DN B cells (though CD27 + ) , further supporting the potential role of Tfh1 cells in the generation of ASCs and CD11c + DN B cells . Intriguingly, a recent study showed that exaggerated activity of Tfh2 cells co‐expressing IL‐21 and IL‐4 is involved in SLE pathogenesis . As IL‐4 potently inhibits the generation of CD11c + DN B cells, it will be interesting to examine whether SLE patients with hyper Tfh2 activity display diminished CD11c + DN B cells than patients with hyper Tfh1 activity.…”

Section: Introductionmentioning

confidence: 90%

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

Ueno

2019

Eur J Immunol

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Generation of autoantibodies is a hallmark of systemic lupus erythematosus (SLE). As demonstrated in a number of lupus mouse models, recent evidence suggests that both GC and extrafollicular pathways contribute to the generation of autoantibodies also in human SLE, and that CD11c+ IgD−CD27−(double negative:DN) B cells play a central role in the latter pathway. In this mini‐review, the author will first briefly summarize the features of CD11c+ DN B cells in human SLE, and discuss how the IL‐12‐STAT4 axis might contribute to the generation of autoantibodies in SLE. In addition, various types of CD4+ helper T cell subsets promoting the generation of autoantibodies in SLE will be described, and finally it will be discussed how these recent discoveries contribute to understanding of SLE pathogenesis and treatment of SLE patients.

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Section: Introductionmentioning

confidence: 90%

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

Ueno

2019

Eur J Immunol

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“…The increases in Tfh2 cells drive B cell activation with development of germinal centers and increased isotype switching, ASC generation, and secretion of autoantibodies. In the same study, a B cell-specific knockout of Ets1 using CD19-Cre was also reported, although not extensively characterized (20). In fact, the only phenotype reported for the B cell deletion of Ets1 was increased serum IgM (20).…”

Section: Discussionmentioning

confidence: 95%

“…Ets1 is expressed at high levels in both B and T lymphocytes and at lower levels in other cell types. Mice with a conventional deletion of the Ets1 gene, where Ets1 is absent in all cell types, develop an autoimmune syndrome similar to lupus (4,8,20), with increased activation of both B and T cells. A recent study has shown that deletion of Ets1 specifically in T cells results in severe autoimmune symptoms that mimic complete deletion of the gene (20).…”

Section: Discussionmentioning

confidence: 99%

“…Transfer of purified Ets1 2/2 B cells into wild-type hosts results in downregulation of several activation markers including CD23, CD80, and CD86 (4), indicating that part of the B cell phenotype in Ets1 2/2 mice is B cell extrinsic. T cells from Ets1 2/2 mice have severe aberrations, including increased differentiation to an effector/memory phenotype and altered differentiation of Th subsets (8)(9)(10)(20)(21)(22). Freshly isolated CD4 + T cells from Ets1 2/2 mice express high levels of mRNA for IL-4, IL-5, IL-10, and IL-13 but reduced levels of mRNA for IFN-g (8).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, impaired Treg function was suggested to be the cause of several B cell defects resulting from the absence of Ets1. However, a more recent study in which Ets1 was specifically deleted in the T cell population shows that the major T cell aberration underlying the autoimmune phenotype of Ets1 2/2 mice is excess T cell differentiation to T follicular helper cells that secrete IL-4 (T follicular helper type 2 [Tfh2] cells) (20). Together, the results described above indicate that abnormalities in the CD4 + T cell population in Ets1 knockout mice may drive the aberrations in the B cell compartment.…”

Section: Introductionmentioning

confidence: 99%

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Ets1 Controls the Development of B Cell Autoimmune Responses in a Cell-Intrinsic Manner

et al. 2019

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Ets1 is emerging as a key transcription factor that is required to prevent autoimmunity in mice and humans. Ets1 is expressed in both B and T cells, and mice lacking Ets1 are characterized by excess B and T cell activation, leading to enhanced formation of Ab-secreting cells and high titers of autoantibodies. In humans, genome-wide association studies have detected associations of single nucleotide polymorphisms in the human ETS1 gene with autoimmune diseases, including lupus. An increased fraction of CD4 + T cells from Ets1 2/2 mice have an activated effector-memory phenotype, and there are aberrations in differentiation that contribute to the autoimmune phenotype. In vitro studies of B cells suggest that Ets1 may have B cell-intrinsic effects as well. To confirm B cell-intrinsic roles for Ets1, we crossed CD19-Cre mice to mice with a floxed allele of Ets1. Mice with a B cell-specific deletion of Ets1 show increases in B cell activation, numbers of Ab-secreting cells, and levels of autoantibodies, despite the fact that T cells are normal. However, when compared with conventional Ets1 knockout mice, mice with B cell-specific loss of Ets1 have a significantly milder phenotype. These results demonstrate that Ets1 is required in B cells to prevent autoimmune responses but that loss of Ets1 activity in other cell types is required for maximal autoimmune phenotypes. ImmunoHorizons, 2019, 3: 331-340.

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Elevated Levels of Interferon‐α Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production

Ferri

Nassar

Manion

et al. 2023

Arthritis & Rheumatology

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ObjectiveElevated levels of serum interferon‐α (IFNα) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFNα levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFNα on B cells.MethodsTwo classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFNα to mimic the sustained elevations of IFNα seen in SLE. The role of B cell IFNα signaling, T cells, and Myd88 signaling was determined using B cell–specific IFNα receptor–knockout, CD4+ T cell–depleted, or Myd88‐knockout mice, respectively. Flow cytometry, enzyme‐linked immunosorbent assay, real‐time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFNα on the immunologic phenotype.ResultsElevation of serum IFNα disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFNα receptor. Many of the IFNα‐mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFNα acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells.ConclusionThe results provide evidence that elevated IFNα levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE.image

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The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus

Cited by 95 publications

References 56 publications

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

Ets1 Controls the Development of B Cell Autoimmune Responses in a Cell-Intrinsic Manner

Elevated Levels of Interferon‐α Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production

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