Up-regulation of transcription factor Blimp1 in systemic lupus erythematosus

Luo, Jie; Niu, Xiaochang; Liu, Hongchun; Zhang, Mingxu; Chen, Ming; Deng, Shaoli

doi:10.1016/j.molimm.2013.05.241

Cited by 28 publications

(21 citation statements)

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“…Epigenetic changes associated with autoimmune responses have been investigated in T cells, but only marginally in B cells (68). We and others have previously shown that highly upregulated AID and Blimp-1 expression is an important feature of lupus patients and lupus-prone mice, including MRL/ Fas lpr/lpr mice (14, 69). In these mice, dysregulation of AID and Blimp-1 causes aberrant rates of CSR and SHM, leading to increased loads of somatic point-mutations and deletions/insertions in the IgH locus, as well as heightened Ig secretion rates that result in abundant production of pathogenic autoantibodies.…”

Section: Discussionmentioning

confidence: 91%

“…In these mice, dysregulation of AID and Blimp-1 causes aberrant rates of CSR and SHM, leading to increased loads of somatic point-mutations and deletions/insertions in the IgH locus, as well as heightened Ig secretion rates that result in abundant production of pathogenic autoantibodies. Accordingly, increased AID and Blimp-1 expression in lupus patients is associated with high levels of mutated IgG autoantibodies, which heighten disease activity (14, 69). Conversely, AID deficiency in MRL/ Fas lpr/lpr Aicda –/– protected mice against disease (64, 70); and, decreased AID expression in MRL/ Fas lpr/lpr HoxC4 +/– and MRL/ Fas lpr/lpr Aicda +/– mice, which display 30-60% of the AID level of MRL/ Fas lpr/lpr Aicda +/+ mice, reduced autoantibody titers and delayed disease (14, 71).…”

Section: Discussionmentioning

confidence: 99%

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Histone Deacetylase Inhibitors Upregulate B Cell microRNAs That Silence AID and Blimp-1 Expression for Epigenetic Modulation of Antibody and Autoantibody Responses

White

Pone

Lam

et al. 2014

The Journal of Immunology

108

140

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Class-switch DNA recombination (CSR) and somatic hypermutation (SHM), which require AID, and plasma cell differentiation, which requires Blimp-1, are critical for the generation of class-switched and hypermutated (mature) antibody and autoantibody responses. We showed here that the histone deacetylase (HDAC) inhibitors (HDI) valproic acid (VPA) and butyrate upregulated miR-155, miR-181b and miR-361, which silenced AICDA/Aicda (AID) mRNA, and miR-23b, miR-30a and miR-125b, which silenced PRDM1/Prdm1 (Blimp-1) mRNA, in human and mouse B cells. This led to downregulation of AID, Blimp-1 and Xbp-1 expression, thereby dampening CSR, SHM and plasma cell differentiation without altering B cell viability or proliferation. The selectivity of HDI-mediated silencing of AICDA/Aicda and PRDM1/Prdm1 was emphasized by unchanged expression of HoxC4 and Irf4 (important inducers/modulators of AICDA/Aicda), Rev1 and Ung (central elements for CSR/SHM), and Bcl6, Bach2 or Pax5 (repressors of PRDM1/Prdm1 expression), as well as unchanged expression of miR-19a/b, miR-20a and miR-25, which are not known to regulate AICDA/Aicda or PRDM1/Prdm1. Through these B cell intrinsic epigenetic mechanisms, VPA blunted class-switched and hypermutated T-dependent and T-independent antibody responses in C57BL/6 mice. In addition, it decreased class-switched and hypermutated autoantibodies, ameliorated disease and extended survival in lupus MRL/Faslpr/lpr mice. Our findings outline epigenetic mechanisms that modulate expression of an enzyme (AID) and transcription factors (Blimp-1 and Xbp-1) that critical to the B cell differentiation processes that underpin antibody and autoantibody responses. They also provide therapeutics proof-of-principle in autoantibody-mediated autoimmunity.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Upregulate B Cell microRNAs That Silence AID and Blimp-1 Expression for Epigenetic Modulation of Antibody and Autoantibody Responses

White

Pone

Lam

et al. 2014

The Journal of Immunology

108

140

View full text Add to dashboard Cite

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“…[34] Perhaps not surprisingly, aberrancies in these key regulators are often found in lymphoma and contribute to oncogenesis; more recent evidence also suggests that dysregulation of certain pro-plasmacytic differentiation factors corresponds with increases in autoantibody production and disease activity in AID such as SLE. [35]…”

Section: Pathogenesismentioning

confidence: 99%

B cells gone rogue: the intersection of diffuse large B cell lymphoma and autoimmune disease

Koff

Flowers

2016

Expert Review of Hematology

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Introduction Diffuse large B cell lymphoma (DLBCL) is characterized by genetic, genomic and clinical heterogeneity. Autoimmune diseases (AIDs) have recently been shown to represent significant risk factors for development of DLBCL. Areas covered Studies that examined the relationships between AIDs and lymphoma in terms of pathogenesis, genetic lesions, and treatment were identified in the MEDLINE database using combinations of medical subject heading (MeSH) terms. Co-authors independently performed study selection for inclusion based on appropriateness of the study question and nature of the study design and sample size. Expert review Identification of AID as a substantial risk factor for DLBCL raises new questions regarding how autoimmunity influences lymphomagenesis and disease behavior. It will be important to identify whether DLBCL cases arising in the setting of AID harbor inferior prognoses, and, if so, whether they also exhibit certain molecular abnormalities that may be targeted to overcome such a gap in clinical outcomes.

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“…The MRL-fas lpr /J mice from this center were confirmed suffering from SLE in previous researches (Guo et al, 2012;Luo et al, 2013). All mice were sacrificed after a five-day adjustment period, the blood was collected for serum preparation, and the kidneys were kept in formalin for pathological examination for further confirmation of this model.…”

Section: Establishment Of Murine Sle Modelsmentioning

confidence: 99%

Hep-2 cell based indirect immunofluorescence assay for antinuclear antibodies as a potential diagnosis of drug-induced autoimmunity in nonclinical toxicity testing

Hong

Zhi

et al. 2015

Regulatory Toxicology and Pharmacology

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Up-regulation of transcription factor Blimp1 in systemic lupus erythematosus

Cited by 28 publications

References 28 publications

Histone Deacetylase Inhibitors Upregulate B Cell microRNAs That Silence AID and Blimp-1 Expression for Epigenetic Modulation of Antibody and Autoantibody Responses

Histone Deacetylase Inhibitors Upregulate B Cell microRNAs That Silence AID and Blimp-1 Expression for Epigenetic Modulation of Antibody and Autoantibody Responses

B cells gone rogue: the intersection of diffuse large B cell lymphoma and autoimmune disease

Hep-2 cell based indirect immunofluorescence assay for antinuclear antibodies as a potential diagnosis of drug-induced autoimmunity in nonclinical toxicity testing

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