Forced miR-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells.

  title={Forced miR-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells.},
  author={Qiuye Guo and Jinjun Zhang and Jingyi Li and Liyun Zou and Jinyu Zhang and Z Xie and Xiao-lan Fu and Shan Jiang and Gang Chen and Qingzhu Jia and Fei Li and Ying Wan and Yuzhang Wu},
  volume={121 24},
By inhibiting target gene expression, microRNAs (miRNAs) play major roles in various physiological and pathological processes. miR-146a, a miRNA induced upon lipopolysaccharide (LPS) stimulation and virus infection, is also highly expressed in patients with immune disorders such as rheumatoid arthritis, Sjögren's syndrome, and psoriasis. Whether the high level of miR-146a contributes to any of these pathogenesis-related processes remains unknown. To elucidate the function of miR-146a in vivo… 

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  • M. Hušáková
  • Biology, Medicine
    Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia
  • 2016
Distinct miRs are differentially expressed in both SLE mice models and human patients and promote autoimmune features of immune processes, suggesting they are important molecules modulating susceptibility to SLE as well as its onset, clinical diversity and progression.

Regulation of T-independent B-cell responses by microRNA-146a

A novel role for miR-146a and TRAF6 in the extrafollicular B-cell responses, which have recently been tied to autoimmune disease pathogenesis are demonstrated.

Excessive expression of miR-27 impairs Treg-mediated immunological tolerance

The data show that miR-27 functions as a key regulator in Treg development and function and suggest that proper regulation of mi R-27 is pivotal to safeguarding Treg-mediated immunological tolerance.

miR-146a in Myasthenia Gravis Thymus Bridges Innate Immunity With Autoimmunity and Is Linked to Therapeutic Effects of Corticosteroids

The overall findings strongly suggest that defective miR-146a expression could contribute to persistent TLR activation, lack of inflammation resolution, and hyperplastic changes in MG thymuses, thus linking TLR-mediated innate immunity to B-cell-mediated autoimmunity.

MiR-146a negatively regulates TLR2-induced inflammatory responses in keratinocytes.

Together, these data identify miR-146a as a regulatory element in keratinocyte innate immunity, which prevents the production of inflammatory mediators under homeostatic conditions and serves as a potent negative feedback regulator after TLR2 stimulation.

Role of microRNA-146a in normal and malignant hematopoietic stem cell function

This review focuses on miR-146a, a negative regulator of immune cell activation by repressing two targets, TRAF6 and IRAK1, and its role in regulating normal and malignant hematopoiesis.

Multiple roles of microRNA-146a in immune responses and hepatocellular carcinoma

The present review focuses on the recent progress in analyzing the multiple roles of miR-146a in mediating the TLR4 pathway and adaptive immune response and the function ofmiR- 146a in the pathogenesis of HCC.

Stabilized β-Catenin Ameliorates ALPS-Like Symptoms of B6/lpr Mice

It is suggested that stabilized β-catenin ameliorated some ALPS-like symptoms of lpr/lpr mice by potentiating Fas-independent signal-mediated T cell apoptosis, which might uncover a potential novel therapeutic direction for ALPS.

MicroRNA-146a Overexpression Impairs the Positive Selection during T Cell Development

Findings further extend the understanding of the function of miR-146a in T cell biology and identify a novel regulatory mechanism underlying the positive selection during T cell development.



Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients

It is demonstrated that microRNA expression in rheumatoid arthritis peripheral blood mononuclear cells mimics that of synovial tissue/fibroblasts and suggested that normal miR-146a function is critical for the regulation of tumor necrosis factor-α production.

MicroRNAs in Sjögren's syndrome as a prototypic autoimmune disease.

Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis.

A novel family with ALPS is described in which three affected siblings carry two distinct missense mutations on both the Fas gene alleles and show lack of Fas-induced apoptosis, but only one developed severe autoimmune manifestations.

NF-κB dysregulation in microRNA-146a–deficient mice drives the development of myeloid malignancies

Genetic ablation of NF-κB p50 suppresses the myeloproliferation, showing that dysregulation of NF -κB is responsible for the myELoproliferative disease.

Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis

The findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR -146a in RA pathogenesis and provide potential novel therapeutic targets.

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes.

Experimental evidence is provided that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR -146a, suggesting a role of this miRNA in the modulation of adaptive immunity.

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 (LMP1) Induces the Expression of the Cellular MicroRNA miR-146a

It is shown that the EBV-encoded latent membrane protein 1 (LMP1) induces the expression of miR-146a via NF-κB, which is involved in sequence-specific cleavage, translational repression or deadenylation of specific target mRNAs resulting in post-transcriptional gene silencing.

Diazoxide potentiates mesenchymal stem cell survival via NF-kappaB-dependent miR-146a expression by targeting Fas.

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A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease.

The clinical and immunological features of this syndrome resemble the lymphoproliferative/autoimmune disease seen in lpr and gld mice, and could be augmented by co-stimulation with an antibody directed at the CD28 determinant.