Microrna-346 Regulation of Follicular Helper T Cells Is Involved in the Pathogenesis of rheumatoid Arthritis Disease

Xinyi Tang¹, Jie Ma² and Shengjun Wang³, ¹Department of Laboratory Medicine, Jiangsu University Affi�liated People’s Hospital, Zhenjiang, China, ²Department of Laboratory Medicine, Jiangsu University Afﬁliated People’s Hospital, Zhenjiang, China, ³Department of Laboratory Medicine, Jiangsu University Affiliated People’s Hospital, Zhenjiang, China

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: MicroRNA, pathogenesis, T cells and rheumatoid arthritis

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose

Follicular helper T (Tfh) cells have been identified as a new subset of effector helper T cells that are essential in regulating the development of antigen-specific B-cell immunity. Tfh differentiation is regulated by specific transcription factor Bcl-6. Several studies have certified the vital role of Tfh cells in the pathogenesis of autoimmune diseases. MicroRNAs (miRNAs) could negatively regulate gene expression post-transcriptionally and participate in the development of autoimmunity. The purpose of this study is to investigate the function of miR-346 in enhancement of Tfh cells during the pathogenesis of RA.

Methods We detected the proportion of Tfh cells, concentration of IL-21, relative expression of Bcl-6 and IL-21 mRNA as well as miR-346 in RA patients and healthy donors. A Luciferase reporter assay was undertaken for directly proves that Bcl-6 is the functional target of miR-346.The level of Bcl-6 protein in Jurkat cells which were transfected with the miR-346 mimics was detected. Percentage of CD4⁺CXCR5⁺T cells in circulating CD4⁺Tcells from healthy donor transfected with miR-346 mimics was examined.

Results

A signiﬁcantly increased frequency of CD4⁺CXCR5⁺ and CD4⁺CXCR5⁺ICOS^high circulating Tfh cells was detected in RA patients, compared with that in healthy controls. Frequency of the circulating Tfh cells showed a positive correlation with anti-CCP antibody in plasma from RA Patients. It has reported that Tfh differentiation is regulated by specific transcription factor Bcl-6. IL-21 is derived from activated Tfh cells and could enhance B cells to produce antibodies. In this study, Bcl-6 and IL-21 mRNA expression in CD4⁺T cells of RA patients was higher than that in control. Also, a higher IL-21 concentration was found in RA Patients.

A sequence motif of the 3’UTR of Bcl-6 matches with miR-346. And level of miR-346 expression in circulating CD4⁺T cells from RA patients was significantly downregulated. We found that miR-346 inhibited the luciferase activity of reporters containing the wild-type UTR1 or UTR2 but not that of the reporter with a mutated 3’UTR unable to bind miR-346.

As Bcl-6 is also expressed in Jurkat cells, miR-346 suppressed the expression of Bcl-6 mRNA in a dose-dependent manner. Manipulation of miR-346 in Jurkat cells also regulated the amount of endogenous Bcl-6 protein.

The percentage of CD4⁺CXCR5⁺T cells in miR-346-transfected group was decreased than that in control group. It could certify the negative function of miR-346 in the differentiation of Tfh cells.

Conclusion In summary, we found that miR-346 could regulate Tfh cells differentiation by targeting Bcl-6, and in RA patients, miR-346 expression was downregulated, which correlated with increased proportion of Tfh cells and disease severity. Collectively, our results may facilitate the validation of miR-346 as a new therapeutic target for the treatment of patients with rheumatoid arthritis.

Disclosure:

X. Tang,
None;

J. Ma,
None;

S. Wang,
None.

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