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Mol Cell Neurosci. 2014 Jan;58:85-94. doi: 10.1016/j.mcn.2013.12.006. Epub 2013 Dec 17.

RNA interference targeting Bcl-6 ameliorates experimental autoimmune myasthenia gravis in mice.

Author information

1
Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
2
Department of Pathogenic Biology and Lab of Infection and Immunology, Xuzhou Medical College, Xuzhou, Jiangsu, China.
3
Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China. Electronic address: zy20037416@163.com.
4
Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China. Electronic address: xiashenxuyi@163.com.
5
Department of Radiation Therapy, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.

Abstract

Follicular helper T (Tfh) cells are dedicated to providing help to B cells and are strongly associated with antibody-mediated autoimmune disease. B cell lymphoma 6 (Bcl-6) is a key transcription factor of Tfh cells, and IL-21 is known to be a critical cytokine produced by Tfh cells. We silenced Bcl-6 gene expression using RNA interference (RNAi) delivered by a lentiviral vector, to evaluate the therapeutic role of Bcl-6 short hairpin RNAs (shRNAs) in experimental autoimmune myasthenia gravis (EAMG). Our data demonstrate that CD4(+)CXCR5(+)PD-1(+) Tfh cells, Bcl-6 and IL-21 were significantly increased in EAMG mice, compared with controls. In addition, we found that frequencies of Tfh cells were positively correlated with the levels of serum anti-AChR Ab. In-vivo transduction of lenti-siRNA-Bcl6 ameliorates the severity of ongoing EAMG with decreased Tfh cells, Bcl-6 and IL-21 expression, and leads to decreased anti-AChR antibody levels. Furthermore, we found that siRNA knockdown of Bcl-6 expression increases the expression of Th1(IFN-γ, T-bet) and Th2 markers (IL-4 and GATA3), but failed to alter the expression of Th17-related markers (RORγt, IL-17) and Treg markers (FoxP3). Our study suggests that Tfh cells contribute to the antibody production and could be one of the most important T cell subsets responsible for development and progression of EAMG or MG. Bcl-6 provides a promising therapeutic target for immunotherapy not only for MG, but also for other antibody-mediated autoimmune diseases.

KEYWORDS:

Bcl-6; Myasthenia gravis; RNA interference; Tfh cells

PMID:
24361642
DOI:
10.1016/j.mcn.2013.12.006
[Indexed for MEDLINE]
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