title: RNA interference targeting Bcl-6 ameliorates experimental autoimmune myasthenia gravis in mice.
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.
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Xin
authors.affiliation: Department of Pathogenic Biology and Lab of Infection and Immunology, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Fu
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China. Electronic address: zy20037416@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Changxin
authors.initials: C
authors.lastname: Dou
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China. Electronic address: xiashenxuyi@163.com.
authors.forename: Xia
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Radiation Therapy, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Yuanhu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Guiyun
authors.initials: G
authors.lastname: Cui
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Yonghai
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Deqin
authors.initials: D
authors.lastname: Geng
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Chenghua
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Zunsheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Ruiguo
authors.initials: R
authors.lastname: Dong
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D051560:Proto-Oncogene Proteins c-bcl-6; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D034741:RNA, Small Interfering
keywords: Bcl-6; Myasthenia gravis; RNA interference; Tfh cells