title: ATRA alters humoral responses associated with amelioration of EAMG symptoms by balancing Tfh/Tfr helper cell profiles.
abstract: All-trans retinoic acid (ATRA) is a vitamin A metabolite with diverse immunomodulatory actions used therapeutically in the treatment of some autoimmune diseases. However, the effects that ATRA may have on diminishing myasthenia gravis (MG) symptoms remain undefined. This study investigated the effect of ATRA on experimental autoimmune myasthenia gravis (EAMG) in vivo and in vitro. Data presented in this study demonstrated that intraperitoneal injection of ATRA ameliorated EAMG pathology in rats associated with reduced total anti-acetylcholine receptor (AChR) serum IgG levels. We observed that EAMG development was accompanied by an increase in follicular helper T cells (Tfh, defined as CD4(+)CXCR5(+)ICOS(high)) and a decrease of follicular regulatory T cells (Tfr, defined as CD4(+)Foxp3(+)CXCR5(+)ICOS(median)) and that the Tfh:Tfr ratio was altered following ATRA administration. In addition, ATRA treatment restored the Th1/Th2/Th17/Treg balance. In vitro, ATRA inhibited AChR-specific cell proliferation and eliciting apoptosis in these cells without affecting the cell cycle. ATRA also altered the Th distribution in animals presenting with EAMG resulting in a reduction in Th1/Th17/Tfh cells and increasing the number of Th2/Treg/Tfr cell types. These results suggested that ATRA reduced EAMG severity by regulating Th cell profiles thereby providing new insights into the development of novel MG (or related) therapies.
authors.affiliation: Department of Neurobiology, Harbin Medical University Provincial Key Lab of Neurobiology, Harbin Medical University, Heilongjiang 150081, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Xie
authors.forename: Lili
authors.initials: L
authors.lastname: Mu
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Yao
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhan
authors.forename: Xinyue
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Kang
authors.forename: Jinghua
authors.initials: J
authors.lastname: Wang
authors.forename: Yumei
authors.initials: Y
authors.lastname: Liu
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Guangyou
authors.initials: G
authors.lastname: Wang
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.forename: Xijun
authors.initials: X
authors.lastname: Liu
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Kong
authors.forename: Hulun
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D056724:Immunity, Humoral / Q000187:drug effects*; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology; D018482:Muscle, Skeletal / Q000276:immunology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D013047:Specific Pathogen-Free Organisms; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D014212:Tretinoin
keywords: AChR; ATRA; All-trans retinoic acid; EAMG; Experimental autoimmune myasthenia gravis; Follicular helper T cells; Follicular regulatory T cells; GCs; Germinal centers; MG; NMJ; R-AChR(97–116); RA; Tfh; Tfr; acetylcholine receptor; all-trans retinoic acid; experimental autoimmune myasthenia gravis; follicular helper T cells; follicular regulatory T cells; germinal centers; myasthenia gravis; neuromuscular junction.; rat AChR α97–116 peptide; retinoic acid