Inhibition of the transcription factor ROR-γ reduces pathogenic Th17 cells in acetylcholine receptor antibody positive myasthenia gravis.
Adult
Aged
Aged, 80 and over
Autoantibodies
/ immunology
Autoantigens
/ immunology
Cell Differentiation
/ drug effects
Female
Humans
Immunologic Factors
/ pharmacology
Interleukin-17
/ immunology
Male
Middle Aged
Myasthenia Gravis
/ immunology
Nuclear Receptor Subfamily 1, Group F, Member 3
/ antagonists & inhibitors
Receptors, Cholinergic
/ immunology
Th17 Cells
/ drug effects
AChR
IL-17
Interferon-gamma
Myasthenia gravis
Receptor-related orphan receptor gamma
Th17 cell
Journal
Experimental neurology
ISSN: 1090-2430
Titre abrégé: Exp Neurol
Pays: United States
ID NLM: 0370712
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
12
08
2019
revised:
27
11
2019
accepted:
10
12
2019
pubmed:
16
12
2019
medline:
24
10
2020
entrez:
16
12
2019
Statut:
ppublish
Résumé
IL-17 producing CD4 T cells (Th17) cells increase significantly with disease severity in myasthenia gravis (MG) patients. To suppress the generation of Th17 cells, we examined the effect of inhibiting retinoic acid receptor-related-orphan-receptor-C (RORγ), a Th17-specific transcription factor critical for differentiation. RORγ inhibition profoundly reduced Th17 cell frequencies, including IFN-γ and IL-17 co-producing pathogenic Th17 cells. Other T helper subsets were not affected. In parallel, CD8 T cell subsets producing IL-17 and IL-17/IFN-γ were increased in MG patients and inhibited by the RORγ inhibitor. These findings provide rationale for exploration of targeted Th17 therapies, including ROR-γ inhibitors, to treat MG patients.
Identifiants
pubmed: 31838097
pii: S0014-4886(19)30293-6
doi: 10.1016/j.expneurol.2019.113146
pmc: PMC7357824
mid: NIHMS1599249
pii:
doi:
Substances chimiques
Autoantibodies
0
Autoantigens
0
IL17A protein, human
0
Immunologic Factors
0
Interleukin-17
0
Nuclear Receptor Subfamily 1, Group F, Member 3
0
Receptors, Cholinergic
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113146Subventions
Organisme : NINDS NIH HHS
ID : K23 NS085049
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no conflicts of interest.
Références
N Engl J Med. 2012 Mar 29;366(13):1181-9
pubmed: 22455412
J Leukoc Biol. 2009 Aug;86(2):435-43
pubmed: 19487306
J Immunol. 2009 Feb 15;182(4):1794-8
pubmed: 19201830
Exp Neurol. 2019 Feb;312:43-50
pubmed: 30472069
Nature. 2008 Jul 17;454(7202):350-2
pubmed: 18469800
Sci Rep. 2016 Dec 01;6:37977
pubmed: 27905482
Annu Rev Immunol. 2013;31:605-33
pubmed: 23516986
J Autoimmun. 2014 Aug;52:130-8
pubmed: 24378287
Eur J Immunol. 2009 Jul;39(7):1716-25
pubmed: 19544308
Mucosal Immunol. 2013 Sep;6(5):900-10
pubmed: 23250275
Cell Rep. 2016 Dec 20;17(12):3206-3218
pubmed: 28009290
Autoimmun Rev. 2014 Jun;13(6):668-77
pubmed: 24418308
J Clin Invest. 2006 Nov;116(11):2843-54
pubmed: 17080188
Muscle Nerve. 2011 Aug;44(2):278-80
pubmed: 21755509
Nat Immunol. 2012 Oct;13(10):991-9
pubmed: 22961052
J Immunol. 2016 Mar 1;196(5):2075-84
pubmed: 26826242
Immunology. 2009 Sep;128(1 Suppl):e826-36
pubmed: 19740344
Ann N Y Acad Sci. 2003 Sep;998:440-4
pubmed: 14592912
J Leukoc Biol. 2007 Aug;82(2):354-60
pubmed: 17505023
Neurology. 2000 Jul 12;55(1):16-23
pubmed: 10891897
Cytokine Growth Factor Rev. 2016 Aug;30:1-17
pubmed: 27481185
Dermatol Ther (Heidelb). 2016 Mar;6(1):1-12
pubmed: 26714681
Ann N Y Acad Sci. 2012 Dec;1274:40-7
pubmed: 23252896
Curr Opin Pharmacol. 2014 Aug;17:12-6
pubmed: 24980083
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18460-5
pubmed: 19015529
Mol Pharm. 2012 Jan 1;9(1):102-10
pubmed: 22023154
PLoS One. 2017 Nov 20;12(11):e0188391
pubmed: 29155882
J Dermatol Sci. 2019 Mar;93(3):176-185
pubmed: 30905492
Clin Sci (Lond). 2012 Jun;122(11):487-511
pubmed: 22324470
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3006-11
pubmed: 20133607
JCI Insight. 2017 Mar 9;2(5):e91127
pubmed: 28289717
Eur J Immunol. 2015 May;45(5):1339-47
pubmed: 25676041
N Engl J Med. 2012 Mar 29;366(13):1190-9
pubmed: 22455413
Eur J Immunol. 2006 Nov;36(11):2868-74
pubmed: 17048276
Ann Rheum Dis. 2008 Dec;67 Suppl 3:iii26-9
pubmed: 19022809
Immunol Lett. 2016 Oct;178:20-6
pubmed: 27173097
Cytokine. 2016 Feb;78:44-6
pubmed: 26618234
Cytokine. 2017 Aug;96:279-285
pubmed: 28599246
Neuroimmunomodulation. 2017;24(4-5):264-270
pubmed: 29414833
PLoS One. 2016 Feb 12;11(2):e0147979
pubmed: 26870941
Continuum (Minneap Minn). 2014 Oct;20(5 Peripheral Nervous System Disorders):1413-25
pubmed: 25299290
Immunol Lett. 2019 May;209:21-27
pubmed: 30946855
J Autoimmun. 2014 Aug;52:53-63
pubmed: 24405842
Cell. 2006 Sep 22;126(6):1121-33
pubmed: 16990136
Nature. 2012 Apr 26;484(7395):514-8
pubmed: 22466287
Nat Commun. 2017 Nov 17;8(1):1600
pubmed: 29150604