Regulatory T cells in erythema nodosum leprosum maintain anti-inflammatory function.
Anti-Inflammatory Agents
/ therapeutic use
Drug Therapy, Combination
Erythema Nodosum
Humans
Interleukin-10
Leprostatic Agents
/ therapeutic use
Leprosy
/ drug therapy
Leprosy, Lepromatous
/ complications
Leukocytes, Mononuclear
Longitudinal Studies
Mycobacterium leprae
Prednisolone
/ pharmacology
T-Lymphocytes, Regulatory
Tumor Necrosis Factor-alpha
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
21
01
2022
accepted:
08
07
2022
revised:
03
08
2022
pubmed:
23
7
2022
medline:
6
8
2022
entrez:
22
7
2022
Statut:
epublish
Résumé
The numbers of circulating regulatory T cells (Tregs) are increased in lepromatous leprosy (LL) but reduced in erythema nodosum leprosum (ENL), the inflammatory complication of LL. It is unclear whether the suppressive function of Tregs is intact in both these conditions. A longitudinal study recruited participants at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before and after 24 weeks of prednisolone treatment for ENL and multidrug therapy (MDT) for participants with LL. We evaluated the suppressive function of Tregs in the peripheral blood mononuclear cells (PBMCs) of participants with LL and ENL by analysis of TNFα, IFNγ and IL-10 responses to Mycobacterium leprae (M. leprae) stimulation before and after depletion of CD25+ cells. 30 LL participants with ENL and 30 LL participants without ENL were recruited. The depletion of CD25+ cells from PBMCs was associated with enhanced TNFα and IFNγ responses to M. leprae stimulation before and after 24 weeks treatment of LL with MDT and of ENL with prednisolone. The addition of autologous CD25+ cells to CD25+ depleted PBMCs abolished these responses. In both non-reactional LL and ENL groups mitogen (PHA)-induced TNFα and IFNγ responses were not affected by depletion of CD25+ cells either before or after treatment. Depleting CD25+ cells did not affect the IL-10 response to M. leprae before and after 24 weeks of MDT in participants with LL. However, depletion of CD25+ cells was associated with an enhanced IL-10 response on stimulation with M. leprae in untreated participants with ENL and reduced IL-10 responses in treated individuals with ENL. The enhanced IL-10 in untreated ENL and the reduced IL-10 response in prednisolone treated individuals with ENL was abolished by addition of autologous CD25+ cells. The findings support the hypothesis that the impaired cell-mediated immune response in individuals with LL is M. leprae antigen specific and the unresponsiveness can be reversed by depleting CD25+ cells. Our results suggest that the suppressive function of Tregs in ENL is intact despite ENL being associated with reduced numbers of Tregs. The lack of difference in IL-10 response in control PBMCs and CD25+ depleted PBMCs in individuals with LL and the increased IL-10 response following the depletion of CD25+ cells in individuals with untreated ENL suggest that the mechanism of immune regulation by Tregs in leprosy appears independent of IL-10 or that other cells may be responsible for IL-10 production in leprosy. The present findings highlight mechanisms of T cell regulation in LL and ENL and provide insights into the control of peripheral immune tolerance, identifying Tregs as a potential therapeutic target.
Sections du résumé
BACKGROUND
The numbers of circulating regulatory T cells (Tregs) are increased in lepromatous leprosy (LL) but reduced in erythema nodosum leprosum (ENL), the inflammatory complication of LL. It is unclear whether the suppressive function of Tregs is intact in both these conditions.
METHODS
A longitudinal study recruited participants at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before and after 24 weeks of prednisolone treatment for ENL and multidrug therapy (MDT) for participants with LL. We evaluated the suppressive function of Tregs in the peripheral blood mononuclear cells (PBMCs) of participants with LL and ENL by analysis of TNFα, IFNγ and IL-10 responses to Mycobacterium leprae (M. leprae) stimulation before and after depletion of CD25+ cells.
RESULTS
30 LL participants with ENL and 30 LL participants without ENL were recruited. The depletion of CD25+ cells from PBMCs was associated with enhanced TNFα and IFNγ responses to M. leprae stimulation before and after 24 weeks treatment of LL with MDT and of ENL with prednisolone. The addition of autologous CD25+ cells to CD25+ depleted PBMCs abolished these responses. In both non-reactional LL and ENL groups mitogen (PHA)-induced TNFα and IFNγ responses were not affected by depletion of CD25+ cells either before or after treatment. Depleting CD25+ cells did not affect the IL-10 response to M. leprae before and after 24 weeks of MDT in participants with LL. However, depletion of CD25+ cells was associated with an enhanced IL-10 response on stimulation with M. leprae in untreated participants with ENL and reduced IL-10 responses in treated individuals with ENL. The enhanced IL-10 in untreated ENL and the reduced IL-10 response in prednisolone treated individuals with ENL was abolished by addition of autologous CD25+ cells.
CONCLUSION
The findings support the hypothesis that the impaired cell-mediated immune response in individuals with LL is M. leprae antigen specific and the unresponsiveness can be reversed by depleting CD25+ cells. Our results suggest that the suppressive function of Tregs in ENL is intact despite ENL being associated with reduced numbers of Tregs. The lack of difference in IL-10 response in control PBMCs and CD25+ depleted PBMCs in individuals with LL and the increased IL-10 response following the depletion of CD25+ cells in individuals with untreated ENL suggest that the mechanism of immune regulation by Tregs in leprosy appears independent of IL-10 or that other cells may be responsible for IL-10 production in leprosy. The present findings highlight mechanisms of T cell regulation in LL and ENL and provide insights into the control of peripheral immune tolerance, identifying Tregs as a potential therapeutic target.
Identifiants
pubmed: 35867720
doi: 10.1371/journal.pntd.0010641
pii: PNTD-D-22-00102
pmc: PMC9348709
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Leprostatic Agents
0
Tumor Necrosis Factor-alpha
0
Interleukin-10
130068-27-8
Prednisolone
9PHQ9Y1OLM
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0010641Subventions
Organisme : World Health Organization
ID : 001
Pays : International
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
BMC Immunol. 2018 Nov 8;19(1):33
pubmed: 30409122
PLoS Negl Trop Dis. 2015 Sep 09;9(9):e0004065
pubmed: 26351858
Am J Trop Med Hyg. 2016 Apr;94(4):721-7
pubmed: 26903606
PLoS One. 2018 Jun 8;13(6):e0196853
pubmed: 29883464
Nat Commun. 2018 Dec 21;9(1):5457
pubmed: 30575716
PLoS Negl Trop Dis. 2017 Oct 13;11(10):e0006011
pubmed: 29028793
FEMS Immunol Med Microbiol. 1999 Apr;23(4):355-62
pubmed: 10225295
Proc Soc Exp Biol Med. 1962 Mar;109:636-8
pubmed: 13911661
Microbiol Mol Biol Rev. 2010 Dec;74(4):589-620
pubmed: 21119019
Nat Commun. 2019 Jan 21;10(1):354
pubmed: 30664665
Nat Rev Immunol. 2008 Jul;8(7):523-32
pubmed: 18566595
J Exp Med. 2010 Jul 5;207(7):1409-20
pubmed: 20547826
Immunol Res. 2011 Apr;49(1-3):124-34
pubmed: 21116872
Am J Transl Res. 2018 Sep 15;10(9):2929-2939
pubmed: 30323879
Cell Discov. 2022 Jan 11;8(1):2
pubmed: 35013182
J Clin Invest. 2003 Nov;112(9):1310-2
pubmed: 14597756
Front Immunol. 2019 Feb 18;10:159
pubmed: 30833946
J Immunol. 1985 Aug;135(2):1443-9
pubmed: 2989366
Immunity. 2020 Sep 15;53(3):581-596.e5
pubmed: 32707034
Int J Lepr Other Mycobact Dis. 1995 Jun;63(2):222-30
pubmed: 7602217
J Infect Dis. 2010 Feb 15;201(4):558-69
pubmed: 20070238
Immunity. 2009 Aug 21;31(2):209-19
pubmed: 19646904
Front Immunol. 2018 Jan 12;8:1949
pubmed: 29375572
J Immunol. 2016 Nov 15;197(10):3762-3770
pubmed: 27815439
Clin Exp Immunol. 1983 Jul;53(1):17-24
pubmed: 6223731
PLoS Negl Trop Dis. 2017 Oct 9;11(10):e0006001
pubmed: 28991896
Crit Rev Immunol. 2012;32(1):23-63
pubmed: 22428854
PLoS Negl Trop Dis. 2014 Jan 16;8(1):e2639
pubmed: 24454972
Arch Immunol Ther Exp (Warsz). 2020 Jun 12;68(4):20
pubmed: 32533319
Int J Lepr Other Mycobact Dis. 1984 Sep;52(3):384-94
pubmed: 6541206
Int J Lepr Other Mycobact Dis. 1966 Jul-Sep;34(3):255-73
pubmed: 5950347
Mult Scler. 2021 Oct;27(11):1695-1705
pubmed: 33300840
Am J Trop Med Hyg. 2006 May;74(5):868-79
pubmed: 16687695
Scand J Immunol. 2009 Oct;70(4):326-36
pubmed: 19751267
Immunology. 1997 Dec;92(4):429-36
pubmed: 9497483
PLoS Negl Trop Dis. 2016 Jan 11;10(1):e0004335
pubmed: 26751388
PLoS Negl Trop Dis. 2012;6(12):e1936
pubmed: 23236531
Int J Dermatol. 2010 Oct;49(10):1152-8
pubmed: 20883403
PLoS Negl Trop Dis. 2019 Sep 10;13(9):e0007368
pubmed: 31504035
Lancet. 1969 Nov 1;2(7627):933-5
pubmed: 4186599
PLoS One. 2013 Jun 06;8(6):e65496
pubmed: 23755239
PLoS Negl Trop Dis. 2014 Apr 10;8(4):e2773
pubmed: 24722473
Front Immunol. 2019 Jan 31;10:43
pubmed: 30804926
Arch Dermatol Res. 2014 Nov;306(9):793-801
pubmed: 25018055
Front Immunol. 2017 May 26;8:605
pubmed: 28603524
Nat Rev Immunol. 2007 Aug;7(8):585-98
pubmed: 17653126
PLoS Negl Trop Dis. 2016 Apr 01;10(4):e0004592
pubmed: 27035913
Front Immunol. 2018 Feb 09;9:189
pubmed: 29479352
Immunol Rev. 2007 Dec;220:199-213
pubmed: 17979848
Int J Lepr. 1965 Jan-Mar;33:28-49
pubmed: 14282354
Eur J Immunol. 2012 Nov;42(11):2925-36
pubmed: 22851198