Increased frequency of interleukin-4 and reduced frequency of interferon-γ and IL-17-producing CD4+ and CD8+ cells in scleromyxedema.
Journal
Journal of the European Academy of Dermatology and Venereology : JEADV
ISSN: 1468-3083
Titre abrégé: J Eur Acad Dermatol Venereol
Pays: England
ID NLM: 9216037
Informations de publication
Date de publication:
May 2020
May 2020
Historique:
received:
10
07
2019
accepted:
12
11
2019
pubmed:
9
1
2020
medline:
15
5
2021
entrez:
9
1
2020
Statut:
ppublish
Résumé
Little is known about the pathogenesis of scleromyxedema, a life-threatening fibromucinosis disease with immunological dysregulation. To investigate on T-cell phenotype, function and cytokine biology in search of new insights supporting the immunopathogenesis of the disease. We analysed the frequency of circulating lymphocyte subsets, the T-cell maturation stage, the generation of antigen-specific T-cell lines and T-cell cytokine secretion. The analysis of T-cell maturation stage and the TCR spectratyping findings revealed that scleromyxedema patients showed clear immunological signs of long-lasting immune system activation and stimulation leading to a skewed T-cell repertoire. Moreover, these analyses showed that both CD4+ and CD8+ T cells from scleromyxedema patients have a profound deficiency (even after stimulation) relatively to the production of IFN-γ and IL17 with respect to healthy donor control cells, while they are massively skewed towards IL4 secretion after stimulation. Our data indicate that a chronic Th2-skewed T-cell response against an unknown target antigen leading to abnormally high IL4 secretion, a pro-fibrotic cytokine, is a main immunological hallmark of scleromyxedema patients. These results, never reported before, may have a translational therapeutic value due to the availability of anti-IL4 agents such as dupilumab.
Sections du résumé
BACKGROUND
BACKGROUND
Little is known about the pathogenesis of scleromyxedema, a life-threatening fibromucinosis disease with immunological dysregulation.
OBJECTIVES
OBJECTIVE
To investigate on T-cell phenotype, function and cytokine biology in search of new insights supporting the immunopathogenesis of the disease.
METHODS
METHODS
We analysed the frequency of circulating lymphocyte subsets, the T-cell maturation stage, the generation of antigen-specific T-cell lines and T-cell cytokine secretion.
RESULTS
RESULTS
The analysis of T-cell maturation stage and the TCR spectratyping findings revealed that scleromyxedema patients showed clear immunological signs of long-lasting immune system activation and stimulation leading to a skewed T-cell repertoire. Moreover, these analyses showed that both CD4+ and CD8+ T cells from scleromyxedema patients have a profound deficiency (even after stimulation) relatively to the production of IFN-γ and IL17 with respect to healthy donor control cells, while they are massively skewed towards IL4 secretion after stimulation.
CONCLUSIONS
CONCLUSIONS
Our data indicate that a chronic Th2-skewed T-cell response against an unknown target antigen leading to abnormally high IL4 secretion, a pro-fibrotic cytokine, is a main immunological hallmark of scleromyxedema patients. These results, never reported before, may have a translational therapeutic value due to the availability of anti-IL4 agents such as dupilumab.
Substances chimiques
Cytokines
0
Interleukin-17
0
Interleukin-4
207137-56-2
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1092-1097Informations de copyright
© 2019 European Academy of Dermatology and Venereology.
Références
Rongioletti F. Lichen myxedematosus (papular mucinosis): new concepts and perspectives for an old disease. Semin Cutan Med Surg 2006; 25: 100.
Rongioletti F, Merlo G, Cinotti E et al. Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients. J Am Acad Dermatol 2013; 69: 66-72.
Merlini G, Stone MJ. Dangerous small B-cell clones. Blood 2006; 108: 2520-2530.
Harper RA, Rispler J. Lichen myxedematosus serum stimulates human skin fibroblast proliferation. Science 1978; 199: 545-547.
Ferrarini M, Helfrich DJ, Walker ER, Medsger TA Jr, Whiteside TL. Scleromyxedema serum increases proliferation but not the glycosaminoglycan synthesis of dermal fibroblasts. J Rheumatol 1989; 16: 837-841.
Yaron M, Yaron I, Yust I, Brenner S. Lichen myxedematosus (scleromyxedema) serum stimulates hyaluronic acid and prostaglandin E production by human fibroblasts. J Rheumatol 1985; 12: 171-175.
Guarneri A, Cioni M, Rongioletti F. High-dose intravenous immunoglobulin therapy for scleromyxoedema: a prospective open-label clinical trial using an objective score of clinical evaluation system. J Eur Acad Dermatol Venereol 2017; 31: 1157-1160.
Rongioletti F, Merlo G, Carli C et al. Histopathologic characteristics of scleromyxedema: a study of a series of 34 cases. J Am Acad Dermatol 2016; 74: 1194-1200.
Conti HR, Shen F, Nayyar N et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 2009; 206: 299-311.
van de Veerdonk FL, Marijnissen RJ, Kullberg BJ et al. The macrophage mannose receptor induces IL-17 in response to Candida albicans. Cell Host Microbe 2009; 5: 329-340.
Mecoli CA, Talbot CC Jr, Fava A et al. Clinical and molecular phenotyping in scleromyxedema pre- and post-treatment with intravenous immunoglobulin. Arthritis Care Res (Hoboken) 2019. https://doi.org/10.1002/acr.23908
Parodi A, Battaglia F, Kalli F et al. CD39 is highly involved in mediating the suppression activity of tumor-infiltrating CD8+ T regulatory lymphocytes. Cancer Immunol Immunother 2013; 62: 851-862.
Fenoglio D, Dentone C, Signori A et al. CD8+CD28-CD127loCD39+ regulatory T-cell expansion: a new possible pathogenic mechanism for HIV infection? J Allergy Clin Immunol 2018; 141: 2220-2233. e4.
Filaci G, Fenoglio D, Fravega M et al. CD8+CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol 2007; 179: 4323-4334.
Fenoglio D, Battaglia F, Parodi A et al. Alteration of Th17 and Treg cell subpopulations co-exist in patients affected with systemic sclerosis. Clin Immunol 2011; 139: 249-257.
Banchereau J, Brière F, Liu YJ, Rousset F. Molecular control of B lymphocyte growth and differentiation. Stem Cells 1994; 12: 278-288.
Jelinek DF. Regulation of B lymphocyte differentiation. Ann Allergy Asthma Immunol 2000; 84: 375-385.
Sato T, Liu X, Basma H et al. IL-4 induces differentiation of human embryonic stem cells into fibrogenic fibroblast-like cells. J Allergy Clin Immunol 2011; 127: 1595-1603.
Yuan W, Yufit T, Li L, Mori Y, Chen SG, Varga J. Negative modulation of alpha1(I) procollagen gene expression in human skin fibroblasts: transcriptional inhibition by interferon-gamma. J Cell Physiol 1999; 179: 97-108.
Park MJ, Moon SJ, Lee EJ et al. IL-1-IL-17 signaling axis contributes to fibrosis and inflammation in two different murine models of systemic sclerosis. Front Immunol 2018; 9: 1611.