Skip to content
2000
Volume 25, Issue 4
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

T helper interplay and cytokines monitoring in auto-immune skin disorders such as Pemphigus Foliaceus (PF) may play a central role in predicting the clinical stratification of the pathology.

Objectives

In order to assess the CD4+ T cell imbalance, (i) this study aims to assess the related immune cells (Th1, Th2, Th17, and Treg cells) as well as the related cytokines (IL-1β, IFNγ, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-17F, IL-22, TNF-β, and TNFα) in peripheral blood, and [ii] their respective transcription factors in the lesioned skin of PF endemic patients during the clinical course.

Methods

Peripheral blood of 22 PF patients was analyzed by flow cytometry to assess the functional associations of Th cell subpopulations and their characteristic cytokines by multiplex bead assay of 14-plex cytokines. Skin mRNA expression of their associated transcription factors was analyzed using the TaqMan detection system.

Results

Our findings revealed that the CD4+ T cell subtypes in PF patients compared to Healthy Controls (HC) were characterized by (i) a similar Th1/Th2 ratio and increased Th17/Treg ratio and (ii) significantly higher plasma levels of Th-17 specific cytokines; IL-6, IL-8, IL-17A. Higher percentages in Th17 and Treg subtypes and a significant increase in plasma IL-17F levels were maintained in relapsing PF patients, arguing the pivotal role of Th17 cells in PF pathogenesis. Furthermore, our findings pointed out the major contribution of the pro-inflammatory cytokine IL-6. Indeed, in addition to being involved in the initial stages of disease development, IL-6 seems to also be involved in the maintenance of the pathophysiological process, probably through its effect on Th17 differentiation. The skin-relative mRNA expression levels of and were significantly higher in relapsing PF patients compared to PF patients.

Conclusion

Our results highlight the central role played by Th17 lymphocytes and their related pro-inflammatory cytokines during the clinical course of the disease, reversing the Th1/Th2 dichotomy in PF.

Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240305096240611064617
2024-06-24
2025-10-01
Loading full text...

Full text loading...

References

  1. FerberI.A. BrockeS. Taylor-EdwardsC. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE).J. Immunol.199615615710.4049/jimmunol.156.1.5 8598493
    [Google Scholar]
  2. Jadidi-NiaraghF. MirshafieyA. The deviated balance between regulatory T cell and Th17 in autoimmunity.Immunopharmacol. Immunotoxicol.201234572773910.3109/08923973.2011.619987 22316060
    [Google Scholar]
  3. Bastuji-GarinS. SouissiR. BlumL. Comparative epidemiology of pemphigus in Tunisia and France: Unusual incidence of Pemphigus foliaceus in young Tunisian women.J. Invest. Dermatol.1995104230230510.1111/1523‑1747.ep12612836 7829889
    [Google Scholar]
  4. MasmoudiH. AbidaO. MasmoudiA. TurkiH. Update on immunogenetics of Tunisian endemic pemphigus foliaceus.J. Leukoc. Biol.2019105225726510.1002/JLB.MR0318‑132R 30577075
    [Google Scholar]
  5. AokiV. RivittiE.A. DiazL.A. Update on fogo selvagem, an endemic form of Pemphigus foliaceus.J. Dermatol.2015421182610.1111/1346‑8138.12675 25558948
    [Google Scholar]
  6. CultonD.A. QianY. LiN. Advances in pemphigus and its endemic Pemphigus foliaceus (Fogo selvagem) phenotype: A paradigm of human autoimmunity.J. Autoimmun.200831431132410.1016/j.jaut.2008.08.003 18838249
    [Google Scholar]
  7. LeeH.E. BerkowitzP. JollyP.S. DiazL.A. ChuaM.P. RubensteinD.S. Biphasic activation of p38MAPK suggests that apoptosis is a downstream event in pemphigus acantholysis.J. Biol. Chem.200928418125241253210.1074/jbc.M808204200 19270308
    [Google Scholar]
  8. WaschkeJ. BruggemanP. BaumgartnerW. ZillikensD. DrenckhahnD. Pemphigus foliaceus IgG causes dissociation of desmoglein 1–containing junctions without blocking desmoglein 1 transinteraction.J. Clin. Invest.2005115113157316510.1172/JCI23475 16211092
    [Google Scholar]
  9. ArmitageR.J. MacduffB.M. SpriggsM.K. FanslowW.C. Human B cell proliferation and Ig secretion induced by recombinant CD40 ligand are modulated by soluble cytokines.J. Immunol.199315093671368010.4049/jimmunol.150.9.3671 8097223
    [Google Scholar]
  10. LinM.S. FuC.L. AokiV. Desmoglein-1–specific T lymphocytes from patients with endemic Pemphigus foliaceus (Fogo selvagem).J. Clin. Invest.2000105220721310.1172/JCI8075 10642599
    [Google Scholar]
  11. GebhardK.L. VeldmanC.M. WassmuthR. SchultzE. SchulerG. HertlM. Ex vivo analysis of desmoglein 1‐responsive T‐helper (Th) 1 and Th2 cells in patients with pemphigus foliaceus and healthy individuals.Exp. Dermatol.200514858659210.1111/j.0906‑6705.2005.00329.x 16026580
    [Google Scholar]
  12. ZeotiD.M. FigueiredoJ.F.C. ChiossiM.P.V. RoselinoA.M.F. Serum cytokines in patients with Brazilian Pemphigus foliaceus (Fogo selvagem).Braz. J. Med. Biol. Res.20003391065106810.1590/S0100‑879X2000000900012 10973139
    [Google Scholar]
  13. XuR.C. ZhuH.Q. LiW.P. The imbalance of Th17 and regulatory T cells in Pemphigus patients.Eur. J. Dermatol.201323679580210.1684/ejd.2013.2177 24192290
    [Google Scholar]
  14. Ben JmaaM. AbidaO. FakhfakhR. Involvement of the IL23/Th17 pathway in the pathogenesis of Tunisian Pemphigus Foliaceus.Mediators Inflamm.2018201811210.1155/2018/8206983 30116153
    [Google Scholar]
  15. HolsteinJ. SolimaniF. BaumC. Immunophenotyping in pemphigus reveals a TH17/TFH17 cell–dominated immune response promoting desmoglein1/3-specific autoantibody production.J. Allergy Clin. Immunol.202114762358236910.1016/j.jaci.2020.11.008 33221382
    [Google Scholar]
  16. Rocha-RodriguesD.B. PaschoiniG. PereiraS.A.L. ReisM.A. TeixeiraV.P.A. RodriguesV.Jr High levels of interleukin-1 in patients with endemic Pemphigus foliaceus.Clin. Vaccine Immunol.200310574174310.1128/CDLI.10.5.741‑743.2003 12965897
    [Google Scholar]
  17. TimóteoR.P. SilvaM.V. da SilvaD.A.A. Cytokine and chemokines alterations in the endemic form of Pemphigus foliaceus (Fogo selvagem).Front. Immunol.2017897810.3389/fimmu.2017.00978 28855908
    [Google Scholar]
  18. HertlM. JedlickovaH. KarpatiS. Pemphigus. S2 Guideline for diagnosis and treatment – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV).J. Eur. Acad. Dermatol. Venereol.201529340541410.1111/jdv.12772 25338479
    [Google Scholar]
  19. BreenE.J. PolaskovaV. KhanA. Bead-based multiplex immuno-assays for cytokines, chemokines, growth factors and other analytes: Median fluorescence intensities versus their derived absolute concentration values for statistical analysis.Cytokine201571218819810.1016/j.cyto.2014.10.030 25461398
    [Google Scholar]
  20. PunnonenJ. AversaG. CocksB.G. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells.Proc. Natl. Acad. Sci. USA19939083730373410.1073/pnas.90.8.3730 8097323
    [Google Scholar]
  21. ToumiA. AbidaO. Ben AyedM. MasmoudiA. TurkiH. MasmoudiH. Cytokine gene polymorphisms in Tunisian endemic Pemphigus foliaceus: A possible role of il-4 variants.Hum. Immunol.201374565866510.1016/j.humimm.2013.01.009 23376457
    [Google Scholar]
  22. FuteiY. AmagaiM. IshiiK. Kuroda-KinoshitaK. OhyaK. NishikawaT. Predominant IgG4 subclass in autoantibodies of Pemphigus vulgaris and foliaceus.J. Dermatol. Sci.2001261556110.1016/S0923‑1811(00)00158‑4 11323221
    [Google Scholar]
  23. ArakawaM. DainichiT. YasumotoS. HashimotoT. Lesional Th17 cells in Pemphigus vulgaris and Pemphigus foliaceus.J. Dermatol. Sci.200953322823110.1016/j.jdermsci.2008.09.008 18980832
    [Google Scholar]
  24. HuD. NotarbartoloS. CroonenborghsT. Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis.Nat. Commun.201781160010.1038/s41467‑017‑01571‑8 29150604
    [Google Scholar]
  25. DuhenT. CampbellD.J. IL-1β promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes.J. Immunol.2014193112012910.4049/jimmunol.1302734
    [Google Scholar]
  26. CosmiL. De PalmaR. SantarlasciV. Human interleukin 17–producing cells originate from a CD161+CD4+ T cell precursor.J. Exp. Med.200820581903191610.1084/jem.20080397 18663128
    [Google Scholar]
  27. AnnunziatoF. CosmiL. LiottaF. MaggiE. RomagnaniS. Defining the human T helper 17 cell phenotype.Trends Immunol.2012331050551210.1016/j.it.2012.05.004 22682163
    [Google Scholar]
  28. McGeachyM.J. ChenY. TatoC.M. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo.Nat. Immunol.200910331432410.1038/ni.1698 19182808
    [Google Scholar]
  29. KleinewietfeldM. HaflerD.A. The plasticity of human Treg and Th17 cells and its role in autoimmunity.Semin. Immunol.201325430531210.1016/j.smim.2013.10.009 24211039
    [Google Scholar]
  30. MeiteiH.T. LalG. T cell receptor signaling in the differentiation and plasticity of CD4+ T cells.Cytokine Growth Factor Rev.202369142710.1016/j.cytogfr.2022.08.001 36028461
    [Google Scholar]
  31. LuiP.P. ChoI. AliN. Tissue regulatory T cells.Immunology2020161141710.1111/imm.13208 32463116
    [Google Scholar]
  32. PereiraN.F. HansenJ.A. LinM.T. RoxoV.M.M.S. BraunK. Petzl-ErlerM.L. Cytokine gene polymorphisms in endemic pemphigus foliaceus: A possible role for IL6 variants.Cytokine200428623324110.1016/j.cyto.2004.08.006 15566952
    [Google Scholar]
  33. FishmanD. FauldsG. JefferyR. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis.J. Clin. Invest.199810271369137610.1172/JCI2629 9769329
    [Google Scholar]
  34. Rivera-ChavezF.A. Peters-HybkiD.L. BarberR.C. O’KeefeG.E. Interleukin-6 promoter haplotypes and interleukin-6 cytokine responses.Shock200320321822310.1097/00024382‑200309000‑00004 12923492
    [Google Scholar]
  35. MiharaM. HashizumeM. YoshidaH. SuzukiM. ShiinaM. IL-6/IL-6 receptor system and its role in physiological and pathological conditions.Clin. Sci.2012122414315910.1042/CS20110340 22029668
    [Google Scholar]
  36. WolskE. MygindH. GrøndahlT.S. PedersenB.K. van HallG. IL-6 selectively stimulates fat metabolism in human skeletal muscle.Am. J. Physiol. Endocrinol. Metab.20102995E832E84010.1152/ajpendo.00328.2010 20823453
    [Google Scholar]
  37. NarbuttJ. LukamowiczJ. BogaczewiczJ. Sysa-JedrzejowskaA. TorzeckaJ.D. LesiakA. Serum concentration of interleukin-6 is increased both in active and remission stages of Pemphigus vulgaris.Mediators Inflamm.2008200887539410.1155/2008/875394
    [Google Scholar]
  38. BholK.C. RojasA.I. KhanI.U. AhmedA.R. Presence of interleukin 10 in the serum and blister fluid of patients with Pemphigus vulgaris and pemphigoid.Cytokine20001271076108310.1006/cyto.1999.0642 10880254
    [Google Scholar]
  39. D’AuriaL. BonifatiC. MussiA. Cytokines in the sera of patients with pemphigus vulgaris: Interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared to healthy subjects and correlate with disease activity.Eur. Cytokine Netw.199784383387 9459618
    [Google Scholar]
  40. MortazaviH. EsmailiN. KhezriS. The effect of conventional immunosuppressive therapy on cytokine serum levels in Pemphigus vulgaris patients.Iran. J. Allergy Asthma Immunol.2014133174183 24659121
    [Google Scholar]
  41. MartinsC.S. de CastroM. Generalized and tissue specific glucocorticoid resistance.Mol. Cell. Endocrinol.202153011127710.1016/j.mce.2021.111277 33864884
    [Google Scholar]
  42. ChriguerR.S. RoselinoA.M. de CastroM. Glucocorticoid sensitivity and proinflammatory cytokines pattern in Pemphigus.J. Clin. Immunol.201232478679310.1007/s10875‑012‑9679‑y 22407150
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240305096240611064617
Loading
/content/journals/cmm/10.2174/0115665240305096240611064617
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test