Abstract
Previous studies demonstrated that Th1 cytokines like IL-2, IL-12 and IFN-γ have initiatory role in alopecia areata (AA) and positive correlation with disease severity. They informed that serum levels of Th17 cytokines, IL-17, IL-22, IL-23 increased in active AA patients and corelated, particularly IL-17, with disease severity. In recent reports it was showed the balance between Th17 and Treg cells is crucial for maintaining tolerance to self-antigens, and an imbalance towards Th17 may contribute to the development of autoimmune diseases like AA. But research on serum Treg markers in AA is limited. It was aimed to investigate whether the Treg cells have a role in the pathogenesis of AA analyzing the serum levels of Treg cytokines IL-35 and TGF-β in the patients with AA. 42 AA patients and 38 healthy controls were enrolled. Patient demographics, clinical data, disease severity assessed by Severity of Alopecia Tool (SALT) scores were recorded. Serum samples were collected and analyzed for TGF-β and IL-35 levels using ELISA kits. The cytokine levels in both groups were statistically compared. Their relation with parameters of demographic and severity of disease was evaluated. The patient and control groups had no statistically significant difference, there was 71.4% males and 28.6% females in patient group, while the control group had 63.2% males and 36.8% females, Severity analysis classified 18 patients with mild AA, 19 with moderate AA, and 5 with alopecia totalis/areata universalis. While TGF-β levels exhibited no significant difference between groups, IL-35 levels were significantly elevated in AA patients (p = 0.002). Logistic regression identified IL-35 as a significant parameter influencing disease status (OR = 1.055). Correlation analysis revealed a weak positive correlation between patient age and IL-35 levels (r = 0.436; p = 0.004). Notably, IL-35 levels displayed a significant decrease in individuals with antinuclear antibody (ANA) positivity. No correlations were identified between cytokine levels and disease severity, prognosis, or disease activity. Elevated IL-35 levels suggest that IL-35 and specific Treg cell subsets can play a role in AA pathogenesis. The nuanced roles of TGF-β and IL-35 highlight the need for comprehensive studies to interpret their implications in the complex immunopathogenesis of AA. These findings open avenues for further research, positioning IL-35 as a prospective target for investigating and potentially intervening in AA pathogenesis.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00403-024-02901-9/MediaObjects/403_2024_2901_Fig1_HTML.png)
Similar content being viewed by others
![](https://media.springernature.com/w215h120/springer-static/image/art%3Aplaceholder%2Fimages/placeholder-figure-springernature.png)
Data availability
No datasets were generated or analysed during the current study.
References
Bertolini M, McElwee K, Gilhar A, Bulfone-Paus S, Paus R (2020) Hair follicle immune privilege and its collapse in alopecia areata. Exp Dermatol 29(8):703–725
Freyschmidt-Paul P, McElwee KJ, Hoffmann R, Sundberg JP, Vitacolonna M, Kissling S et al (2006) Interferon-γ-deficient mice are resistant to the development of Alopecia Areata. Br J Dermatol 155(3):515–521
Gautam RK, Singh Y, Gupta A, Arora P, Khurana A, Chitkara A (2020) The profile of cytokines (IL-2, IFN-γ, IL-4, IL-10, IL-17A, and IL-23) in active Alopecia Areata. J Cosmet Dermatol 19(1):234–240
Lee GR (2018) The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci. ;19(3)
Han YM, Sheng YY, Xu F, Qi SS, Liu XJ, Hu RM et al (2015) Imbalance of T-helper 17 and regulatory T cells in patients with Alopecia Areata. J Dermatol 42(10):981–988
Speiser JJ, Mondo D, Mehta V, Marcial SA, Kini A, Hutchens KA et al Regulatory T-cells in Alopecia Areata
Tembhre MK, Sharma VK (2013) T-helper and regulatory T-cell cytokines in the peripheral blood of patients with active Alopecia Areata. Br J Dermatol 169(3):543–548
El-Refaey A, El-Habak D, Khashaba R, Fawzy R (2021) Serum levels of transforming growth factor Beta1 (TGF β1) in patients with Alopecia Areata. Benha Med J 0(0):0–0
Wojciechowska-Zdrojowy M, Jankowska-Konsur A, Nowicka-Suszko D, Szepietowski JC, Hryncewicz-Gwóźdź A (2021) Comparison of serum concentrations of interleukins 10, 12, 17 and 35 between patients with alopecia areata and controls. Postep Dermatologii i Alergol 38(6):1052–1057
Kavak A, Yeşildal N, Parlak AH, Gökdemir G, Aydoğan I, Anul H et al (2008) Alopecia Areata in Turkey: demographic and clinical features. J Eur Acad Dermatol Venereol 22(8):977–981
Aoki CA, Borchers AT, Li M, Flavell RA, Bowlus CL, Ansari AA et al (2005) Transforming growth factor β (TGF-β) and autoimmunity. Autoimmun Rev 4(7):450–459
Manolova I, Gerenova J, Ivanova M (2013) Serum levels of transforming growth factor-β1 (TGF-β1) in patients with systemic lupus erythematosus and Hashimoto’s thyroiditis. Eur Cytokine Netw 24(1):69–74
Tu CX, ** WW, Lin M, Wang ZH, Man MQ (2011) Levels of TGF-β 1 in serum and culture supernatants of CD4 + CD25 + T cells from patients with non-segmental vitiligo. Arch Dermatol Res 303(9):685–689
Zhou L, Shi Y-L, Li K, Hamzavi I, Gao T-W, Huggins RH et al (2015) Increased circulating Th17 cells and elevated serum levels of TGF-beta and IL-21 are correlated with human non-segmental vitiligo development. Pigment Cell Melanoma Res 28(3):324–329
Paus R, Ito N, Takigawa M, Ito T (2003) The hair follicle and immune privilege. J Investig Dermatology Symp Proc 8(2):188–194
Loh S-H, Moon H-N, Lew B-L, Sim W-Y (2018) Role of T helper 17 cells and T regulatory cells in Alopecia Areata: comparison of lesion and serum cytokine between controls and patients. J Eur Acad Dermatol Venereol 32(6):1028–1033
Manimaran RP, Ramassamy S, Rajappa M, Chandrashekar L (2022) Therapeutic outcome of diphencyprone and its correlation with serum cytokine profile in Alopecia Areata. J Dermatolog Treat 33(1):324–328
Lan Q, Fan H, Quesniaux V, Ryffel B, Liu Z, Zheng SG (2012) Induced Foxp3(+) regulatory T cells: a potential new weapon to treat autoimmune and inflammatory diseases? J Mol Cell Biol 4(1):22–28
Hasegawa H, Mizoguchi I, Chiba Y, Ohashi M, Xu M, Yoshimoto T (2016) Expanding diversity in molecular structures and functions of the IL-6/IL-12 heterodimeric cytokine family. Front Immunol 7(NOV):1–10
Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J et al (2010) IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol [Internet]. ;11(12):1093–101. https://doi.org/10.1038/ni.1952
Choi J, Leung PSC, Bowlus C, Gershwin ME (2015) IL-35 and autoimmunity: a comprehensive perspective. Clin Rev Allergy Immunol 49(3):327–332
Guan SY, Leng RX, Khan MI, Qureshi H, Li XP, Ye DQ et al (2017) Interleukin-35: a Potential Therapeutic Agent for Autoimmune Diseases. Inflammation [Internet]. ;40(1):303–10. https://doi.org/10.1007/s10753-016-0453-9
Wang R-X, Yu C-R, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV et al (2014) Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med 20(6):633–641
Shams R, Ali EM (2017) IL-35- and IL-10-Dependent immunoregulatory lymphocytes in rheumatoid arthritis. Sci J Immunol Immunother [Internet] 2(1):11–017 Available from: www.scireslit.com
Espes D, Singh K, Sandler S, Carlsson P-O (2017) Increased Interleukin-35 levels in patients with type 1 diabetes with remaining C-Peptide. Diabetes Care 40(8):1090–1095
Saeed M-H, Kurosh K, Zahra A, Hossein DM, Davood R, Ataollahi MR (2021) Decreased serum levels of IL-27and IL-35 in patients with Graves disease. Arch Endocrinol Metab 64(5):521–527
Shuai M, Ni Y, Jian X, He S, Zhang J-A (2019) The level of IL-35 in the circulation of patients with Graves’ disease. Endokrynol Pol 70(4):318–322
Fonseca-Camarillo G, Furuzawa-Carballeda J, Yamamoto-Furusho JK (2015) Interleukin 35 (IL-35) and IL-37: Intestinal and peripheral expression by T and B regulatory cells in patients with Inflammatory Bowel Disease. Cytokine [Internet]. ;75(2):389–402. https://doi.org/10.1016/j.cyto.2015.04.009
Zhu J-J, Shan N-N (2020) Immunomodulatory cytokine interleukin-35 and immune thrombocytopaenia. J Int Med Res 48(12):300060520976477
Yu C-R, Yadav MK, Kang M, Jittayasothorn Y, Dong L, Egwuagu CE (2022) Photoreceptor cells Constitutively Express IL-35 and promote ocular Immune Privilege. Int J Mol Sci. ;23(15)
Terayama H, Yoshimoto T, Hirai S, Naito M, Qu N, Hatayama N et al (2014) Contribution of IL-12/IL-35 common subunit p35 to maintaining the testicular immune privilege. PLoS ONE 9(4):e96120
Zhao Z, Chen X, Hao S, Jia R, Wang N, Chen S et al (2017) Increased interleukin-35 expression in tumor-infiltrating lymphocytes correlates with poor prognosis in patients with breast cancer. Cytokine [Internet]. ;89:76–81. https://doi.org/10.1016/j.cyto.2016.09.012
Cai Z, Wong CK, Dong J, Chu M, Jiao D, Kam NW et al (2015) Remission of systemic lupus erythematosus disease activity with regulatory cytokine interleukin (IL)-35 in Murphy Roths large (MRL)/lpr mice. Clin Exp Immunol 181(2):253–266
Funding
Not applicable.
Author information
Authors and Affiliations
Contributions
T.Y. collected the participants data, T.Y and M.G. wrote the main manuscript text and prepared the figures, S.P.K took part in statistical analysis and contributed the discussion section of the manuscript, E.B.G and S.I.H performed the biochemical tests. All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Ethical approval
Informed consent form was taken from all of the participants.
Consent for publication
This paper submitted with consent and knowledge of all co-authors.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Yuksek, T., Gonul, M., Kartal, S.P. et al. Elucidating the role of T-Reg related cytokines: serum transforming growth factor beta and interleukin-35 in alopecia areata. Arch Dermatol Res 316, 205 (2024). https://doi.org/10.1007/s00403-024-02901-9
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00403-024-02901-9