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Th Pathways in Immune-Mediated Skin Disorders: A Guide for Strategic Treatment Decisions

  • Received : 2024.04.11
  • Accepted : 2024.06.19
  • Published : 2024.10.31
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Abstract

In recent years, there have been significant breakthroughs in the identification of immunological components of skin diseases and in the development of immunomodulatory drugs. Novel therapies create exciting prospects for personalized care. This article provides an overview of the role played by Th1, Th2, Th17, and follicular Th pathways in the most common skin diseases. Additionally, it elucidates the impact of current and upcoming treatments on each of these signaling cascades. Skin diseases predominantly influenced by a single dominant Th pathway such as psoriasis and atopic dermatitis are well-suited for biologics. However, in many other disorders a complex interplay between different immune pathways exists. This can lead to inconsistent efficacy of biologics based on individual patient profiles. In case of activation of several Th pathways, it may be more suitable to consider conventional therapies or JAK inhibitors. Increasing immunological insights have transitioned from laboratory research to practical applications, a trend that is expected to continue growing in the future.

Keywords

References

  1. Pawlak M, Ho AW, Kuchroo VK. Cytokines and transcription factors in the differentiation of CD4+ T helper cell subsets and induction of tissue inflammation and autoimmunity. Curr Opin Immunol 2020;67:57-67. 
  2. Ho AW, Kupper TS. T cells and the skin: from protective immunity to inflammatory skin disorders. Nat Rev Immunol 2019;19:490-502.
  3. Kortekaas Krohn I, Aerts JL, Breckpot K, Goyvaerts C, Knol E, Van Wijk F, Gutermuth J. T-cell subsets in the skin and their role in inflammatory skin disorders. Allergy 2022;77:827-842.
  4. Harris JE, Harris TH, Weninger W, Wherry EJ, Hunter CA, Turka LA. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-γ for autoreactive CD8+ T-cell accumulation in the skin. J Invest Dermatol 2012;132:1869-1876.
  5. Freyschmidt-Paul P, McElwee KJ, Hoffmann R, Sundberg JP, Vitacolonna M, Kissling S, Zoller M. Interferon-gamma-deficient mice are resistant to the development of alopecia areata. Br J Dermatol 2006;155:515-521.
  6. Bradley LM, Dalton DK, Croft M. A direct role for IFN-gamma in regulation of Th1 cell development. J Immunol 1996;157:1350-1358.
  7. Kang S, Brown HM, Hwang S. Direct antiviral mechanisms of interferon-gamma. Immune Netw 2018;18:e33.
  8. Sareneva T, Julkunen I, Matikainen S. IFN-alpha and IL-12 induce IL-18 receptor gene expression in human NK and T cells. J Immunol 2000;165:1933-1938.
  9. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 2006;6:595-601.
  10. Kalia V, Sarkar S. Regulation of effector and memory CD8 T cell differentiation by IL-2-A balancing act. Front Immunol 2018;9:2987.
  11. Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res 2015;3:219-227.
  12. Finkelman FD, Urban JF Jr. The other side of the coin: the protective role of the TH2 cytokines. J Allergy Clin Immunol 2001;107:772-780.
  13. Howell MD, Kim BE, Boguniewicz M, Leung DYM. Modulation of filaggrin by Th2 cytokines in the skin of atopic dermatitis (AD). J Allergy Clin Immunol 2007;119:S283.
  14. Tazawa T, Sugiura H, Sugiura Y, Uehara M. Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis. Arch Dermatol Res 2004;295:459-464.
  15. Zhu J. T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. Cytokine 2015;75:14-24.
  16. Punnonen J, Aversa G, Cocks BG, McKenzie AN, Menon S, Zurawski G, de Waal Malefyt R, de Vries JE. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci U S A 1993;90:3730-3734.
  17. Gieseck RL 3rd, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol 2018;18:62-76.
  18. Speeckaert R, Lambert J, Grine L, Van Gele M, De Schepper S, van Geel N. The many faces of interleukin-17 in inflammatory skin diseases. Br J Dermatol 2016;175:892-901.
  19. Amatya N, Garg AV, Gaffen SL. IL-17 signaling: the yin and the yang. Trends Immunol 2017;38:310-322. 
  20. Nies JF, Panzer U. IL-17C/IL-17RE: emergence of a unique axis in TH17 biology. Front Immunol 2020;11:341. 
  21. Ge Y, Huang M, Yao YM. Biology of interleukin-17 and its pathophysiological significance in sepsis. Front Immunol 2020;11:1558.
  22. Huangfu L, Li R, Huang Y, Wang S. The IL-17 family in diseases: from bench to bedside. Signal Transduct Target Ther 2023;8:402.
  23. Borowczyk J, Buerger C, Tadjrischi N, Drukala J, Wolnicki M, Wnuk D, Modarressi A, Boehncke WH, Brembilla NC. IL-17E (IL-25) and IL-17A differentially affect the functions of human keratinocytes. J Invest Dermatol 2020;140:1379-1389.e2.
  24. Stritesky GL, Yeh N, Kaplan MH. IL-23 promotes maintenance but not commitment to the Th17 lineage. J Immunol 2008;181:5948-5955.
  25. Tollenaere MA, Hebsgaard J, Ewald DA, Lovato P, Garcet S, Li X, Pilger SD, Tiirikainen ML, Bertelsen M, Krueger JG, et al. Signalling of multiple interleukin (IL)-17 family cytokines via IL-17 receptor A drives psoriasis-related inflammatory pathways. Br J Dermatol 2021;185:585-594.
  26. Lauffer F, Jargosch M, Baghin V, Krause L, Kempf W, Absmaier-Kijak M, Morelli M, Madonna S, Marsais F, Lepescheux L, et al. IL-17C amplifies epithelial inflammation in human psoriasis and atopic eczema. J Eur Acad Dermatol Venereol 2020;34:800-809.
  27. Borowczyk J, Shutova M, Brembilla NC, Boehncke WH. IL-25 (IL-17E) in epithelial immunology and pathophysiology. J Allergy Clin Immunol 2021;148:40-52.
  28. Walker LS. The link between circulating follicular helper T cells and autoimmunity. Nat Rev Immunol 2022;22:567-575.
  29. Ma CS, Deenick EK, Batten M, Tangye SG. The origins, function, and regulation of T follicular helper cells. J Exp Med 2012;209:1241-1253.
  30. Speeckaert R, Belpaire A, Speeckaert MM, van Geel N. A meta-analysis of chemokines in vitiligo: recruiting immune cells towards melanocytes. Front Immunol 2023;14:1112811.
  31. Zainodini N, Hassanshahi G, Arababadi MK, Khorramdelazad H, Mirzaei A. Differential expression of CXCL1, CXCL9, CXCL10 and CXCL12 chemokines in alopecia areata. Iran J Immunol 2013;10:40-46.
  32. Hsueh YC, Wang Y, Riding RL, Catalano DE, Lu YJ, Richmond JM, Siegel DL, Rusckowski M, Stanley JR, Harris JE. A keratinocyte-tethered biologic enables location-precise treatment in mouse vitiligo. J Invest Dermatol 2022;142:3294-3303.
  33. Valsecchi R, Imberti G, Martino D, Cainelli T. Alopecia areata and interleukin-2 receptor. Dermatology 1992;184:126-128.
  34. Speeckaert R, Lambert J, van Geel N. Clinical significance of serum soluble CD molecules to assess disease activity in vitiligo. JAMA Dermatol 2016;152:1194-1200.
  35. Montilla AM, Gomez-Garcia F, Gomez-Arias PJ, Gay-Mimbrera J, Hernandez-Parada J, Isla-Tejera B, Ruano J. Scoping review on the use of drugs targeting JAK/STAT pathway in atopic dermatitis, vitiligo, and alopecia areata. Dermatol Ther (Heidelb) 2019;9:655-683.
  36. Speeckaert R, Speeckaert M, De Schepper S, van Geel N. Biomarkers of disease activity in vitiligo: a systematic review. Autoimmun Rev 2017;16:937-945.
  37. Passeron T, King B, Seneschal J, Steinhoff M, Jabbari A, Ohyama M, Tobin DJ, Randhawa S, Winkler A, Telliez JB, et al. Inhibition of T-cell activity in alopecia areata: recent developments and new directions. Front Immunol 2023;14:1243556.
  38. Lauffer F, Jargosch M, Krause L, Garzorz-Stark N, Franz R, Roenneberg S, Bohner A, Mueller NS, Theis FJ, Schmidt-Weber CB, et al. Type I immune response induces keratinocyte necroptosis and is associated with interface dermatitis. J Invest Dermatol 2018;138:1785-1794.
  39. Solimani F, Pollmann R, Schmidt T, Schmidt A, Zheng X, Savai R, Muhlenbein S, Pickert J, Eubel V, Mobs C, et al. Therapeutic targeting of Th17/Tc17 cells leads to clinical improvement of lichen planus. Front Immunol 2019;10:1808.
  40. Pietschke K, Holstein J, Meier K, Schafer I, Muller-Hermelink E, Gonzalez-Menendez I, Quintanilla-Martinez L, Ghoreschi FC, Solimani F, Ghoreschi K. The inflammation in cutaneous lichen planus is dominated by IFN-ϒ and IL-21-A basis for therapeutic JAK1 inhibition. Exp Dermatol 2021;30:262-270. 
  41. Tan YQ, Li Q, Zhang J, Du GF, Lu R, Zhou G. Increased circulating CXCR5+ CD4+ T follicular helper-like cells in oral lichen planus. J Oral Pathol Med 2017;46:803-809.
  42. Wang H, Jiang Y, Wang H, Luo Z, Wang Y, Guan X. IL-25 promotes Th2-type reactions and correlates with disease severity in the pathogenesis of oral lichen planus. Arch Oral Biol 2019;98:115-121.
  43. Terlou A, Santegoets LAM, van der Meijden WI, Heijmans-Antonissen C, Swagemakers SMA, van der Spek PJ, Ewing PC, van Beurden M, Helmerhorst TJ, Blok LJ. An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155. J Invest Dermatol 2012;132:658-666.
  44. Wang L, Lv Q, Guo J, Wang J, Pan J. Transcriptome profiling and network analysis provide insights into the pathogenesis of vulvar lichen sclerosus. Front Genet 2022;13:905450.
  45. Peterson DM, Damsky WE, Vesely MD. Treatment of lichen sclerosus and hypertrophic scars with dupilumab. JAAD Case Rep 2022;23:76-78.
  46. Muhammad Yusoff F, Wong KK, Mohd Redzwan N. Th1, Th2, and Th17 cytokines in systemic lupus erythematosus. Autoimmunity 2020;53:8-20.
  47. Nakayamada S, Tanaka Y. Clinical relevance of T follicular helper cells in systemic lupus erythematosus. Expert Rev Clin Immunol 2021;17:1143-1150.
  48. Bitar C, Maghfour J, Ho-Pham H, Stumpf B, Boh E. Apremilast as a potential treatment for moderate to severe dermatomyositis: a retrospective study of 3 patients. JAAD Case Rep 2019;5:191-194.
  49. Shimojima Y, Ishii W, Matsuda M, Ikeda S. Phenotypes of peripheral blood lymphocytes and cytokine expression in polymyositis and dermatomyositis before treatment and after clinical remission. Clin Med Insights Arthritis Musculoskelet Disord 2012;5:77-87.
  50. Broos CE, Koth LL, van Nimwegen M, In 't Veen JC, Paulissen SM, van Hamburg JP, Annema JT, Heller-Baan R, Kleinjan A, Hoogsteden HC, et al. Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes. Eur Respir J 2018;51:1701124.
  51. Bordignon M, Rottoli P, Agostini C, Alaibac M. Adaptive immune responses in primary cutaneous sarcoidosis. Clin Dev Immunol 2011;2011:235142.
  52. Zhou ER, Arce S. Key players and biomarkers of the adaptive immune system in the pathogenesis of sarcoidosis. Int J Mol Sci 2020;21:7398.
  53. Antiga E, Maglie R, Volpi W, Bianchi B, Berti E, Marzano AV, Caproni M. T helper type 1-related molecules as well as interleukin-15 are hyperexpressed in the skin lesions of patients with pyoderma gangrenosum. Clin Exp Immunol 2017;189:383-391.
  54. Flora A, Kozera E, Frew JW. Pyoderma gangrenosum: a systematic review of the molecular characteristics of disease. Exp Dermatol 2022;31:498-515.
  55. Min MS, Wu J, He H, Sanz-Cabanillas JL, Del Duca E, Zhang N, Renert-Yuval Y, Pavel AB, Lebwohl M, Guttman-Yassky E. Granuloma annulare skin profile shows activation of T-helper cell type 1, T-helper cell type 2, and Janus kinase pathways. J Am Acad Dermatol 2020;83:63-70.
  56. Paganini C, Talamonti M, Campione E, Bianchi L, Galluzzo M. Letter in response to the case report: "recalcitrant generalized granuloma annulare treated successfully with dupilumab". JAAD Case Rep 2023;39:152-154.
  57. Orfali RL, Aoki V. Blockage of the IL-31 pathway as a potential target therapy for atopic dermatitis. Pharmaceutics 2023;15:577.
  58. Li H, Zhang Z, Zhang H, Guo Y, Yao Z. Update on the pathogenesis and therapy of atopic dermatitis. Clin Rev Allergy Immunol 2021;61:324-338.
  59. Noda S, Suarez-Farinas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, Peng X, Estrada YD, Nakajima S, Honda T, et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol 2015;136:1254-1264.
  60. Leonard A, Guttman-Yassky E. The unique molecular signatures of contact dermatitis and implications for treatment. Clin Rev Allergy Immunol 2019;56:1-8.
  61. Nosbaum A, Vocanson M, Rozieres A, Hennino A, Nicolas JF. Allergic and irritant contact dermatitis. Eur J Dermatol 2009;19:325-332.
  62. Chen Q, Zhong H, Chen WC, Zhai Z, Zhou Z, Song Z, Hao F. Different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines correlate with serum autoreactivity and allergen sensitivity in chronic spontaneous urticaria. J Eur Acad Dermatol Venereol 2018;32:441-448.
  63. LaChance AH, Goldman N, Kassamali B, Vleugels RA. Immunologic underpinnings and treatment of morphea. Expert Rev Clin Immunol 2022;18:461-483.
  64. Shao Y, Wang D, Zhu Y, Xiao Z, Jin T, Peng L, Shen Y, Tang H. Molecular mechanisms of pruritus in prurigo nodularis. Front Immunol 2023;14:1301817.
  65. Park K, Mori T, Nakamura M, Tokura Y. Increased expression of mRNAs for IL-4, IL-17, IL-22 and IL-31 in skin lesions of subacute and chronic forms of prurigo. Eur J Dermatol 2011;21:135-136.
  66. Belzberg M, Alphonse MP, Brown I, Williams KA, Khanna R, Ho B, Wongvibulsin S, Pritchard T, Roh YS, Sutaria N, et al. Prurigo nodularis is characterized by systemic and cutaneous T helper 22 immune polarization. J Invest Dermatol 2021;141:2208-2218.e14.
  67. Bachelez H. Interleukin 23 inhibitors for psoriasis: not just another number. Lancet 2017;390:208-210. 
  68. Hu P, Wang M, Gao H, Zheng A, Li J, Mu D, Tong J. The role of helper T cells in psoriasis. Front Immunol 2021;12:788940.
  69. Gu H, Zhang Y, Zeng W, Xia Y. Participation of interferons in psoriatic inflammation. Cytokine Growth Factor Rev 2022;64:12-20.
  70. Qu Y, Li D, Xiong H, Shi D. Transcriptional regulation on effector T cells in the pathogenesis of psoriasis. Eur J Med Res 2023;28:182.
  71. Kelhala HL, Palatsi R, Fyhrquist N, Lehtimaki S, Vayrynen JP, Kallioinen M, Kubin ME, Greco D, Tasanen K, Alenius H, et al. IL-17/Th17 pathway is activated in acne lesions. PLoS One 2014;9:e105238.
  72. Kistowska M, Meier B, Proust T, Feldmeyer L, Cozzio A, Kuendig T, Contassot E, French LE. Propionibacterium acnes promotes Th17 and Th17/Th1 responses in acne patients. J Invest Dermatol 2015;135:110-118.
  73. Buhl T, Sulk M, Nowak P, Buddenkotte J, McDonald I, Aubert J, Carlavan I, Deret S, Reiniche P, Rivier M, et al. Molecular and morphological characterization of inflammatory infiltrate in rosacea reveals activation of Th1/Th17 pathways. J Invest Dermatol 2015;135:2198-2208.
  74. Heibel HD, Hendricks AJ, Foshee JP, Shi VY. Rosacea associated with dupilumab therapy. J Dermatolog Treat 2021;32:114-116.
  75. Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, Shi X, Wang G. Follicular helper T cells (Tfh) and IL-21 involvement in the pathogenesis of bullous pemphigoid. PLoS One 2013;8:e68145.
  76. Huang R, Hu L, Jiang F. Study of cytokine-induced immunity in bullous pemphigoid: recent developments. Ann Med 2023;55:2280991.
  77. Plee J, Le Jan S, Giustiniani J, Barbe C, Joly P, Bedane C, Vabres P, Truchetet F, Aubin F, Antonicelli F, et al. Integrating longitudinal serum IL-17 and IL-23 follow-up, along with autoantibodies variation, contributes to predict bullous pemphigoid outcome. Sci Rep 2015;5:18001.
  78. Hennerici T, Pollmann R, Schmidt T, Seipelt M, Tackenberg B, Mobs C, Ghoreschi K, Hertl M, Eming R. Increased frequency of t follicular helper cells and elevated interleukin-27 plasma levels in patients with pemphigus. PLoS One 2016;11:e0148919.
  79. Zou Y, Yuan H, Zhou S, Zhou Y, Zheng J, Zhu H, Pan M. The pathogenic role of CD4+ tissue-resident memory T cells bearing t follicular helper-like phenotype in pemphigus lesions. J Invest Dermatol 2021;141:2141-2150.
  80. Holstein J, Solimani F, Baum C, Meier K, Pollmann R, Didona D, Tekath T, Dugas M, Casadei N, Hudemann C, et al. Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production. J Allergy Clin Immunol 2021;147:2358-2369. 
  81. Kim AR, Han D, Choi JY, Seok J, Kim SE, Seo SH, Takahashi H, Amagai M, Park SH, Kim SC, et al. Targeting inducible costimulator expressed on CXCR5+ PD-1+ TH cells suppresses the progression of pemphigus vulgaris. J Allergy Clin Immunol 2020;146:1070-1079.e8.
  82. Zhao Y, Lutalo PMK, Thomas JE, Sangle S, Choong LM, Tyler JR, Tree T, Spencer J, D'Cruz DP. Circulating T follicular helper cell and regulatory T cell frequencies are influenced by B cell depletion in patients with granulomatosis with polyangiitis. Rheumatology (Oxford) 2014;53:621-630.
  83. Gensous N, Charrier M, Duluc D, Contin-Bordes C, Truchetet ME, Lazaro E, Duffau P, Blanco P, Richez C. T follicular helper cells in autoimmune disorders. Front Immunol 2018;9:1637.
  84. Sanders JSF, Stegeman CA, Kallenberg CGM. The Th1 and Th2 paradigm in ANCA-associated vasculitis. Kidney Blood Press Res 2003;26:215-220.
  85. Liberman AC, Budzinski ML, Sokn C, Gobbini RP, Steininger A, Arzt E. Regulatory and mechanistic actions of glucocorticoids on T and inflammatory cells. Front Endocrinol (Lausanne) 2018;9:235.
  86. van Geel N, Speeckaert R, Mollet I, De Schepper S, De Wolf J, Tjin EPM, Luiten RM, Lambert J, Brochez L. In vivo vitiligo induction and therapy model: double-blind, randomized clinical trial. Pigment Cell Melanoma Res 2012;25:57-65.
  87. Flores C, Fouquet G, Moura IC, Maciel TT, Hermine O. Lessons to learn from low-dose cyclosporin-a: a new approach for unexpected clinical applications. Front Immunol 2019;10:588.
  88. Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP. Methotrexate is a JAK/STAT pathway inhibitor. PLoS One 2015;10:e0130078.
  89. Gerards AH, de Lathouder S, de Groot ER, Dijkmans BAC, Aarden LA. Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis. Rheumatology (Oxford) 2003;42:1189-1196.
  90. Karnell JL, Karnell FG 3rd, Stephens GL, Rajan B, Morehouse C, Li Y, Swerdlow B, Wilson M, Goldbach-Mansky R, Groves C, et al. Mycophenolic acid differentially impacts B cell function depending on the stage of differentiation. J Immunol 2011;187:3603-3612.
  91. Heidt S, Roelen DL, Eijsink C, Eikmans M, van Kooten C, Claas FHJ, Mulder A. Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clin Exp Immunol 2010;159:199-207. 
  92. Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, Lehr HA, Wirtz S, Becker C, Atreya R, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003;111:1133-1145.
  93. Sulaimani J, Cluxton D, Clowry J, Petrasca A, Molloy OE, Moran B, Sweeney CM, Malara A, McNicholas N, McGuigan C, et al. Dimethyl fumarate modulates the Treg-Th17 cell axis in patients with psoriasis. Br J Dermatol 2021;184:495-503.
  94. Holm Hansen R, Hojsgaard Chow H, Sellebjerg F, Rode von Essen M. Dimethyl fumarate therapy suppresses B cell responses and follicular helper T cells in relapsing-remitting multiple sclerosis. Mult Scler 2019;25:1289-1297.
  95. In 't Veld AE, Grievink HW, van der Plas JL, Eveleens Maarse BC, van Kraaij SJW, Woutman TD, Schoonakker M, Klarenbeek NB, de Kam ML, Kamerling IM, et al. Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study. Immunol Res 2023;71:617-627.
  96. Han J, Zhou Q, Li X, He J, Han Y, Jie H, He Y, Sun E. Novel function of hydroxychloroquine: down regulation of T follicular helper cells in collagen-induced arthritis. Biomed Pharmacother 2018;97:838-843. 
  97. Espinosa E, Valitutti S, Laroche M, Laurent C, Apoil PA, Hermine O, Lavit M, Paul C, Bulai Livideanu C. Hydroxychloroquine as a novel therapeutic approach in mast cell activation diseases. Clin Immunol 2018;194:75-79.
  98. Gao W, Wang Z, Li W, Li Y, Liu M. Biomarkers and biologics related with psoriasis and psoriatic arthritis. Int Immunopharmacol 2023;122:110646.
  99. Calabrese L, Malvaso D, Coscarella G, Antonelli F, D'Amore A, Gori N, Rubegni P, Peris K, Chiricozzi A. Therapeutic potential of IL-1 antagonism in hidradenitis suppurativa. Biomolecules 2024;14:175.
  100. Yahyazadeh S, Esmaeil N, Shaygannejad V, Mirmosayyeb O. Comparison of follicular T helper cells, monocytes, and T cells priming between newly diagnosed and rituximab-treated MS patients and healthy controls. Res Pharm Sci 2022;17:315-323.
  101. Kubo M. T follicular helper and TH2 cells in allergic responses. Allergol Int 2017;66:377-381.
  102. Nebert DW. Aryl hydrocarbon receptor (AHR): "pioneer member" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of "sensors" of foreign and endogenous signals. Prog Lipid Res 2017;67:38-57. 
  103. Esser C, Rannug A. The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol Rev 2015;67:259-279.
  104. Quintana FJ, Sherr DH. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 2013;65:1148-1161.
  105. Desai SR, Stein Gold L, Cameron MC, Golant A, Lewitt GM, Bruno MJ, Martin G, Brown PM, Rubenstein DS, Butners V, et al. Tapinarof cream 1% once daily for the treatment of plaque psoriasis: case photography of clinical outcomes from three phase 3 trials. Dermatol Ther (Heidelb) 2023;13:2443-2460. 
  106. Fernandez-Gallego N, Sanchez-Madrid F, Cibrian D. Role of AHR ligands in skin homeostasis and cutaneous inflammation. Cells 2021;10:3176.
  107. Napolitano M, Fabbrocini G, Martora F, Picone V, Morelli P, Patruno C. Role of aryl hydrocarbon receptor activation in inflammatory chronic skin diseases. Cells 2021;10:3559.
  108. Laouini D, Elkhal A, Yalcindag A, Kawamoto S, Oettgen H, Geha RS. COX-2 inhibition enhances the TH2 immune response to epicutaneous sensitization. J Allergy Clin Immunol 2005;116:390-396.
  109. Hirata T, Narumiya S. Prostanoids as regulators of innate and adaptive immunity. Adv Immunol 2012;116:143-174.
  110. Dec M, Arasiewicz H. Aryl hydrocarbon receptor role in chronic inflammatory skin diseases: a narrative review. Postepy Dermatol Alergol 2024;41:9-19.
  111. Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, McKenzie BS, Kastelein RA, Cua DJ, de Waal Malefyt R. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med 2009;206:535-548.
  112. Silverberg JI, French LE, Warren RB, Strober B, Kjoller K, Sommer MO, Andres P, Felding J, Weiss A, Tutkunkardas D, et al. Pharmacology of orismilast, a potent and selective PDE4 inhibitor. J Eur Acad Dermatol Venereol 2023;37:721-729.
  113. Schafer PH, Adams M, Horan G, Truzzi F, Marconi A, Pincelli C. Apremilast normalizes gene expression of inflammatory mediators in human keratinocytes and reduces antigen-induced atopic dermatitis in mice. Drugs R D 2019;19:329-338.
  114. Bianchi L, Del Duca E, Romanelli M, Saraceno R, Chimenti S, Chiricozzi A. Pharmacodynamic assessment of apremilast for the treatment of moderate-to-severe plaque psoriasis. Expert Opin Drug Metab Toxicol 2016;12:1121-1128.
  115. Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, Bartlett JB, Loveland MA, Gilhar A, Cheung YF, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol 2010;159:842-855.
  116. Carmona-Rocha E, Rusinol L, Puig L. New and emerging oral/topical small-molecule treatments for psoriasis. Pharmaceutics 2024;16:239.
  117. McLornan DP, Pope JE, Gotlib J, Harrison CN. Current and future status of JAK inhibitors. Lancet 2021;398:803-816.
  118. Tanaka Y, Luo Y, O'Shea JJ, Nakayamada S. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol 2022;18:133-145.
  119. Martin DA, Telliez JB, Pleasic-Williams S, Zhang Y, Tierney B, Blatnik M, Gale JD, Banfield C, Zhou Y, Lejeune A, et al. Target occupancy and functional inhibition of JAK3 and TEC family kinases by ritlecitinib in healthy adults: an open-label, phase 1 study. J Clin Pharmacol 2024;64:67-79.
  120. A phase 2 multicenter, randomized, double-blind placebo-controlled study to evaluate the safety and efficacy of lutikizumab (ABT-981) in adult subjects with moderate to severe hidradenitis suppurativa who have failed anti-TNF therapy: amended protocol to include a lutikizumab open-label sub-study in subjects naive to biologic therapy [Internet]. Available at https://clinicaltrials.gov/study/NCT05139602 [accessed on 22 March 2024].
  121. Fleischmann RM, Bliddal H, Blanco FJ, Schnitzer TJ, Peterfy C, Chen S, Wang L, Feng S, Conaghan PG, Berenbaum F, et al. A phase II trial of lutikizumab, an anti-interleukin-1α/β dual variable domain immunoglobulin, in knee osteoarthritis patients with synovitis. Arthritis Rheumatol 2019;71:1056-1069. 
  122. Teufel LU, Arts RJW, Netea MG, Dinarello CA, Joosten LA. IL-1 family cytokines as drivers and inhibitors of trained immunity. Cytokine 2022;150:155773.
  123. Tuttle J, Drescher E, Simon-Campos JA, Emery P, Greenwald M, Kivitz A, Rha H, Yachi P, Kiley C, Nirula A. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. N Engl J Med 2023;388:1853-1862. 
  124. Scully M, Moulton VR, Clarke S, Ota T, Chen D, Liva S, Cunningham M, Ghorayeb E, Yang D, Macleod A, et al., editors. Efficacy, safety, and tolerability of JNJ-67484703 in adult patients with moderate to severe atopic dermatitis: design of a phase 2a study. 32nd EADV Congress 2023; 2023 Oct 10-14; Berlin, Germany. Lugano, Switzerland: EADV; 2023.
  125. Gilfillan AM, Rivera J. The tyrosine kinase network regulating mast cell activation. Immunol Rev 2009;228:149-169.
  126. Aoki Y, Isselbacher KJ, Pillai S. Bruton tyrosine kinase is tyrosine phosphorylated and activated in pre-B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci USA 1994;91:10606-10609.
  127. Neys SFH, Hendriks RW, Corneth OBJ. Targeting Bruton's tyrosine kinase in inflammatory and autoimmune pathologies. Front Cell Dev Biol 2021;9:668131.
  128. Ellmeier W, Abramova A, Schebesta A. Tec family kinases: regulation of FcεRI-mediated mast-cell activation. FEBS J 2011;278:1990-2000.
  129. Xing Y, Chu KA, Wadhwa J, Chen W, Zhu J, Bradshaw JM, Shu J, Foulke MC, Loewenstein N, Nunn P, et al. Preclinical mechanisms of topical PRN473, a Bruton tyrosine kinase inhibitor, in immune-mediated skin disease models. Immunohorizons 2021;5:581-589.
  130. Mendes-Bastos P, Brasileiro A, Kolkhir P, Frischbutter S, Scheffel J, Monino-Romero S, Maurer M. Bruton's tyrosine kinase inhibition-an emerging therapeutic strategy in immune-mediated dermatological conditions. Allergy 2022;77:2355-2366.
  131. Vinuesa CG, Linterman MA, Yu D, MacLennan ICM. Follicular helper T cells. Annu Rev Immunol 2016;34:335-368.
  132. Spolski R, Leonard WJ. Interleukin-21: a double-edged sword with therapeutic potential. Nat Rev Drug Discov 2014;13:379-395.
  133. Caprioli F, Sarra M, Caruso R, Stolfi C, Fina D, Sica G, MacDonald TT, Pallone F, Monteleone G. Autocrine regulation of IL-21 production in human T lymphocytes. J Immunol 2008;180:1800-1807. 
  134. Mesas-Fernandez A, Bodner E, Hilke FJ, Meier K, Ghoreschi K, Solimani F. Interleukin-21 in autoimmune and inflammatory skin diseases. Eur J Immunol 2023;53:e2250075.
  135. Brunner PM, Pavel AB, Khattri S, Leonard A, Malik K, Rose S, Jim On S, Vekaria AS, Traidl-Hoffmann C, Singer GK, et al. Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab. J Allergy Clin Immunol 2019;143:142-154.
  136. Nakashima C, Otsuka A, Kabashima K. Interleukin-31 and interleukin-31 receptor: new therapeutic targets for atopic dermatitis. Exp Dermatol 2018;27:327-331.
  137. Le AM, Torres T. OX40-OX40L inhibition for the treatment of atopic dermatitis-focus on rocatinlimab and amlitelimab. Pharmaceutics 2022;14:2753.
  138. Fu N, Xie F, Sun Z, Wang Q. The OX40/OX40L axis regulates T follicular helper cell differentiation: implications for autoimmune diseases. Front Immunol 2021;12:670637.
  139. Khoryati L, Pham MN, Sherve M, Kumari S, Cook K, Pearson J, Bogdani M, Campbell DJ, Gavin MA. An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice. Sci Immunol 2020;5:eaba5264.
  140. Richmond JM, Strassner JP, Zapata L Jr, Garg M, Riding RL, Refat MA, Fan X, Azzolino V, Tovar-Garza A, Tsurushita N, et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci Transl Med 2018;10:eaam7710.
  141. Zhu LN, Hou HM, Wang S, Zhang S, Wang GG, Guo ZY, Wu J. FcRn inhibitors: a novel option for the treatment of myasthenia gravis. Neural Regen Res 2023;18:1637-1644.
  142. Maho-Vaillant M, Sips M, Golinski ML, Vidarsson G, Goebeler M, Stoevesandt J, Bata-Csorgo Z, Balbino B, Verheesen P, Joly P, et al. FcRn antagonism leads to a decrease of desmoglein-specific B cells: secondary analysis of a phase 2 study of efgartigimod in pemphigus vulgaris and pemphigus foliaceus. Front Immunol 2022;13:863095.
  143. Guttman-Yassky E, Renert-Yuval Y, Bares J, Chima M, Hawkes JE, Gilleaudeau P, Sullivan-Whalen M, Singer GK, Garcet S, Pavel AB, et al. Phase 2a randomized clinical trial of dupilumab (anti-IL-4Rα) for alopecia areata patients. Allergy 2022;77:897-906.
  144. Datsi A, Steinhoff M, Ahmad F, Alam M, Buddenkotte J. Interleukin-31: the "itchy" cytokine in inflammation and therapy. Allergy 2021;76:2982-2997.
  145. Langenberg C, Hingorani AD, Whitty CJM. Biological and functional multimorbidity-from mechanisms to management. Nat Med 2023;29:1649-1657.