{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:17:27Z","timestamp":1791389847948,"version":"4.3.3"},"reference-count":116,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lichen sclerosus (LS) is a chronic inflammatory skin disorder primarily affecting the anogenital region, leading to symptoms such as itching, pain, and sexual dysfunction, all of which significantly impact patients\u2019 quality of life. Due to the non-specific nature of its early symptoms, diagnosis is often delayed. This review examines the cytokine networks involved in LS, with a focus on immune activation, the role of T-helper (Th)1 cells, and the interaction between inflammatory mediators and the extracellular matrix, particularly in fibrosis. By providing an updated understanding of LS immunopathogenesis, this review highlights key mediators involved in disease progression and offers insights into personalized treatment strategies that may improve patient outcomes. Additionally, current therapeutic approaches and future directions in LS management are discussed.<\/jats:p>","DOI":"10.3390\/ijms26094315","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T07:44:58Z","timestamp":1746171898000},"page":"4315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Cytokine Networks in Lichen Sclerosus: A Roadmap for Diagnosis and Treatment?"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0916-7769","authenticated-orcid":false,"given":"Alessia","family":"Paganelli","sequence":"first","affiliation":[{"name":"Dermatology Unit, IDI-IRCCS Istituto Dermopatico dell\u2019Immacolata, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6119-1870","authenticated-orcid":false,"given":"Dario","family":"Didona","sequence":"additional","affiliation":[{"name":"Rare Diseases Unit, IDI-IRCCS Istituto Dermopatico dell\u2019Immacolata, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6848-3262","authenticated-orcid":false,"given":"Emanuele","family":"Scala","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, IDI-IRCCS Istituto Dermopatico dell\u2019Immacolata, 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1097\/JW9.0000000000000131","article-title":"The Impact of Genital Lichen Sclerosus in Men and Women on Quality of Life: A Prospective Cohort Study","volume":"10","author":"Liljeberg","year":"2024","journal-title":"Int. J. Womens Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1111\/jdv.13136","article-title":"Evidence-Based (S3) Guideline on (Anogenital) Lichen Sclerosus","volume":"29","author":"Kirtschig","year":"2015","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s40257-012-0006-4","article-title":"Diagnosis and Treatment of Lichen Sclerosus: An Update","volume":"14","author":"Fistarol","year":"2013","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_4","first-page":"337","article-title":"Lichen Sclerosus-Presentation, Diagnosis and Management","volume":"113","author":"Kirtschig","year":"2016","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-4943(00)00059-5","article-title":"Vulvovaginal Examinations in Elderly Nursing Home Women Residents","volume":"31","author":"Leibovitz","year":"2000","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1111\/1471-0528.16175","article-title":"Incidence of Lichen Sclerosus and Subsequent Causes of Death: A Nationwide Finnish Register Study","volume":"127","author":"Halonen","year":"2020","journal-title":"BJOG"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/00007611-200301000-00004","article-title":"Balanitis Xerotica Obliterans: Epidemiologic Distribution in an Equal Access Health Care System","volume":"96","author":"Kizer","year":"2003","journal-title":"South Med. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1097\/PGP.0b013e3181a9fb0d","article-title":"Diagnosis of Vulval Inflammatory Dermatoses: A Pathological Study with Clinical Correlation","volume":"28","author":"Niamh","year":"2009","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1111\/ajd.14417","article-title":"Evaluating Lichen Sclerosus in Phimosis: Insights From a Multidisciplinary Retrospective Study","volume":"66","author":"Bighetti","year":"2025","journal-title":"Australas. J. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.jaad.2023.06.016","article-title":"Vulvar Lichen Sclerosus and Vitiligo: Overlap and Clinical Features","volume":"89","author":"Esse","year":"2023","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1097\/LGT.0000000000000361","article-title":"Development of the Adult Vulvar Lichen Sclerosus Severity Scale\u2014A Delphi Consensus Exercise for Item Generation","volume":"22","author":"Sheinis","year":"2018","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_12","first-page":"143","article-title":"Clinical Presentations and Complications of Lichen Sclerosus: A Systematic Review","volume":"23","author":"Conte","year":"2025","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1258\/ijsa.2009.009102","article-title":"Psychological and Psychiatric Morbidity in Lichen Sclerosus in a Cohort Recruited from a Genitourinary Medicine Clinic","volume":"21","author":"Shasi","year":"2010","journal-title":"Int. J. STD AIDS"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e042","DOI":"10.1097\/JW9.0000000000000042","article-title":"The Impact of Genital Lichen Sclerosus and Lichen Planus on Quality of Life: A Review","volume":"8","author":"Ranum","year":"2022","journal-title":"Int. J. Womens Dermatol."},{"key":"ref_15","first-page":"e84","article-title":"Lichen Sclerosus and Its Association with Cancer: A Retrospective Cohort Study","volume":"62","author":"Notario","year":"2023","journal-title":"Int. J. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1001\/jamadermatol.2015.0643","article-title":"Long-Term Management of Adult Vulvar Lichen Sclerosus: A Prospective Cohort Study of 507 Women","volume":"151","author":"Lee","year":"2015","journal-title":"JAMA Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"De Luca, D.A., Papara, C., Vorobyev, A., Staiger, H., Bieber, K., Tha\u00e7i, D., and Ludwig, R.J. (2023). Lichen Sclerosus: The 2023 Update. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1106318"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1111\/jdv.20082","article-title":"EuroGuiderm Guideline on Lichen Sclerosus-Introduction into Lichen Sclerosus","volume":"38","author":"Kirtschig","year":"2024","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1016\/j.jaad.2014.07.008","article-title":"Extragenital Lichen Sclerosus: Clinical, Dermoscopic, Confocal Microscopy and Histologic Correlations","volume":"72","author":"Lacarrubba","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1159\/000484947","article-title":"Dermoscopy of Morphea and Cutaneous Lichen Sclerosus: Clinicopathological Correlation Study and Comparative Analysis","volume":"233","author":"Errichetti","year":"2017","journal-title":"Dermatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1159\/000439198","article-title":"Dermoscopic Features of Vulvar Lichen Sclerosus in the Setting of a Prospective Cohort of Patients: New Observations","volume":"232","author":"Borghi","year":"2016","journal-title":"Dermatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1111\/exd.14888","article-title":"Reflectance Confocal Microscopy as a Non-Invasive Imaging Tool in Vulvar High-Grade Squamous Intraepithelial Lesions and Lichen Sclerosus: A Descriptive Morphological Study in Patients and Healthy Volunteers","volume":"32","author":"Huisman","year":"2023","journal-title":"Exp. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e13234","DOI":"10.1111\/srt.13234","article-title":"In Vivo Evaluation of Vulvar Lichen Sclerosus with Reflectance Confocal Microscopy and Therapeutic Monitoring in Children","volume":"29","author":"Chen","year":"2023","journal-title":"Ski. Res. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1016\/S0140-6736(98)08228-2","article-title":"Lichen Sclerosus","volume":"353","author":"Powell","year":"1999","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/j.0022-202X.2005.23905.x","article-title":"The Association between HLA DR, DQ Antigens, and Vulval Lichen Sclerosus in the UK: HLA DRB112 and Its Associated DRB112\/DQB10301\/04\/09\/010 Haplotype Confers Susceptibility to Vulval Lichen Sclerosus, and HLA DRB10301\/04 and Its Associated DRB10301\/04\/DQB10201\/02\/03 Haplotype Protects from Vulval Lichen Sclerosus","volume":"125","author":"Gao","year":"2005","journal-title":"J. Investig. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Corazza, M., Schettini, N., Zedde, P., and Borghi, A. (2021). Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects. Biomedicines, 9.","DOI":"10.3390\/biomedicines9080950"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1111\/j.1468-3083.2010.03572.x","article-title":"The High Rate of Familial Lichen Sclerosus Suggests a Genetic Contribution: An Observational Cohort Study","volume":"24","author":"Sherman","year":"2010","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1111\/j.1610-0387.2006.06087.x","article-title":"HLA Markers in Familial Lichen Sclerosus","volume":"4","author":"Aslanian","year":"2006","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_29","first-page":"586","article-title":"Recovery of Pupillomotor Function after Cataract Surgery","volume":"60","author":"Peters","year":"1989","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1046\/j.1365-2133.1999.02611.x","article-title":"Lichen Sclerosus in Adult Men: A Study of HLA Associations and Susceptibility to Autoimmune Disease","volume":"140","author":"Azurdia","year":"1999","journal-title":"Br. J. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/j.1365-2133.1995.tb05013.x","article-title":"The Association between Lichen Sclerosus and Antigens of the HLA System","volume":"132","author":"Marren","year":"1995","journal-title":"Br. J. Dermatol."},{"key":"ref_32","first-page":"143","article-title":"Skin Phototype and Local Trauma in the Onset of Balanitis Xerotica Obliterans (BXO) in Circumcised Patients","volume":"26","author":"Villa","year":"2012","journal-title":"In Vivo"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3109\/01443615.2011.649320","article-title":"A Population-Based Case-Control Study of Aetiological Factors Associated with Vulval Lichen Sclerosus","volume":"32","author":"Higgins","year":"2012","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s10354-016-0525-3","article-title":"Radiation-Induced Lichen Sclerosus of the Vulva: First Report in the Medical Literature","volume":"167","author":"Edwards","year":"2017","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_35","first-page":"932","article-title":"[Study on the risk factors of 100 cases with vulvar dystrophy]","volume":"24","author":"Tang","year":"2003","journal-title":"Zhonghua Liu Xing Bing Xue Za Zhi"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1001\/archderm.144.5.591","article-title":"Possible Role of Borrelia Burgdorferi Sensu Lato Infection in Lichen Sclerosus","volume":"144","author":"Eisendle","year":"2008","journal-title":"Arch. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1111\/j.1468-3083.2012.04542.x","article-title":"Role of Human Papillomaviruses in Persistent and Glucocorticoid-Resistant Juvenile Phimosis","volume":"27","author":"Pilatz","year":"2013","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/ijd.13933","article-title":"Human Papillomavirus Infection and Lichen Sclerosus: Coincidence or Link?","volume":"57","author":"Nasca","year":"2018","journal-title":"Int. J. Dermatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1111\/aogs.14353","article-title":"The Evidence behind the Use of LASER for Genitourinary Syndrome of Menopause, Vulvovaginal Atrophy, Urinary Incontinence and Lichen Sclerosus: A State-of-the-Art Review","volume":"101","author":"Mortensen","year":"2022","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"ski2.13","DOI":"10.1002\/ski2.13","article-title":"Is Urinary Incontinence Associated with Lichen Sclerosus in Females? A Systematic Review and Meta-Analysis","volume":"1","author":"Kirby","year":"2021","journal-title":"Ski. Health Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1097\/LGT.0000000000000796","article-title":"Risk Factors for Lichen Sclerosus: A Case-Control Study of 43,000 Finnish Women","volume":"28","author":"Halonen","year":"2024","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/ced.14869","article-title":"Male Genital Lichen Sclerosus Associated with Urological Interventions and Microincontinence: A Case Series of 21 Patients","volume":"47","author":"Panou","year":"2022","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1111\/ced.15127","article-title":"Male Genital Lichen Sclerosus, Microincontinence and Occlusion: Mapping the Disease across the Prepuce","volume":"47","author":"Kravvas","year":"2022","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"56","DOI":"10.4103\/0378-6323.58681","article-title":"Lichen Sclerosus: Role of Occlusion of the Genital Skin in the Pathogenesis","volume":"76","author":"Gupta","year":"2010","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/bjd.12220","article-title":"Humoral and Cell-Mediated Autoimmunity in Lichen Sclerosus","volume":"169","author":"Gambichler","year":"2013","journal-title":"Br. J. Dermatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1111\/j.1365-2133.2006.07414.x","article-title":"Cytokine Alterations in Lichen Sclerosus: An Immunohistochemical Study","volume":"155","author":"Farrell","year":"2006","journal-title":"Br. J. Dermatol."},{"key":"ref_47","first-page":"CR39","article-title":"The Involvement of Immunoregulatory T Cells in the Pathogenesis of Lichen Sclerosus","volume":"11","author":"Rotsztejn","year":"2005","journal-title":"Med. Sci. Monit."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s11255-022-03130-7","article-title":"The Role of Occlusion and Micro-Incontinence in the Pathogenesis of Penile Lichen Sclerosus: An Observational Study of pro-Inflammatory Cytokines\u2019 Gene Expression","volume":"54","author":"Czajkowski","year":"2022","journal-title":"Int. Urol. Nephrol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1097\/LGT.0000000000000862","article-title":"Adalimumab Use in Severe Recalcitrant Vulval Lichen Sclerosus and Vulval Lichen Planus","volume":"29","author":"Courtney","year":"2025","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/BF00201602","article-title":"Interleukin 1 Receptor Antagonist Gene Polymorphism Association with Lichen Sclerosus","volume":"94","author":"Clay","year":"1994","journal-title":"Hum. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/jid.2011.369","article-title":"An Autoimmune Phenotype in Vulvar Lichen Sclerosus and Lichen Planus: A Th1 Response and High Levels of microRNA-155","volume":"132","author":"Terlou","year":"2012","journal-title":"J. Investig. Dermatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.jdcr.2022.03.002","article-title":"Treatment of Lichen Sclerosus and Hypertrophic Scars with Dupilumab","volume":"23","author":"Peterson","year":"2022","journal-title":"JAAD Case Rep."},{"key":"ref_53","first-page":"161","article-title":"Fibrogenic Cytokines in Vulvar Lichen Sclerosus. An Immunohistochemical Study","volume":"42","author":"Carli","year":"1997","journal-title":"J. Reprod. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"220","DOI":"10.5114\/ada.2024.139142","article-title":"IL-17: A Novel Player in the Pathogenesis of Vulvar Lichen Sclerosus","volume":"41","author":"Baran","year":"2024","journal-title":"Postep. Dermatol Alergol"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"eabi4613","DOI":"10.1126\/sciimmunol.abi4613","article-title":"Transforming Growth Factor-\u03921 in Regulatory T Cell Biology","volume":"7","author":"Moreau","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1615\/CritRevImmunol.v32.i1.30","article-title":"Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease","volume":"32","author":"Iyer","year":"2012","journal-title":"Crit. Rev. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.biopha.2018.02.030","article-title":"MicroRNA Signature of Regulatory T Cells in Health and Autoimmunity","volume":"100","author":"Shahbazi","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"924","DOI":"10.4049\/jimmunol.1002218","article-title":"Dicer Insufficiency and microRNA-155 Overexpression in Lupus Regulatory T Cells: An Apparent Paradox in the Setting of an Inflammatory Milieu","volume":"186","author":"Divekar","year":"2011","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Stahl, H.F., Fauti, T., Ullrich, N., Bopp, T., Kubach, J., Rust, W., Labhart, P., Alexiadis, V., Becker, C., and Hafner, M. (2009). miR-155 Inhibition Sensitizes CD4+ Th Cells for TREG Mediated Suppression. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007158"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.jdermsci.2020.09.006","article-title":"Tissue Cytokine\/Chemokine Profile in Vulvar Lichen Sclerosus: An Observational Study on Keratinocyte and Fibroblast Cultures","volume":"100","author":"Corazza","year":"2020","journal-title":"J. Dermatol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"156161","DOI":"10.1016\/j.cyto.2023.156161","article-title":"The Role of Interleukin -1 Family in Fibrotic Diseases","volume":"165","author":"Wang","year":"2023","journal-title":"Cytokine"},{"key":"ref_62","first-page":"104","article-title":"Lymphoid Elements and Apoptosis-Related Proteins (Fas, Fas Ligand, P53 and Bcl-2) in Lichen Sclerosus and Carcinoma of the Vulva","volume":"22","author":"Ashkenazi","year":"2001","journal-title":"Eur. J. Gynaecol. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.7150\/ijbs.34613","article-title":"Lichen Sclerosus: An Autoimmunopathogenic and Genomic Enigma with Emerging Genetic and Immune Targets","volume":"15","author":"Tran","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jid.2019.05.026","article-title":"IL-17A Dissociates Inflammation from Fibrogenesis in Systemic Sclerosis","volume":"140","author":"Dufour","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wei, L., Abraham, D., and Ong, V. (2022). The Yin and Yang of IL-17 in Systemic Sclerosis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.885609"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1146\/annurev.immunol.21.120601.140942","article-title":"Molecular Mechanisms Regulating Th1 Immune Responses","volume":"21","author":"Szabo","year":"2003","journal-title":"Annu. Rev. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1182\/blood-2005-11-4567","article-title":"TNF Downmodulates the Function of Human CD4+CD25hi T-Regulatory Cells","volume":"108","author":"Valencia","year":"2006","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1159\/000236334","article-title":"In Situ Localization of Interleukin-6 in Normal Skin and Atrophic Cutaneous Disease","volume":"99","author":"Romero","year":"1992","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Johnson, B.Z., Stevenson, A.W., Pr\u00eale, C.M., Fear, M.W., and Wood, F.M. (2020). The Role of IL-6 in Skin Fibrosis and Cutaneous Wound Healing. Biomedicines, 8.","DOI":"10.3390\/biomedicines8050101"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/j.1365-3083.2009.02308.x","article-title":"How Do Regulatory T Cells Work?","volume":"70","author":"Corthay","year":"2009","journal-title":"Scand. J. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T Cells and Immune Tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.0906-6705.2006.00409.x","article-title":"Extracellular Matrix Protein 1 Inhibits the Activity of Matrix Metalloproteinase 9 through High-Affinity Protein\/Protein Interactions","volume":"15","author":"Fujimoto","year":"2006","journal-title":"Exp. Dermatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"16385","DOI":"10.1074\/jbc.270.27.16385","article-title":"Molecular Cloning, Characterization, and Genetic Mapping of the cDNA Coding for a Novel Secretory Protein of Mouse. Demonstration of Alternative Splicing in Skin and Cartilage","volume":"270","author":"Bhalerao","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/j.1365-2230.2004.01440.x","article-title":"The Role of Extracellular Matrix Protein 1 in Human Skin","volume":"29","author":"Chan","year":"2004","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1093\/hmg\/11.7.833","article-title":"Lipoid Proteinosis Maps to 1q21 and Is Caused by Mutations in the Extracellular Matrix Protein 1 Gene (ECM1)","volume":"11","author":"Hamada","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1046\/j.1365-2230.2002.01143.x","article-title":"Lipoid Proteinosis","volume":"27","author":"Hamada","year":"2002","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/S0140-6736(03)13863-9","article-title":"Autoantibodies to Extracellular Matrix Protein 1 in Lichen Sclerosus","volume":"362","author":"Oyama","year":"2003","journal-title":"Lancet"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/j.1365-2133.2011.10326.x","article-title":"Extracellular Matrix Protein 1 Autoantibodies in Male Genital Lichen Sclerosus: Correspondence","volume":"165","author":"Edmonds","year":"2011","journal-title":"Br. J. Dermatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"17491","DOI":"10.1074\/jbc.M210529200","article-title":"Perlecan Protein Core Interacts with Extracellular Matrix Protein 1 (ECM1), a Glycoprotein Involved in Bone Formation and Angiogenesis","volume":"278","author":"Mongiat","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"37823","DOI":"10.1074\/jbc.M110.136408","article-title":"Phospholipid Scramblase 1 Is Secreted by a Lipid Raft-Dependent Pathway and Interacts with the Extracellular Matrix Protein 1 in the Dermal Epidermal Junction Zone of Human Skin","volume":"285","author":"Merregaert","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/j.1524-475X.2008.00410.x","article-title":"Growth Factors and Cytokines in Wound Healing","volume":"16","author":"Barrientos","year":"2008","journal-title":"Wound Repair Regen."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jdermsci.2020.06.010","article-title":"Gene Silencing of Extracellular Matrix Protein 1 (ECM1) Results in Phenotypic Alterations of Dermal Fibroblasts Reminiscent of Clinical Features of Lichen Sclerosus","volume":"100","author":"Utsunomiya","year":"2020","journal-title":"J. Dermatol. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"356","DOI":"10.6061\/clinics\/2015(05)09","article-title":"Unusual Remodeling of the Hyalinization Band in Vulval Lichen Sclerosus by Type V Collagen and ECM 1 Protein","volume":"70","author":"Godoy","year":"2015","journal-title":"Clinics"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1042\/BJ20101061","article-title":"Identification of Binding Partners Interacting with the A1-N-Propeptide of Type V Collagen","volume":"433","author":"Symoens","year":"2011","journal-title":"Biochem. J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/ar.23330","article-title":"Type V Collagen in Health, Disease, and Fibrosis","volume":"299","author":"Mak","year":"2016","journal-title":"Anat. Rec."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1053\/j.gastro.2019.07.036","article-title":"ECM1 Prevents Activation of Transforming Growth Factor \u03b2, Hepatic Stellate Cells, and Fibrogenesis in Mice","volume":"157","author":"Fan","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"18758","DOI":"10.1073\/pnas.0805411105","article-title":"Perturbation of Transforming Growth Factor (TGF)-Beta1 Association with Latent TGF-Beta Binding Protein Yields Inflammation and Tumors","volume":"105","author":"Yoshinaga","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"TGF-\u03b2: The Master Regulator of Fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.juro.2012.09.010","article-title":"Congenital Phimosis in Patients with and without Lichen Sclerosus: Distinct Expression Patterns of Tissue Remodeling Associated Genes","volume":"189","author":"Pilatz","year":"2013","journal-title":"J. Urol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Sun, P., Kraus, C.N., Zhao, W., Xu, J., Suh, S., Nguyen, Q., Jia, Y., Nair, A., Oakes, M., and Tinoco, R. (2024). Single-Cell and Spatial Transcriptomics of Vulvar Lichen Sclerosus Reveal Multi-Compartmental Alterations in Gene Expression and Signaling Cross-Talk. bioRxiv.","DOI":"10.1101\/2024.08.14.607986"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1136\/gutjnl-2024-333213","article-title":"ECM1 Attenuates Hepatic Fibrosis by Interfering with Mediators of Latent TGF-\u03921 Activation","volume":"74","author":"Link","year":"2025","journal-title":"Gut"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1111\/bjd.16445","article-title":"Updates in Lichen Sclerosis: British Association of Dermatologists Guidelines for the Management of Lichen Sclerosus 2018","volume":"178","author":"Akel","year":"2018","journal-title":"Br. J. Dermatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1111\/jdv.20083","article-title":"EuroGuiderm Guideline on Lichen Sclerosus-Treatment of Lichen Sclerosus","volume":"38","author":"Kirtschig","year":"2024","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1111\/bjd.12273","article-title":"Proactive Maintenance Therapy with a Topical Corticosteroid for Vulvar Lichen Sclerosus: Preliminary Results of a Randomized Study","volume":"168","author":"Virgili","year":"2013","journal-title":"Br. J. Dermatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"313","DOI":"10.2165\/11310750-000000000-00000","article-title":"The Role of Calcineurin Inhibitors in the Management of Lichen Sclerosus","volume":"10","author":"Yesudian","year":"2009","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1684\/ejd.2013.1987","article-title":"Long-Term Maintenance Therapy for Vulvar Lichen Sclerosus: The Results of a Randomized Study Comparing Topical Vitamin E with an Emollient","volume":"23","author":"Virgili","year":"2013","journal-title":"Eur. J. Dermatol."},{"key":"ref_97","first-page":"CD008240","article-title":"Topical Interventions for Genital Lichen Sclerosus","volume":"2011","author":"Chi","year":"2011","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Rijal, H., Sood, S., Bagit, A., Maliyar, K., Georgakopoulos, J.R., Mufti, A., and Yeung, J. (2025). Biologics and Small Molecules in Lichen Sclerosus: A Systematic Review. J. Cutan. Med. Surg., 12034754251316490.","DOI":"10.1177\/12034754251316490"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1111\/jdv.14458","article-title":"European Dermatology Forum S1-Guideline on the Diagnosis and Treatment of Sclerosing Diseases of the Skin, Part 1: Localized Scleroderma, Systemic Sclerosis and Overlap Syndromes","volume":"31","author":"Knobler","year":"2017","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Gerkowicz, A., Szczepanik-Ku\u0142ak, P., and Krasowska, D. (2021). Photodynamic Therapy in the Treatment of Vulvar Lichen Sclerosus: A Systematic Review of the Literature. J. Clin. Med., 10.","DOI":"10.3390\/jcm10235491"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1097\/LGT.0000000000000362","article-title":"Photodynamic Therapy for Vulvar Lichen Sclerosus-A Systematic Review","volume":"22","author":"Prodromidou","year":"2018","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Paganelli, A., Contu, L., Condorelli, A., Ficarelli, E., Motolese, A., Paganelli, R., and Motolese, A. (2023). Platelet-Rich Plasma (PRP) and Adipose-Derived Stem Cell (ADSC) Therapy in the Treatment of Genital Lichen Sclerosus: A Comprehensive Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216107"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e2024262","DOI":"10.5826\/dpc.1404a262","article-title":"Management of Lichen Sclerosus and Related Comorbidities at a Tertiary Referral Center: Beyond Topical Steroids","volume":"14","author":"Paganelli","year":"2024","journal-title":"Dermatol. Pract. Concept."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e452","DOI":"10.1111\/ijd.17277","article-title":"Platelet-Rich Plasma and Stromal Vascular Fraction as Regenerative Strategies for Lichen Sclerosus: A Single-Center Experience","volume":"63","author":"Paganelli","year":"2024","journal-title":"Int. J. Dermatol."},{"key":"ref_105","first-page":"9774","article-title":"Treatment and Follow-up of Genital Lichen Sclerosus in Male Children: Multidisciplinary Management at a Tertiary Care Center","volume":"15","author":"Paganelli","year":"2023","journal-title":"Dermatol. Rep."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"153298","DOI":"10.1016\/j.phymed.2020.153298","article-title":"Biochanin-A Ameliorates Pulmonary Fibrosis by Suppressing the TGF-\u03b2 Mediated EMT, Myofibroblasts Differentiation and Collagen Deposition in in Vitro and in Vivo Systems","volume":"78","author":"Andugulapati","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"174510","DOI":"10.1016\/j.ejphar.2021.174510","article-title":"TGF-\u03b2-Induced Fibrosis: A Review on the Underlying Mechanism and Potential Therapeutic Strategies","volume":"911","author":"Ong","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/ced.12783","article-title":"mRNA and Protein Expression of the Angiogenesis-Related Genes EDIL3, AMOT and ECM1 in Mesenchymal Stem Cells in Psoriatic Dermis","volume":"41","author":"Niu","year":"2016","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_109","first-page":"188","article-title":"Novel Clinical Applications of Topical Ruxolitinib: A Case Series","volume":"23","author":"Zundell","year":"2024","journal-title":"J. Drugs Dermatol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e15942","DOI":"10.1111\/dth.15942","article-title":"Bullous Lichen Sclerosus-Generalized Morphea Overlap Syndrome Improved by Tofacitinib","volume":"35","author":"Liu","year":"2022","journal-title":"Dermatol. Ther."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"202","DOI":"10.4111\/icu.2016.57.3.202","article-title":"Diversity of Patient Profile, Urethral Stricture, and Other Disease Manifestations in a Cohort of Adult Men with Lichen Sclerosus","volume":"57","author":"Kirk","year":"2016","journal-title":"Investig. Clin. Urol."},{"key":"ref_112","first-page":"1491","article-title":"Risk of Cancer, Tuberculosis and Serious Infections in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Psoriasis Treated with IL-17 and TNF-\u03b1 Inhibitors: A Nationwide Nested Case-Control Analysis","volume":"41","author":"Kim","year":"2023","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Song, J., Kim, S.R., Kim, Y.-J., Park, S.J., Jeong, S., and Park, S.M. (2025). Risk of Hematologic Malignancies in Psoriasis and Rheumatoid Arthritis Patients Using Long Term TNF-\u03b1 Inhibitors: A Retrospective Nationwide Study. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-90996-z"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1007\/s13555-024-01166-4","article-title":"Biologics Versus JAK Inhibitors. Part I: Cancer Risk. A Narrative Review","volume":"14","year":"2024","journal-title":"Dermatol. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1007\/s40257-023-00787-3","article-title":"Association Between the Use of Topical Calcineurin Inhibitors and the Risk of Cancer Among Patients with Atopic Dermatitis: A Nationwide, Population-Based, Retrospective Cohort Study","volume":"24","author":"Huang","year":"2023","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_116","first-page":"e78750","article-title":"Differences in Tolerability of Antifibrotic Agents Between Connective Tissue Disease-Associated and Non-Connective Tissue Disease-Associated Interstitial Lung Disease","volume":"17","author":"Nakamura","year":"2025","journal-title":"Cureus"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4315\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:26:02Z","timestamp":1760030762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,1]]},"references-count":116,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094315"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094315","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,1]]}}}