Aetiopathogenesis of Vitiligo
Keywords:
vitiligo, melanocytes, keratinocytes, fibroblasts, immune cells, resident memory T cells, cytokinesAbstract
Vitiligo is a chronic auto-immune disease characterized by skin depigmentation due to the loss of melanocytes. The better understanding of the disease mechanisms is currently undergoing a significant dynamism, opening a new era in therapeutic development. The pathophysiology of vitiligo has attracted the attention of researchers for years and many advances have been made in clarifying the crosstalk between the cellular players involved in the development of vitiligo lesions. The understanding of the complex interactions between epidermal cells (i.e. melanocytes and keratinocytes), dermal fibroblasts, and immune cells, led to a better characterization of the signals leading to the loss of melanocytes. Recent advances highlighted the role resident T memory cells in the development and recurrence of lesions. This narrative review aims to give an overview of the mechanisms leading to melanocyte disappearance in vitiligo, with a focus on the intercellular interaction network involved in the activation of the local skin immune response.
References
Boniface K, Seneschal J, Picardo M, Taïeb A. Vitiligo: Focus on Clinical Aspects, Immunopathogenesis, and Therapy. Clin Rev Allergy Immunol. 2018;54:52–67. [PMID: 28685247].
Spritz RA. Modern vitiligo genetics sheds new light on an ancient disease. J Dermatol. 2013;40:310–8. [PMID: 23668538].
Spritz RA, Santorico SA. The Genetic Basis of Vitiligo. J Invest Dermatol. 2021;141:265–73. [PMID: 32778407].
Jin Y, Andersen G, Yorgov D, et al. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet. 2016;48:1418–24. [PMID: 27723757].
Jin Y, Mailloux CM, Gowan K, et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007;356:1216–25. [PMID: 17377159].
Jin Y, Birlea SA, Fain PR, et al. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet. 2012;44:676–80. [PMID: 22561518].
Jin Y, Birlea SA, Fain PR, et al. Genome-wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset. J Invest Dermatol. 2011;131:1308–12. [PMID: 21326295].
Chang W-L, Ko C-H. The Role of Oxidative Stress in Vitiligo: An Update on Its Pathogenesis and Therapeutic Implications. Cells. 2023;12:936. [PMID: 36980277].
Kovacs D, Bastonini E, Ottaviani M, et al. Vitiligo Skin: Exploring the Dermal Compartment. J Invest Dermatol. 2018;138:394–404. [PMID: 29024688].
Zhang Y, Liu L, Jin L, et al. Oxidative stress-induced calreticulin expression and translocation: new insights into the destruction of melanocytes. J Invest Dermatol. 2014;134:183–91. [PMID: 23771121].
Cui T, Zhang W, Li S, et al. Oxidative Stress-Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo. J Invest Dermatol. 2019;139:2174-2184.e4. [PMID: 30998983].
Zhang K, Anumanthan G, Scheaffer S, Cornelius LA. HMGB1/RAGE Mediates UVB-Induced Secretory Inflammatory Response and Resistance to Apoptosis in Human Melanocytes. J Invest Dermatol. 2019;139:202–12. [PMID: 30030153].
Mosenson JA, Zloza A, Nieland JD, et al. Mutant HSP70 reverses autoimmune depigmentation in vitiligo. Sci Transl Med. 2013;5:174ra28. [PMID: 23447019].
Jacquemin C, Rambert J, Guillet S, et al. Heat shock protein 70 potentiates interferon alpha production by plasmacytoid dendritic cells: relevance for cutaneous lupus and vitiligo pathogenesis. Br J Dermatol. 2017;177:1367–75. [PMID: 28380264].
Migayron L, Boniface K, Seneschal J. Vitiligo, From Physiopathology to Emerging Treatments: A Review. Dermatol Ther. 2020;10:1185–98. [PMID: 32949337].
Henning SW, Fernandez MF, Mahon JP, et al. HSP70iQ435A-Encoding DNA Repigments Vitiligo Lesions in Sinclair Swine. J Invest Dermatol. 2018;138:2531–9. [PMID: 30031029].
Mosenson JA, Eby JM, Hernandez C, Le Poole IC. A central role for inducible heat-shock protein 70 in autoimmune vitiligo. Exp Dermatol. 2013;22:566–9. [PMID: 23786523].
Denman CJ, McCracken J, Hariharan V, et al. HSP70i accelerates depigmentation in a mouse model of autoimmune vitiligo. J Invest Dermatol. 2008;128:2041–8. [PMID: 18337834].
Kovacs D, Bastonini E, Briganti S, et al. Altered epidermal proliferation, differentiation, and lipid composition: Novel key elements in the vitiligo puzzle. Sci Adv. 2022;8:eabn9299. [PMID: 36054352].
Moellmann G, Klein-Angerer S, Scollay DA, Nordlund JJ, Lerner AB. Extracellular granular material and degeneration of keratinocytes in the normally pigmented epidermis of patients with vitiligo. J Invest Dermatol. 1982;79:321–30. [PMID: 7130745].
Marie J, Kovacs D, Pain C, et al. Inflammasome activation and vitiligo/nonsegmental vitiligo progression. Br J Dermatol. 2014;170:816–23. [PMID: 24734946].
Li S, Zhu G, Yang Y, et al. Oxidative stress drives CD8+ T-cell skin trafficking in patients with vitiligo through CXCL16 upregulation by activating the unfolded protein response in keratinocytes. J Allergy Clin Immunol. 2017;140:177-189.e9. [PMID: 27826097].
Richmond JM, Bangari DS, Essien KI, et al. Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease. J Invest Dermatol. 2017;137:350–8. [PMID: 27686391].
Boniface K, Jacquemin C, Darrigade A-S, et al. Vitiligo Skin Is Imprinted with Resident Memory CD8 T Cells Expressing CXCR3. J Invest Dermatol. 2018;138:355–64. [PMID: 28927891].
Xu Z, Chen D, Hu Y, et al. Anatomically distinct fibroblast subsets determine skin autoimmune patterns. Nature. 2022;601:118–24. [PMID: 34912121].
Bertolotti A, Boniface K, Vergier B, et al. Type I interferon signature in the initiation of the immune response in vitiligo. Pigment Cell Melanoma Res. 2014;27:398–407. [PMID: 24438589].
Martins C, Migayron L, Drullion C, et al. Vitiligo Skin T Cells Are Prone to Produce Type 1 and Type 2 Cytokines to Induce Melanocyte Dysfunction and Epidermal Inflammatory Response Through Jak Signaling. J Invest Dermatol. 2022;142:1194-1205.e7. [PMID: 34655610].
Tulic MK, Cavazza E, Cheli Y, et al. Innate lymphocyte-induced CXCR3B-mediated melanocyte apoptosis is a potential initiator of T-cell autoreactivity in vitiligo. Nat Commun. 2019;10:2178. [PMID: 31097717].
Cheuk S, Schlums H, Gallais Sérézal I, et al. CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin. Immunity. 2017;46:287–300. [PMID: 28214226].
Richmond JM, Strassner JP, Zapata L, et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci Transl Med. 2018;10:eaam7710. [PMID: 30021889].
Richmond JM, Strassner JP, Rashighi M, et al. Resident Memory and Recirculating Memory T Cells Cooperate to Maintain Disease in a Mouse Model of Vitiligo. J Invest Dermatol. 2019;139:769–78. [PMID: 30423329].
Strobl J, Haniffa M. Functional heterogeneity of human skin-resident memory T cells in health and disease. Immunol Rev. 2023;316:104–19. [PMID: 37144705].
Milner JJ, Goldrath AW. Transcriptional programming of tissue-resident memory CD8+ T cells. Curr Opin Immunol. 2018;51:162–9. [PMID: 29621697].
Rotrosen E, Kupper TS. Assessing the generation of tissue resident memory T cells by vaccines. Nat Rev Immunol. 2023:1–11. [PMID: 37002288].
Clark RA, Chong B, Mirchandani N, et al. The vast majority of CLA+ T cells are resident in normal skin. J Immunol Baltim Md 1950. 2006;176:4431–9. [PMID: 16547281].
Mackay LK, Rahimpour A, Ma JZ, et al. The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin. Nat Immunol. 2013;14:1294–301. [PMID: 24162776].
Nicolaidou E, Antoniou C, Stratigos AJ, Stefanaki C, Katsambas AD. Efficacy, predictors of response, and long-term follow-up in patients with vitiligo treated with narrowband UVB phototherapy. J Am Acad Dermatol. 2007;56:274–8. [PMID: 17224369].
Matos TR, O’Malley JT, Lowry EL, et al. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones. J Clin Invest. 2017;127:4031–41. [PMID: 28945199].
Cheuk S, Wikén M, Blomqvist L, et al. Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. J Immunol Baltim Md 1950. 2014;192:3111–20. [PMID: 24610014].
Brunner PM, Emerson RO, Tipton C, et al. Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues. Allergy. 2017;72:2017–25. [PMID: 28599078].
Seneschal J, Boniface K, D’Arino A, Picardo M. An update on Vitiligo pathogenesis. Pigment Cell Melanoma Res. 2021;34:236–43. [PMID: 33278065].
Martins C, Darrigade A-S, Jacquemin C, et al. Phenotype and function of circulating memory T cells in human vitiligo. Br J Dermatol. 2020;183:899–908. [PMID: 32012221].
Rashighi M, Agarwal P, Richmond JM, et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med. 2014;6:223ra23. [PMID: 24523323].
Regazzetti C, Joly F, Marty C, et al. Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients. J Invest Dermatol. 2015;135:3105–14. [PMID: 26322948].
Richmond JM, Masterjohn E, Chu R, et al. CXCR3 Depleting Antibodies Prevent and Reverse Vitiligo in Mice. J Invest Dermatol. 2017;137:982–5. [PMID: 28126463].
Jacquemin C, Martins C, Lucchese F, et al. NKG2D Defines a Subset of Skin Effector Memory CD8 T Cells with Proinflammatory Functions in Vitiligo. J Invest Dermatol. 2020;140:1143-1153.e5. [PMID: 31877315].
Qi F, Liu F, Gao L. Janus Kinase Inhibitors in the Treatment of Vitiligo: A Review. Front Immunol. 2021;12:790125. [PMID: 34868078].
Rosmarin D, Pandya AG, Lebwohl M, et al. Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. Lancet Lond Engl. 2020;396:110–20. [PMID: 32653055].
Rosmarin D, Passeron T, Pandya AG, et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo. N Engl J Med. 2022;387:1445–55. [PMID: 36260792].
Englaro W, Bahadoran P, Bertolotto C, et al. Tumor necrosis factor alpha-mediated inhibition of melanogenesis is dependent on nuclear factor kappa B activation. Oncogene. 1999;18:1553–9. [PMID: 10102625].
Son J, Kim M, Jou I, Park KC, Kang HY. IFN-γ inhibits basal and α-MSH-induced melanogenesis. Pigment Cell Melanoma Res. 2014;27:201–8. [PMID: 24267286].
Yang L, Wei Y, Sun Y, et al. Interferon-gamma Inhibits Melanogenesis and Induces Apoptosis in Melanocytes: A Pivotal Role of CD8+ Cytotoxic T Lymphocytes in Vitiligo. Acta Derm Venereol. 2015;95:664–70. [PMID: 25721262].
Boukhedouni N, Martins C, Darrigade A-S, et al. Type-1 cytokines regulate MMP-9 production and E-cadherin disruption to promote melanocyte loss in vitiligo. JCI Insight. 2020;5:e133772, 133772. [PMID: 32369451].
Natarajan VT, Ganju P, Singh A, et al. IFN-γ signaling maintains skin pigmentation homeostasis through regulation of melanosome maturation. Proc Natl Acad Sci U S A. 2014;111:2301–6. [PMID: 24474804].
Ng CY, Chan Y-P, Chiu Y-C, et al. Targeting the elevated IFN-γ in vitiligo patients by human anti- IFN-γ monoclonal antibody hampers direct cytotoxicity in melanocyte. J Dermatol Sci. 2023;110:78–88. [PMID: 37221109].
Singh RK, Lee KM, Vujkovic-Cvijin I, et al. The role of IL-17 in vitiligo: A review. Autoimmun Rev. 2016;15:397–404. [PMID: 26804758].
Speeckaert R, Mylle S, van Geel N. IL-17A is not a treatment target in progressive vitiligo. Pigment Cell Melanoma Res. 2019;32:842–7. [PMID: 31063266].
Khan R, Gupta S, Sharma A. Circulatory levels of T-cell cytokines (interleukin [IL]-2, IL-4, IL-17, and transforming growth factor-β) in patients with vitiligo. J Am Acad Dermatol. 2012;66:510–1. [PMID: 22342018].
Vaccaro M, Cicero F, Mannucci C, et al. IL-33 circulating serum levels are increased in patients with non-segmental generalized vitiligo. Arch Dermatol Res. 2016;308:527–30. [PMID: 27388717].
Choi H, Choi H, Han J, et al. IL-4 inhibits the melanogenesis of normal human melanocytes through the JAK2-STAT6 signaling pathway. J Invest Dermatol. 2013;133:528–36. [PMID: 22992805].
Han J, Lee E, Kim E, et al. Role of epidermal γδ T-cell-derived interleukin 13 in the skin-whitening effect of Ginsenoside F1. Exp Dermatol. 2014;23:860–2. [PMID: 25091975].
Czarnowicki T, He H, Leonard A, et al. Blood endotyping distinguishes the profile of vitiligo from that of other inflammatory and autoimmune skin diseases. J Allergy Clin Immunol. 2019;143:2095–107. [PMID: 30576756].
Jin R, Zhou M, Lin F, Xu W, Xu A. Pathogenic Th2 Cytokine Profile Skewing by IFN-γ-Responding Vitiligo Fibroblasts via CCL2/CCL8. Cells. 2023;12:217. [PMID: 36672151].
Birlea SA, Jin Y, Bennett DC, et al. Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP. J Invest Dermatol. 2011;131:371–81. [PMID: 21085187].
Aydıngöz IE, Kanmaz-Özer M, Gedikbaşi A, et al. The combination of tumour necrosis factor-α -308A and interleukin-10 -1082G gene polymorphisms and increased serum levels of related cytokines: susceptibility to vitiligo. Clin Exp Dermatol. 2015;40:71–7. [PMID: 25283497].
Dwivedi M, Kemp EH, Laddha NC, et al. Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics. Autoimmun Rev. 2015;14:49–56. [PMID: 25308528].
Giri PS, Mistry J, Dwivedi M. Meta-Analysis of Alterations in Regulatory T Cells’ Frequency and Suppressive Capacity in Patients with Vitiligo. J Immunol Res. 2022;2022:6952299. [PMID: 36164321].
Eby JM, Kang H-K, Tully ST, et al. CCL22 to Activate Treg Migration and Suppress Depigmentation in Vitiligo. J Invest Dermatol. 2015;135:1574–80. [PMID: 25634358].
Gellatly KJ, Strassner JP, Essien K, et al. scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in Treg function. Sci Transl Med. 2021;13:eabd8995. [PMID: 34516831].
Le Poole IC, Mehrotra S. Replenishing Regulatory T Cells to Halt Depigmentation in Vitiligo. J Investig Dermatol Symp Proc. 2017;18:S38–45. [PMID: 28941492].
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