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2020, Number 2-3

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Rev Cent Dermatol Pascua 2020; 29 (2-3)

Pathogenesis of vitiligo. Autoimmune theory

Guerrero OG, Trejo OX, Peralta PML, Pérez MG, Morales SMA, Jurado SCF

Language: Spanish
References: 180
Page: 61-76
PDF size: 400.98 Kb.


ABSTRACT

Vitiligo is considered the most frequent acquired dyschromia, causing 2 to 4% of the dermatological consultation in Mexico, being this one of the countries with the highest incidence. Understanding the mechanisms by which melanocyte loss occurs is a fragmented approach, it is a complex, multifactorial disorder, the same causal mechanisms cannot have problems in all cases, and different pathogenic mechanisms can work together, the present work has as its objective to show the overall picture that it has regarding the immunological theory of vitiligo, intrinsic and extrinsic triggers are addressed, cellular processes, participation of reactive oxygen species, participation of the immune system and its relationship with other diseases. The genetic and environmental bases that have been seen to interact in the death of melanocytes are also included, and information is collected on the different lines of research in which work continues to learn more about the pathogenesis of this disease.


REFERENCES

  1. Rodríguez-Cerdeira C, Arenas GR. El vitíligo, una enfermedad estigmática: un recorrido a través de su historia. Med Cutan Iber Lat Am. 2011; 39: 278-282.

  2. Gawkrodger DJ, Ormerod AD, Shaw L, Mauri-Sole I, Whitton ME, Watts MJ et al. Guideline for the diagnosis and management of vitiligo. Br J Dermatol. 2008; 159: 1051-1076.

  3. Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet. 2015; 386: 74-84.

  4. Picardo M, Dell'Anna ML, Ezzedine K, Hamzavi I, Harris JE, Parsad D, Taieb A. Vitiligo. Nat Rev Dis Primers. 2015; 1: 15011.

  5. Taieb A. Vitiligo as an inflammatory skin disorder: a therapeutic perspective. Pigment Cell Melanoma Res. 2012; 25: 9-13.

  6. Ezzedine K, Lim HW, Suzuki T, Katayama I, Hamzavi I, Lan CC et al. Revised classification/nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res. 2012; 25: E1-13.

  7. Goding CR. Melanocytes: the new black. Int J Biochem Cell Biol. 2007; 39: 275-279.

  8. Bassiouny DA, Shaker O. Role of interleukin-17 in the pathogenesis of vitiligo. Clin Exp Dermatol. 2011; 36: 292-297.

  9. Khan R, Satyam A, Gupta S, Sharma VK, Sharma A. Circulatory levels of antioxidants and lipid peroxidation in Indian patients with generalized and localized vitiligo. Arch Dermatol Res. 2009; 301: 731-737.

  10. Schallreuter KU, Moore J, Wood JM, Beazley WD, Gaze DC, Tobin DJ et al. In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J Investig Dermatol Symp Proc. 1999; 4: 91-96.

  11. Dammak I, Boudaya S, Ben Abdallah F, Turki H, Attia H, Hentati B. Antioxidant enzymes and lipid peroxidation at the tissue level in patients with stable and active vitiligo. Int J Dermatol. 2009; 48: 476-480.

  12. Sravani PV, Babu NK, Gopal KV, Rao GR, Rao AR, Moorthy B et al. Determination of oxidative stress in vitiligo by measuring superoxide dismutase and catalase levels in vitiliginous and non-vitiliginous skin. Indian J Dermatol Venereol Leprol. 2009; 75: 268-271.

  13. Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE; Vitiligo Working Group. New discoveries in the pathogenesis and classification of vitiligo. J Am Acad Dermatol. 2017; 77: 1-13. Available from: http://dx.doi.org/10.1016/j.jaad.2016.10.048

  14. Le Poole IC, van den Wijngaard RM, Westerhof W, Das PK. Tenascin is overexpressed in vitiligo lesional skin and inhibits melanocyte adhesion. Br J Dermatol. 1997; 137: 171-178.

  15. Gauthier Y, Cario-Andre M, Lepreux S, Pain C, Taieb A. Melanocyte detachment after skin friction in non lesional skin of patients with generalized vitiligo. Br J Dermatol. 2003; 148: 95-101.

  16. Gauthier Y, Cario Andre M, Taieb A. A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocytorrhagy? Pigment Cell Res. 2003; 16: 322-332.

  17. Kroll TM, Bommiasamy H, Boissy RE, Hernandez C, Nickoloff BJ, Mestril R et al. 4-Tertiary butyl phenol exposure sensitizes human melanocytes to dendritic cell-mediated killing: relevance to vitiligo. J Invest Dermatol. 2005; 124: 798-806.

  18. Ricard AS, Pain C, Daubos A, Ezzedine K, Lamrissi-Garcia I, Bibeyran A et al. Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. Exp Dermatol. 2012; 21: 411-416.

  19. Cario-André M, Pain C, Gauthier Y, Taieb A. The melanocytorrhagic hypothesis of vitiligo tested on pigmented, stressed, reconstructed epidermis. Pigment Cell Res. 2007; 20: 385-393.

  20. Boniface K, Seneschal J, Picardo M, Taieb A. Vitiligo: focus on clinical aspects, immunopathogenesis, and therapy. Clin Rev Allergy Immunol. 2018; 54: 52-67.

  21. Patel S, Rauf A, Khan H, Meher BR, Hassan SSU. A holistic review on the autoimmune disease vitiligo with emphasis on the causal factors. Biomed Pharmacother. 2017; 92: 501-508. Available from: http://dx.doi.org/10.1016/j.biopha.2017.05.095

  22. Manolache L, Benea V. Stress in patients with alopecia areata and vitiligo. J Eur Acad Dermatol Venereol. 2007; 21: 921-928.

  23. Strassner JP, Harris JE. Understanding mechanisms of autoimmunity through translational research in vitiligo. Curr Opin Immunol. 2016; 43: 81-88. Available from: http://dx.doi.org/10.1016/j.coi.2016.09.008

  24. Colucci R, Dragoni F, Moretti S. Oxidative stress and immune system in vitiligo and thyroid diseases. Oxid Med Cell Longev. 2015; 2015: 631927.

  25. Picardo M, Taieb A, editors. Vitiligo. London: Springer; 2010.

  26. Le Poole IC, Luiten RM. Autoimmune etiology of generalized vitiligo. Curr Dir Autoimmun. 2008; 10: 227-243.

  27. Manga P, Elbuluk N, Orlow SJ. Recent advances in understanding vitiligo. F1000Res. 2016; 5: F1000 Faculty Rev-2234. Available from: https://f1000research.com/articles/5-2234/v1

  28. Spritz RA. Shared genetic relationships underlying generalized vitiligo and autoimmune thyroid disease. Thyroid. 2010; 20: 745-754.

  29. van Geel NA, Mollet IG, De Schepper S, Tjin EP, Vermaelen K, Clark RA et al. First histopathological and immunophenotypic analysis of early dynamic events in a patient with segmental vitiligo associated with halo nevi. Pigment Cell Melanoma Res. 2010; 23: 375-384.

  30. Rashighi M, Harris JE. Vitiligo pathogenesis and emerging treatments. Dermatol Clin. 2017; 35: 257-265. Available from: http://dx.doi.org/10.1016/j.det.2016.11.014

  31. Nicolaidou E, Mastraftsi S, Tzanetakou V, Rigopoulos D. Childhood vitiligo. Am J Clin Dermatol. 2019; 20: 515-526. Available from: https://doi.org/10.1007/s40257-019-00430-0

  32. Dell'Anna ML, Cario-André M, Bellei B, Taieb A, Picardo M. In vitro research on vitiligo: strategies, principles, methodological options and common pitfalls. Exp Dermatol. 2012; 21: 490-496.

  33. Le Poole IC, Mehrotra S. Replenishing regulatory T cells to halt depigmentation in vitiligo. J Investig Dermatol Symp Proc. 2017; 18: S38-S45. Available from: https://doi.org/10.1016/j.jisp.2016.10.023

  34. Spritz RA. Recent progress in the genetics of generalized vitiligo. J Genet Genomics. 2011; 38: 271-278. Available from: http://dx.doi.org/10.1016/j.jgg.2011.05.005

  35. Bunney PE, Zink AN, Holm AA, Billington CJ, Kotz CM. Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet. Physiol Behav. 2017; 176: 139-148.

  36. Czajkowski R, Mecinska-Jundzill K. Current aspects of vitiligo genetics. Postepy Dermatol Alergol. 2014; 31: 247-255.

  37. Jin Y, Birlea SA, Fain PR, Gowan K, Riccardi SL, Holland PJ 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: 1308-1312.

  38. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007; 356: 1216-1225.

  39. Birlea SA, Jin Y, Bennett DC, Herbstman DM, Wallace MR, McCormack WT et al. Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP. J Invest Dermatol. 2011; 131: 371-381.

  40. Spritz RA. The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma. Genome Med. 2010; 2: 78.

  41. Spritz RA. Six decades of vitiligo genetics: genome-wide studies provide insights into autoimmune pathogenesis. J Invest Dermatol. 2012; 132: 268-273.

  42. Rork JF, Rashighi M, Harris JE. Understanding autoimmunity of vitiligo and alopecia areata. Curr Opin Pediatr. 2016; 28: 463-469.

  43. Jin Y, Andersen GHL, Santorico SA, Spritz RA. Multiple functional variants of IFIH1, a gene involved in triggering innate immune responses, protect against vitiligo. J Invest Dermatol. 2017; 137: 522-524.

  44. Levy C, Khaled M. Ecad vitiliGONE. Pigment Cell Melanoma Res. 2015; 28: 376-377.

  45. Xie H, Zhou F, Liu L, Zhu G, Li Q, Li C et al. Vitiligo: how do oxidative stress-induced autoantigens trigger autoimmunity? J Dermatol Sci. 2016; 81: 3-9. Available from: http://dx.doi.org/10.1016/j.jdermsci.2015.09.003

  46. Chen JJ, Huang W, Gui JP, Yang S, Zhou FS, Xiong QG et al. A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families. Am J Hum Genet. 2005; 76: 1057-1065.

  47. Ren Y, Yang S, Xu S, Gao M, Huang W, Gao T et al. Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genet. 2009; 5: e1000523.

  48. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C et al. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell. 2007; 27: 53-66.

  49. Boissy RE, Spritz RA. Frontiers and controversies in the pathobiology of vitiligo: separating the wheat from the chaff. Exp Dermatol. 2009; 18: 583-585.

  50. Guerra L, Dellambra E, Brescia S, Raskovic D. Vitiligo: pathogenetic hypotheses and targets for current therapies. Curr Drug Metab. 2010; 11: 451-467.

  51. Iannella G, Greco A, Didona D, Didona B, Granata G, Manno A et al. Vitiligo: pathogenesis, clinical variants and treatment approaches. Autoimmun Rev. 2016; 15: 335-343. Available from: http://dx.doi.org/10.1016/j.autrev.2015.12.006

  52. Picardo M, Bastonini E. A new view of vitiligo: looking at normal-appearing skin. J Invest Dermatol. 2015; 135: 1713-1714. Available from: http://dx.doi.org/10.1038/jid.2015.92

  53. Jimbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br J Dermatol. 2001; 144: 55-65.

  54. Bishnoi A, Parsad D. Clinical and molecular aspects of vitiligo treatments. Int J Mol Sci. 2018; 19: 1509.

  55. Tobin DJ, Swanson NN, Pittelkow MR, Peters EM, Schallreuter KU. Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol. 2000; 191: 407-416.

  56. Yildirim M, Baysal V, Inaloz HS, Can M. The role of oxidants and antioxidants in generalized vitiligo at tissue level. J Eur Acad Dermatol Venereol. 2004; 18: 683-686.

  57. Maresca V, Roccella M, Roccella F, Camera E, Del Porto G, Passi S et al. Increased sensitivity to peroxidative agents as a possible pathogenic factor of melanocyte damage in vitiligo. J Invest Dermatol. 1997; 109: 310-313.

  58. Richmond JM, Frisoli ML, Harris JE. Innate immune mechanisms in vitiligo: danger from within. Curr Opin Immunol. 2013; 25: 676-682. Available from: http://dx.doi.org/10.1016/j.coi.2013.10.010

  59. Puri N, Mojamdar M, Ramaiah A. In vitro growth characteristics of melanocytes obtained from adult normal and vitiligo subjects. J Invest Dermatol. 1987; 88: 434-438.

  60. Zailaie MZ. Epidermal hydrogen peroxide is not increased in lesional and non-lesional skin of vitiligo. Arch Dermatol Res. 2017; 309: 31-42.

  61. Shi MH, Wu Y, Li L, Cai YF, Liu M, Gao XH et al. Meta-analysis of the association between vitiligo and the level of superoxide dismutase or malondialdehyde. Clin Exp Dermatol. 2017; 42: 21-29.

  62. Xiao BH, Shi M, Chen H, Cui S, Wu Y, Gao XH et al. Glutathione peroxidase level in patients with vitiligo: a meta-analysis. Biomed Res Int. 2016; 2016: 3029810. doi: 10.1155/2016/3029810.

  63. Hann SK, Nordlund J. Vitiligo: a monograph on basic and clinical science. Oxford: Blackwell Science; 2000. pp. 137-141.

  64. Morrone A, Picardo M, de Luca C, Terminali O, Passi S, Ippolito F. Catecholamines and vitiligo. Pigment Cell Res. 1992; 5: 65-69.

  65. Wood JM, Schallreuter KU. Studies on the reactions between human tyrosinase, superoxide anion, hydrogen peroxide and thiols. Biochim Biophys Acta. 1991; 1074: 378-385. doi: 10.1016/0304-4165(91)90088-x. PMID: 1653610.

  66. Camara-Lemarroy CR, Salas-Alanis JC. The role of tumor necrosis factor-α in the pathogenesis of vitiligo. Am J Clin Dermatol. 2013; 14: 343-350.

  67. Wang Y, Li S, Li C. Perspectives of new advances in the pathogenesis of vitiligo: from oxidative stress to autoimmunity. Med Sci Monit. 2019; 25: 1017-1023.

  68. Laddha NC, Dwivedi M, Mansuri MS, Gani AR, Ansarullah M, Ramachandran AV et al. Vitiligo: interplay between oxidative stress and immune system. Exp Dermatol. 2013; 22: 245-250.

  69. Rezaei N, Gavalas NG, Weetman AP, Kemp EH. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol. 2007; 21: 865-876.

  70. Jin Y, Birlea SA, Fain PR, Gowan K, Riccardi SL, Holland PJ et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med. 2010; 362: 1686-1697.

  71. Kang P, Zhang W, Chen X, Yi X, Song P, Chang Y et al. TRPM2 mediates mitochondria-dependent apoptosis of melanocytes under oxidative stress. Free Radic Biol Med. 2018; 126: 259-268. Available from: https://doi.org/10.1016/j.freeradbiomed.2018.08.022

  72. Boissy RE, Liu YY, Medrano EE, Nordlund JJ. Structural aberration of the rough endoplasmic reticulum and melanosome compartmentalization in long-term cultures of melanocytes from vitiligo patients. J Invest Dermatol. 1991; 97: 395-404.

  73. Eletto D, Chevet E, Argon Y, Appenzeller-Herzog C. Redox controls UPR to control redox. J Cell Sci. 2014; 127: 3649-3658.

  74. Zhang Y, Liu L, Jin L, Yi X, Dang E, Yang Y et al. Oxidative stress-induced calreticulin expression and translocation: new insights into the destruction of melanocytes. J Invest Dermatol. 2014; 134: 183-191. Available from: http://dx.doi.org/10.1038/jid.2013.268

  75. Wagner RY, Luciani F, Cario-André M, Rubod A, Petit V, Benzekri L et al. Altered E-cadherin levels and distribution in melanocytes precede clinical manifestations of vitiligo. J Invest Dermatol. 2015; 135: 1810-1819.

  76. Tang A, Eller MS, Hara M, Yaar M, Hirohashi S, Gilchrest BA. E-cadherin is the major mediator of human melanocyte adhesion to keratinocytes in vitro. J Cell Sci. 1994; 107: 983-992

  77. Rotzer V, Hartlieb E, Vielmuth F, Gliem M, Spindler V, Waschke J. E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion. Cell Mol Life Sci. 2015; 72: 4885-4897.

  78. Roskoski R Jr. Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol Res. 2015; 94: 9-25. Available from: http://dx.doi.org/10.1016/j.phrs.2015.01.003

  79. Gayrard C, Bernaudin C, Déjardin T, Seiler C, Borghi N. Src- and confinement-dependent FAK activation causes E-cadherin relaxation and β-catenin activity. J Cell Biol. 2018; 217: 1063-1077.

  80. Delmas V, Larue L. Molecular and cellular basis of depigmentation in vitiligo patients. Exp Dermatol. 2019; 28: 662-666.

  81. Reichert Faria A, Jung JE, Silva de Castro CC, de Noronha L. Reduced immunohistochemical expression of adhesion molecules in vitiligo skin biopsies. Pathol Res Pract. 2017; 213: 199-204. Available from: http://dx.doi.org/10.1016/j.prp.2016.12.019

  82. Schallreuter KU, Wood JM, Ziegler I, Lemke KR, Pittelkow MR, Lindsey NJ et al. Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochim Biophys Acta. 1994; 1226: 181-192.

  83. Filipp FV, Birlea S, Bosenberg MW, Brash D, Cassidy PB, Chen S et al. Frontiers in pigment cell and melanoma research. Pigment Cell Melanoma Res. 2018; 31: 728-735. doi: 10.1111/pcmr.12728.

  84. Elela MA, Hegazy RA, Fawzy MM, Rashed LA, Rasheed H. Interleukin 17, interleukin 22 and FoxP3 expression in tissue and serum of non-segmental vitiligo: a case- controlled study on eighty-four patients. Eur J Dermatol. 2013; 23: 350-355.

  85. Basak PY, Adiloglu AK, Ceyhan AM, Tas T, Akkaya VB. The role of helper and regulatory T cells in the pathogenesis of vitiligo. J Am Acad Dermatol. 2009; 60: 256-260. Available from: http://dx.doi.org/10.1016/j.jaad.2008.09.048

  86. Wang CQ, Cruz-Inigo AE, Fuentes-Duculan J, Moussai D, Gulati N, Sullivan-Whalen M et al. Th17 cells and activated dendritic cells are increased in vitiligo lesions. PLoS One. 2011; 6: e18907.

  87. Wang CQF, Akalu YT, Suarez-Farinas M, Gonzalez J, Mitsui H, Lowes MA et al. IL-17 and TNF synergistically modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis. J Invest Dermatol. 2013; 133: 2741-2752. Available from: http://dx.doi.org/10.1038/jid.2013.237

  88. Parsad D, Pandhi R, Juneja A. Effectiveness of oral Ginkgo biloba in treating limited, slowly spreading vitiligo. Clin Exp Dermatol. 2003; 28: 285-287.

  89. Dell'Anna ML, Mastrofrancesco A, Sala R, Venturini M, Ottaviani M, Vidolin AP et al. Antioxidants and narrow band-UVB in the treatment of vitiligo: a double-blind placebo controlled trial. Clin Exp Dermatol. 2007; 32: 631-636.

  90. Middelkamp-Hup MA, Bos JD, Rius-Diaz F, Gonzalez S, Westerhof W. Treatment of vitiligo vulgaris with narrow-band UVB and oral Polypodium leucotomos extract: a randomized double-blind placebo-controlled study. J Eur Acad Dermatol Venereol. 2007; 21: 942-950.

  91. Singh A, Kanwar AJ, Parsad D, Mahajan R. Randomized controlled study to evaluate the effectiveness of dexamethasone oral minipulse therapy versus oral minocycline in patients with active vitiligo vulgaris. Indian J Dermatol Venereol Leprol. 2014; 80: 29-35.

  92. Song X, Xu A, Pan W, Wallin B, Kivlin R, Lu S et al. Minocycline protects melanocytes against H2O2-induced cell death via JNK and p38 MAPK pathways. Int J Mol Med. 2008; 22: 9-16.

  93. Konigsberg FM. Nrf2: La historia de un nuevo factor de transcripción que responde a estrés oxidativo. Rev Educ Bioquimica. 2007; 26: 18-25.

  94. Song P, Li K, Liu L, Wang X, Jian Z, Zhang W et al. Genetic polymorphism of the Nrf2 promoter region is associated with vitiligo risk in Han Chinese populations. J Cell Mol Med. 2016; 20: 1840-1850.

  95. Chang Y, Li S, Guo W, Yang Y, Zhang W, Zhang Q et al. Simvastatin Protects Human Melanocytes from H2O2-Induced Oxidative Stress by Activating Nrf2. J Invest Dermatol. 2017; 137: 1286-1296. Available from: http://dx.doi.org/10.1016/j.jid.2017.01.020

  96. Jian Z, Li K, Song P, Zhu G, Zhu L, Cui T et al. Impaired activation of the Nrf2-ARE signaling pathway undermines H2O2-induced oxidative stress response: a possible mechanism for melanocyte degeneration in vitiligo. J Invest Dermatol. 2014; 134: 2221-2230. Available from: http://dx.doi.org/10.1038/jid.2014.152

  97. Richmond JM, Frisoli ML, Harris JE. Innate immune mechanisms in vitiligo: danger from within. Curr Opin Immunol. 2013; 25: 676-682. Available from: http://dx.doi.org/10.1016/j.coi.2013.10.010

  98. van den Boorn JG, Picavet DI, van Swieten PF, van Veen HA, Konijnenberg D, van Veelen PA et al. Skin-depigmenting agent monobenzone induces potent T-cell autoimmunity toward pigmented cells by tyrosinase haptenation and melanosome autophagy. J Invest Dermatol. 2011; 131: 1240-1251. Available from: http://dx.doi.org/10.1038/jid.2011.16

  99. Denman CJ, McCracken J, Hariharan V, Klarquist J, Oyarbide-Valencia K, Guevara-Patiño JA et al. HSP70i accelerates depigmentation in a mouse model of autoimmune vitiligo. J Invest Dermatol. 2008; 128: 2041-2048.

  100. Mosenson JA, Zloza A, Nieland JD, Garrett-Mayer E, Eby JM, Huelsmann EJ et al. Mutant HSP70 reverses autoimmune depigmentation in vitiligo. Sci Transl Med. 2013; 5: 174ra28.

  101. Mosenson JA, Zloza A, Klarquist J, Barfuss AJ, Guevara-Patino JA, Poole IC. HSP70i is a critical component of the immune response leading to vitiligo. Pigment Cell Melanoma Res. 2012; 25: 88-98. doi: 10.1111/j.1755-148x.2011.00916.x

  102. Mosenson JA, Flood K, Klarquist J, Eby JM, Koshoffer A, Boissy RE et al. Preferential secretion of inducible HSP70 by vitiligo melanocytes under stress. Pigment Cell Melanoma Res. 2014; 27: 209-220.

  103. Jacquemin C, Rambert J, Guillet S, Thiolat D, Boukhedouni N, Doutre MS 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: 1367-1375.

  104. Vázquez MB, Sureda M, Rebollo J. Dendritic cells I: basic biology and functions. Inmunologia. 2012; 31: 21-30.

  105. Kumar R, Herbert PE, Warrens AN. An introduction to death receptors in apoptosis. Int J Surg. 2005; 3: 268-277.

  106. Bhardwaj S, Rani S, Srivastava N, Kumar R, Parsad D. Increased systemic and epidermal levels of IL-17A and IL-1β promotes progression of non-segmental vitiligo. Cytokine. 2017; 91: 153-161. Available from: http://dx.doi.org/10.1016/j.cyto.2016.12.014

  107. Mesa-Villanueva M, Patiño PJ. Receptores tipo Toll: entre el reconocimiento de lo no propio infeccioso y las señales endógenas de peligro. Inmunologia. 2006; 25: 115-130.

  108. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408: 740-745.

  109. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004; 303: 1526-1529. doi: 10.1126/science.1093620

  110. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413: 732-738.

  111. Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe. 2011; 9: 363-375. doi: 10.1016/j.chom.2011.04.008.

  112. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009; 458: 514-518. Available from: http://dx.doi.org/10.1038/nature07725

  113. Schroder K, Tschopp J. The inflammasomes. Cell. 2010; 140: 821-832.

  114. Marie J, Kovacs D, Pain C, Jouary T, Cota C, Vergier B et al. Inflammasome activation and vitiligo/nonsegmental vitiligo progression. Br J Dermatol. 2014; 170: 816-823.

  115. Ferrari SM, Fallahi P, Santaguida G, Virili C, Ruffilli I, Ragusa F et al. Circulating CXCL10 is increased in non-segmental vitiligo, in presence or absence of autoimmune thyroiditis. Autoimmun Rev. 2017; 16: 946-950.

  116. Kemp EH, Gavalas NG, Gawkrodger DJ, Weetman AP. Autoantibody responses to melanocytes in the depigmenting skin disease vitiligo. Autoimmun Rev. 2007; 6: 138-142.

  117. Le Poole IC, van den Wijngaard RM, Westerhof W, Das PK. Presence of T cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Pathol. 1996; 148: 1219-1228.

  118. Zhang XD, Nguyen T, Thomas WD, Sanders JE, Hersey P. Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types. FEBS Lett. 2000; 482: 193-199.

  119. Dwivedi M, Kemp EH, Laddha NC, Mansuri MS, Weetman AP, Begum R. Regulatory T cells in vitiligo: implications for pathogenesis and therapeutics. Autoimmun Rev. 2015; 14: 49-56. Available from: http://dx.doi.org/10.1016/j.autrev.2014.10.002

  120. Taher ZA, Lauzon G, Maguiness S, Dytoc MT. Analysis of interleukin-10 levels in lesions of vitiligo following treatment with topical tacrolimus. Br J Dermatol. 2009; 161: 654-659.

  121. Reviews A, Pintelaan D. Autoimmunity Reviews. 2014.

  122. 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. Available from: http://dx.doi.org/10.1038/jid.2011.463

  123. Antonelli A, Ferrari SM, Fallahi P. The role of the Th1 chemokine CXCL10 in vitiligo. Ann Transl Med. 2015; 3: S16.

  124. Rashighi M, Agarwal P, Richmond JM, Harris TH, Dresser K, Su MW et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med. 2014; 6: 223ra23.

  125. Santaguida MG, Del Duca SC, Virili C, Gargano L, Centanni M. The presence of non-segmental vitiligo modifies intracellular cytokine subsets in patients with chronic lymphocytic thyroiditis. Int J Immunopathol Pharmacol. 2010; 23: 1203-1209.

  126. Ogg GS, Dunbar PR, Romero P, Chen JL, Cerundolo V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med. 1998; 188: 1203-1208.

  127. van den Boorn JG, Konijnenberg D, Dellemijn TA, van der Veen JP, Bos JD, Melief CJ et al. Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients. J Invest Dermatol. 2009; 129: 2220-2232. Available from: http://dx.doi.org/10.1038/jid.2009.32

  128. Wankowicz-Kalinska A, van den Wijngaard RM, Tigges BJ, Westerhof W, Ogg GS, Cerundolo V et al. Immunopolarization of CD4+ and CD8+ T cells to type-1-like is associated with melanocyte loss in human vitiligo. Lab Invest. 2003; 83: 683-695.

  129. Lili Y, Yi W, Ji Y, Yue S, Weimin S, Ming L. Global activation of CD8+ cytotoxic T lymphocytes correlates with an impairment in regulatory T cells in patients with generalized vitiligo. PLoS One. 2012; 7: e37513.

  130. Lang KS, Caroli CC, Muhm A, Wernet D, Moris A, Schittek B et al. HLA-A2 restricted, melanocyte-specific CD8(+) T lymphocytes detected in vitiligo patients are related to disease activity and are predominantly directed against MelanA/MART1. J Invest Dermatol. 2001; 116: 891-897.

  131. Palermo B, Campanelli R, Garbelli S, Mantovani S, Lantelme E, Brazzelli V et al. Specific cytotoxic T lymphocyte responses against Melan-A/MART1, tyrosinase and gp100 in vitiligo by the use of major histocompatibility complex/peptide tetramers: the role of cellular immunity in the etiopathogenesis of vitiligo. J Invest Dermatol. 2001; 117: 326-332.

  132. Mandelcorn-Monson RL, Shear NH, Yau E, Sambhara S, Barber BH, Spaner D et al. Cytotoxic T lymphocyte reactivity to gp100, MelanA/MART-1, and tyrosinase, in HLA-A2-positive vitiligo patients. J Invest Dermatol. 2003; 121: 550-556.

  133. Adams S, Lowes MA, O'Neill DW, Schachterle S, Romero P, Bhardwaj N. Lack of functionally active Melan-A(26-35)-specific T cells in the blood of HLA-A2β vitiligo patients. J Invest Dermatol. 2008; 128: 1977e80.

  134. Zhou L, Shi YL, Li K, Hamzavi I, Gao TW, Huggins RH et al. 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. 2015; 28: 324-329. doi: 10.1111/pcmr.12355.

  135. Naughton GK, Eisinger M, Bystryn JC. Antibodies to normal human melanocytes in vitiligo. J Exp Med. 1983; 158: 246-251.

  136. Naughton GK, Reggiardo D, Bystryn JC. Correlation between vitiligo antibodies and extent of depigmentation in vitiligo. J Am Acad Dermatol. 1986; 15: 978-981.

  137. Harning R, Cui J, Bystryn JC. Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Dermatol. 1991; 97: 1078-1080. doi: 10.1111/1523-1747.ep12492607.

  138. Cui J, Harning R, Henn M, Bystryn JC. Identification of pigment cell antigens defined by vitiligo antibodies. J Invest Dermatol. 1992; 98: 162-165. doi: 10.1111/1523-1747.ep12555773.

  139. Zúñiga-Rosales Y, González-Herrera Y, Miyares-Díaz E, Rodríguez-Pelier CV. Vitíligo: hipótesis autoinmune. Rev Biomed. 2014; 25: 145-155.

  140. Englaro W, Bahadoran P, Bertolotto C, Busca R, Dérijard B, Livolsi A et al. Tumor necrosis factor alpha-mediated inhibition of melanogenesis is dependent on nuclear factor kappa B activation. Oncogene. 1999; 18: 1553-1559.

  141. Wang S, Zhou M, Lin F, Liu D, Hong W, Lu L et al. Interferon-γ induces senescence in normal human melanocytes. PLoS One. 2014; 9: e93232.

  142. Gregg RK, Nichols L, Chen Y, Lu B, Engelhard VH. Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice. J Immunol. 2010; 184: 1909-1917.

  143. Webb KC, Tung R, Winterfield LS, Gottlieb AB, Eby JM, Henning SW et al. Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo. Br J Dermatol. 2015; 173: 641-650.

  144. Yang L, Wei Y, Sun Y, Shi W, Yang J, Zhu L 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: 664-670.

  145. Chatterjee S, Eby JM, Al-Khami AA, Soloshchenko M, Kang HK, Kaur N et al. A quantitative increase in regulatory T cells controls development of vitiligo. J Invest Dermatol. 2014; 134: 1285-1294. Available from: http://dx.doi.org/10.1038/jid.2013.540

  146. Richmond JM, Masterjohn E, Chu R, Tedstone J, Youd ME, Harris JE. CXCR3 depleting antibodies prevent and reverse vitiligo in mice. J Invest Dermatol. 2017; 137: 982-985. Available from: http://dx.doi.org/10.1016/j.jid.2016.10.048

  147. Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy. JAMA Dermatol. 2015; 151: 1110-1112. doi: 10.1001/jamadermatol.2015.1520

  148. Richmond JM, Bangari DS, Essien KI, Currimbhoy SD, Groom JR, Pandya AG 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: 350-358.

  149. Lee AY. Role of keratinocytes in the development of vitiligo. Ann Dermatol. 2012; 24: 115-125.

  150. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK et al. The vast majority of CLA+ T cells are resident in normal skin. J Immunol. 2006; 176: 4431-4439.

  151. Lotti T, D'Erme AM. Vitiligo as a systemic disease. Clin Dermatol. 2014; 32: 430-434. Available from: http://dx.doi.org/10.1016/j.clindermatol.2013.11.011

  152. Watanabe R, Gehad A, Yang C, Scott LL, Teague JE, Schlapbach C et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Transl Med. 2015; 7: 279ra39.

  153. Park CO, Kupper TS. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat Med. 2015; 21: 688-697.

  154. Boniface K, Jacquemin C, Darrigade AS, Dessarthe B, Martins C, Boukhedouni N et al. Vitiligo skin is imprinted with resident memory CD8 T cells expressing CXCR3. J Invest Dermatol. 2018; 138: 355-364. Available from: http://dx.doi.org/10.1016/j.jid.2017.08.038

  155. Granata G, Greco A, Iannella G, Granata M, Manno A, Savastano E et al. Posterior reversible encephalopathy syndrome--Insight into pathogenesis, clinical variants and treatment approaches. Autoimmun Rev. 2015; 14: 830-836. Available from: http://dx.doi.org/10.1016/j.autrev.2015.05.006

  156. Greco A, De Virgilio A, Rizzo MI, Gallo A, Magliulo G, Fusconi M et al. Microscopic polyangiitis: Advances in diagnostic and therapeutic approaches. Autoimmun Rev. 2015; 14: 837-844. Available from: http://dx.doi.org/10.1016/j.autrev.2015.05.005

  157. Greco A, Gallo A, Fusconi M, Magliulo G, Turchetta R, Marinelli C et al. Cogan's syndrome: an autoimmune inner ear disease. Autoimmun Rev. 2013; 12: 396-400. Available from: http://dx.doi.org/10.1016/j.autrev.2012.07.012

  158. Seneschal J, Clark RA, Gehad A, Baecher-Allan CM, Kupper TS. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity. 2012; 36: 873-884.

  159. Maeda Y, Nishikawa H, Sugiyama D, Ha D, Hamaguchi M, Saito T et al. Detection of self-reactive CD8? T cells with an anergic phenotype in healthy individuals. Science. 2014; 346: 1536-1540.

  160. Ben Ahmed M, Zaraa I, Rekik R, Elbeldi-Ferchiou A, Kourda N, Belhadj Hmida N et al. Functional defects of peripheral regulatory T lymphocytes in patients with progressive vitiligo. Pigment Cell Melanoma Res. 2012; 25: 99-109.

  161. Kroon MW, Vrijman C, Chandeck C, Wind BS, Wolkerstorfer A, Luiten RM et al. High prevalence of autoimmune thyroiditis in children and adolescents with vitiligo. Horm Res Paediatr. 2013; 79: 137-144.

  162. Sawicki J, Siddha S, Rosen C. Vitiligo and associated autoimmune disease: retrospective review of 300 patients. J Cutan Med Surg. 2012; 16: 261-266.

  163. Balagula Y, Garbe C, Myskowski PL, Hauschild A, Rapoport BL, Boers-Doets CB et al. Clinical presentation and management of dermatological toxicities of epidermal growth factor receptor inhibitors. Int J Dermatol. 2011; 50: 129-146.

  164. Palermo B, Garbelli S, Mantovani S, Scoccia E, Da Prada GA, Bernabei P et al. Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo. Eur J Immunol. 2005; 35: 3153-3162.

  165. Sheth VM, Guo Y, Qureshi AA. Comorbidities associated with vitiligo: a ten-year retrospective study. Dermatology. 2013; 227: 311-315.

  166. Dahir AM, Thomsen SF. Comorbidities in vitiligo: comprehensive review. Int J Dermatol. 2018; 57: 1157-1164.

  167. Baldini E, Odorisio T, Tuccilli C, Persechino S, Sorrenti S, Catania A et al. Thyroid diseases and skin autoimmunity. Rev Endocr Metab Disord. 2018; 19: 311-323.

  168. Castanet J, Ortonne JP. Pathophysiology of vitiligo. Clin Dermatol. 1997; 15: 845-851. doi: 10.1016/s0738-081x(97)00125-9.

  169. Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003; 16: 208-214.

  170. Cunliffe WJ, Hall R, Newell DJ, Stevenson CJ. Vitiligo, thyroid disease and autoimmunity. Br J Dermatol. 1968; 80: 135-139.

  171. Amerio P, Tracanna M, De Remigis P, Betterle C, Vianale L, Marra ME et al. Vitiligo associated with other autoimmune diseases: polyglandular autoimmune syndrome types 3B+C and 4. Clin Exp Dermatol. 2006; 31: 746-749.

  172. Kemp EH, Emhemad S, Akhtar S, Watson PF, Gawkrodger DJ, Weetman AP. Autoantibodies against tyrosine hydroxylase in patients with non-segmental (generalised) vitiligo. Exp Dermatol. 2011; 20: 35-40.

  173. Kemp EH, Gawkrodger DJ, Watson PF, Weetman AP. Immunoprecipitation of melanogenic enzyme autoantigens with vitiligo sera: evidence for cross-reactive autoantibodies to tyrosinase and tyrosinase-related protein-2 (TRP-2). Clin Exp Immunol. 1997; 109: 495-500.

  174. Kemp EH, Waterman EA, Gawkrodger DJ, Watson PF, Weetman AP. Autoantibodies to tyrosinase-related protein-1 detected in the sera of vitiligo patients using a quantitative radiobinding assay. Br J Dermatol. 1998; 139: 798-805.

  175. Baharav E, Merimski O, Shoenfeld Y, Zigelman R, Gilbrud B, Yecheskel G et al. Tyrosinase as an autoantigen in patients with vitiligo. Clin Exp Immunol. 1996; 105: 84-88.

  176. Neumeister P, Strunk D, Apfelbeck U, Sill H, Linkesch W. Adoptive transfer of vitiligo after allogeneic bone marrow transplantation for non-Hodgkin's lymphoma. Lancet. 2000; 355: 1334-1335.

  177. Cho SB, Roh MR, Chung KY, Lee KH, Park YK. Generalized vitiligo after allogeneic bone marrow transplantation. Acta Derm Venereol. 2005; 85: 82-83.

  178. Kawakami Y, Suzuki Y, Shofuda T, Kiniwa Y, Inozume T, Dan K et al. T cell immune responses against melanoma and melanocytes in cancer and autoimmunity. Pigment Cell Res. 2000; 13 Suppl 8: 163-169.

  179. Yee C, Thompson JA, Roche P, Byrd DR, Lee PP, Piepkorn M et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo. J Exp Med. 2000; 192: 1637-1644.

  180. Dwivedi M, Laddha NC, Arora P, Marfatia YS, Begum R. Decreased regulatory T-cells and CD4(+) /CD8(+) ratio correlate with disease onset and progression in patients with generalized vitiligo. Pigment Cell Melanoma Res. 2013; 26: 586-591. doi: 10.1111/pcmr.12105.




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