Vitiligo pp 277-283 | Cite as

Oxidative Stress and Intrinsic Defects

  • Mauro PicardoEmail author
  • Maria Lucia Dell’Anna


Overall, experimental data support intrinsic damage and a close link between oxidative stress and immune responses. For example, histological analysis of developing lesions shows NALP1 (NACHT, LRR, and PYD domain-containing protein 1), IL-1, and catalase expression; moreover, the expression levels of heme oxygenase 1 in plasma have been linked to the activity phase of the disease and to IL-2 levels. All of these factors are involved both in stress responses and triggering of innate immunity. In summary, genetic, experimental, and clinical studies have revealed important pathways in the pathogenesis of vitiligo and have identified targets for the development of new therapies.

Our unified view considers the intrinsic defect in melanocytes as the initial event. In this model, oxidative stress in the melanocytes leads to a local inflammatory response and the activation of innate immune processes, which, in subjects with a genetic predisposition to develop autoimmunity, generate melanocyte-specific cytotoxic immune responses.


  1. 1.
    Le Poole IC, Das PK, van den Wijngaard RM, Bos JD, Westerhof W. Review of the etiopathomechanism of vitiligo: a convergence theory. Exp Dermatol. 1993;4:145–53.CrossRefGoogle Scholar
  2. 2.
    Schallreuter KU, et al. Vitiligo pathogenesis: autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else? Exp Dermatol. 2008;2:139–140; discussion 139–160.Google Scholar
  3. 3.
    Dell’Anna ML, Picardo M. A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo. Pigment Cell Res. 2006;5:406–11.CrossRefGoogle Scholar
  4. 4.
    Liu L, et al. Promoter variant in the catalase gene is associated with vitiligo in Chinese people. J Invest Dermatol. 2010;11:2647–53.CrossRefGoogle Scholar
  5. 5.
    Sravani PV, 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;3:268–2671.Google Scholar
  6. 6.
    Schallreuter KU, Wood JM, Berger J. Low catalase levels in the epidermis of patients with vitiligo. J Invest Dermatol. 1991;97:1081–5.CrossRefGoogle Scholar
  7. 7.
    Maresca V, et al. Increased sensitivity to peroxidative agents as a possible pathogenic factor of melanocyte damage in vitiligo. J Invest Dermatol. 1997;3:310–3.CrossRefGoogle Scholar
  8. 8.
    Bulut H, et al. Lack of association between catalase gene polymorphism (T/C exon 9) and susceptibility to vitiligo in a Turkish population. Genet Mol Res. 2011;4:4126–32.CrossRefGoogle Scholar
  9. 9.
    Kostyuk VA, et al. Dysfunction of glutathione S-transferase leads to excess 4-hydroxy-2-nonenal and H(2)O(2) and impaired cytokine pattern in cultured keratinocytes and blood of vitiligo patients. Antiox Redox Signal. 2010;5:607–20.CrossRefGoogle Scholar
  10. 10.
    Vafaee T, Rokos H, Salem MM, Schallreuter KU. In vivo and in vitro evidence for epidermal H2O2-mediated oxidative stress in piebaldism. Exp Dermatol. 2010;10:883–7.Google Scholar
  11. 11.
    Ozturk IC, Batcioglu K, Karatas F, Hazneci E, Genc M. Comparison of plasma malondialdehyde, glutathione, glutathione peroxidase, hydroxyproline and selenium levels in patients with vitiligo and healthy controls. Indian J Dermatol. 2008;3:106–10. Scholar
  12. 12.
    Dell’Anna ML, et al. Membrane lipid alterations as a possible basis for melanocyte degeneration in vitiligo. J Invest Dermatol. 2007;5:1226–33.CrossRefGoogle Scholar
  13. 13.
    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;1:55–65.CrossRefGoogle Scholar
  14. 14.
    Boissy RE, Manga P. On the etiology of contact/occupational vitiligo. Pigment Cell Res. 2004;3:208–14.CrossRefGoogle Scholar
  15. 15.
    Hasse S, Gibbons NC, Rokos H, Marles LK, Schallreuter KU. Perturbed 6-tetrahydrobiopterin recycling via decreased dihydropteridine reductase in vitiligo: more evidence for H2O2 stress. J Invest Dermatol. 2004;2:307–13.CrossRefGoogle Scholar
  16. 16.
    Schallreuter KU, Elwary SM, Gibbons NC, Rokos H, Wood JM. Activation/deactivation of acetylcholinesterase by H2O2: more evidence for oxidative stress in vitiligo. Biochem Biophys Res Commun. 2004;2:502–8.CrossRefGoogle Scholar
  17. 17.
    Dell’Anna ML, et al. Membrane lipid defects are responsible for the generation of reactive oxygen species in peripheral blood mononuclear cells from vitiligo patients. J Cell Physiol. 2010;1:187–93.Google Scholar
  18. 18.
    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;2:171–8.CrossRefGoogle Scholar
  19. 19.
    Wagner R, et al. Altered e-cadherin levels and distribution in melanocytes precedes clinical manifestations of vitiligo. J Invest Dermatol. 2015.
  20. 20.
    Gauthier Y, Cario-Andrè 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.CrossRefGoogle Scholar
  21. 21.
    Rokos H, Beazley WD, Schallreuter KU. Oxidative stress in vitiligo: photo-oxidation of pterins produces H(2)O(2) and pterin-6-carboxylic acid. Biochem Biophys Res Commun. 2002;4:805–11.CrossRefGoogle Scholar
  22. 22.
    Moore J, Wood JM, Schallreuter KU. Evidence for specific complex formation between alpha-melanocyte stimulating hormone and 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin using near infrared Fourier transform Raman spectroscopy. Biochemistry. 1999;46:15317–24.CrossRefGoogle Scholar
  23. 23.
    Schallreuter KU, et al. Epidermal H(2)O(2) accumulation alters tetrahydrobiopterin (6BH4) recycling in vitiligo: identification of a general mechanism in regulation of all 6BH4-dependent processes? J Invest Dermatol. 2001;1:167–74.CrossRefGoogle Scholar
  24. 24.
    Bellei B, et al. Vitiligo: a possible model of degenerative diseases. PLoS One. 2013;3:e59782.CrossRefGoogle Scholar
  25. 25.
    Salem MMAEL, Shalbaf M, Gibbons NCJ, Chavan B, Thornton JM, Schallreuter KU. Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage. FASEB J. 2009;23:3790–807.CrossRefGoogle Scholar
  26. 26.
    Xavier JM, Morgado AL, Solá S, Rodrigues CM. Mitochondrial translocation of p53 modulates neuronal fate by preventing differentiation-induced mitochondrial stress. Antiox Redox Signal. 2014;21:1009–24.CrossRefGoogle Scholar
  27. 27.
    Dell’Anna ML, et al. Alterations of mitochondria in peripheral blood mononuclear cells of vitiligo patients. Pigment Cell Res. 2003;16:553–9.CrossRefGoogle Scholar
  28. 28.
    Dell’Anna ML, Maresca V, Briganti S, Camera E, Falchi M, Picardo M. Mitochondrial impairment in peripheral blood mononuclear cells during the active phase of vitiligo. J Invest Dermatol. 2001;117:908–13.CrossRefGoogle Scholar
  29. 29.
    Nakagawa T, Guarente L. SnapShot: sirtuins, NAD, and aging. Cell Metab. 2014;20:192.CrossRefGoogle Scholar
  30. 30.
    Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24:464–71.CrossRefGoogle Scholar
  31. 31.
    Shulyakova N, Sidorova-Darmos E, Fong J, Zhang G, Mills LR, Eubanks JH. Over-expression of the Sirt3 sirtuin protects neuronally differentiated PC12 cells from degeneration induced by oxidative stress and trophic withdrawal. Brain Res. 2014. pii:S0006-8993(14)01161-5.Google Scholar
  32. 32.
    Vega-Naredo I, Cunha-Oliveira T, Serafim TL, Sardao VA, Oliveira PJ. Analysis of pro-apoptotic protein trafficking to and from mitochondria. Methods Mol Biol. 2015;1241:163–80.CrossRefGoogle Scholar
  33. 33.
    Green DR, Galluzzi L, Kroemer G. Cell biology. Metabolic control of cell death. Science. 2014;345:1250256.CrossRefGoogle Scholar
  34. 34.
    Martel C, Wang Z, Brenner C. VDAC phosphorylation, a lipid sensor influencing the cell fate. Mitochondrion. 2014. pii: 1400100-7.Google Scholar
  35. 35.
    Basak NP, Roy A, Banerjee S. Alteration of mitochondrial proteome due to activation of Notch1 signaling pathway. J Biol Chem. 2014;11:7320–34.CrossRefGoogle Scholar
  36. 36.
    de Moura MB, Uppala R, Zhang Y, Van Houten B, Goetzman ES. Overexpression of mitochondrial sirtuins alters glycolysis and mitochondrial function in HEK293 cells. PLoS One. 2014;9:e106028.CrossRefGoogle Scholar
  37. 37.
    Dai SH, et al. Sirt3 attenuates hydrogen peroxide-induced oxidative stress through the preservation of mitochondrial function in HT22 cells. Int J Mol Med. 2014;34:1159–68.CrossRefGoogle Scholar
  38. 38.
    Wu YT, Wu SB, Wie YH. Roles of sirtuins in the regulation of antioxidant defense and bioenergetic function of mitochondria under oxidative stress. Free Radic Res. 2014;48:1070–84.CrossRefGoogle Scholar
  39. 39.
    Giblin W, Skinner ME, Lombard DB. Sirtuins: guardians of mammalian healthspan. Trends Genet. 2014;30:271–86.CrossRefGoogle Scholar
  40. 40.
    Prignano F, et al. Ultrastructural and functional alterations of mitochondria in perilesional vitiligo skin. J Dermatol Sci. 2009;54:157–67.CrossRefGoogle Scholar
  41. 41.
    Bondanza S, et al. Keratinocyte cultures from involved skin in vitiligo patients show an impaired in vitro behaviour. Pigment Cell Res. 2007;20:288–300.CrossRefGoogle Scholar
  42. 42.
    Bastonini E, Kovacs D, Ottaviani M, Dell’Anna ML, Picardo M. Vitiligo: focusing on the dermal compartment. OP at XII International Pigment Cell Conference, 4–7 September 2014, Singapore, abstract book p970; 2014.Google Scholar
  43. 43.
    Zhang CF, et al. Suppression of autophagy dysregulates the antioxidant response and causes premature senescence of melanocytes. J Invest Dermatol. 2014;
  44. 44.
    Ainger SA, et al. DCT protects human melanocytic cells from UVR and ROS damage and increases cell viability. Exp Dermatol. 2014;
  45. 45.
    Lee A-Y, Kim N-H, Choi W-I, Youm Y-H. Less keratinocyte-derived factors related to more keratinocyte apoptosis in depigmented than normally pigmented suction-blistered epidermis may cause passive melanocyte death in vitiligo. J Invest Dermatol. 2005;124:976–83.CrossRefGoogle Scholar
  46. 46.
    Cario-André M, Pain C, Gauthier Y, Casoli V, Taoeb A. In vivo and in vitro evidence of dermal fibroblasts influence on human epidermal pigmentation. Pigment Cell Res. 2006;19:434–42.CrossRefGoogle Scholar
  47. 47.
    Imokawa G. Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders. Pigment Cell Res. 2004;17:96–100.CrossRefGoogle Scholar
  48. 48.
    Shi Y, Luo LF, Liu XM, Zhou Q, Xu SZ, Lei TC. Premature graying as a consequence of compromised antioxidant activity in hair bulb melanocytes and their precursors. PLoS One. 2014;9:e93589. Scholar
  49. 49.
    Kim J, et al. p53 induces skin aging by depleting Blimp1+ sebaceous gland cells. Cell Death Dis. 2014;5:e1141. Scholar
  50. 50.
    Laddha NC, et al. Role of oxidative stress and autoimmunity in onset and progression of vitiligo. Exp Dermatol. 2014;5:352–3.CrossRefGoogle Scholar
  51. 51.
    Mosenson JA, et al. Mutant HSP70 reverses autoimmune depigmentation in vitiligo. Science Transl Med. 2013;5:174ra128.CrossRefGoogle Scholar
  52. 52.
    Yu R, et al. Transcriptome analysis reveals markers of aberrantly activated innate immunity in vitiligo lesional and non-lesional skin. PLoS One. 2012;7:e51040.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Cutaneous Physiopathology and CIRMSan Gallicano Dermatological Institute, IRCCSRomeItaly
  2. 2.Laboratory of Cutaneous PhysiopathologySan Gallicano Dermatological Institute IFORomeItaly

Personalised recommendations