|SYMPOSIUM - VITILIGO
|Year : 2012 | Volume
| Issue : 1 | Page : 24-29
On the pathophysiology of vitiligo: Possible treatment options
Raymond E Boissy1, Maria Lucia Dell'Anna2, Mauro Picardo2
1 Department of Dermatology, University of Cincinnati, Cincinnati, Ohio, USA
2 Cutaneous Physiopathology and CIRM San Gallicano Dermatologic Institute-IFO, Rome, Italy
|Date of Web Publication||17-Dec-2011|
Cutaneous Physiopathology and CIRM, San Gallicano Dermatologic Institute-IFO, via Elio Chianesi, 53, 00100 Rome
Source of Support: None, Conflict of Interest: None
Vitiligo is an acquired depigmenting disorder usually classified as non-segmental and segmental types with a higher incidence of the non-segmental ones. The cause of non-segmental vitiligo is still unknown. Currently, it is a dogma that there are several genes affecting the immune system and the pigment system that predisposes someone to develop vitiligo. A precipitating factor must then ellicit an interaction between the immune system and the melanocyte, resulting in destruction of the melanocyte population in discrete areas of the skin. Starting from the overlapping but distinct pathomechanisms, treatment should be finalized to the cellular targets and possibly related to the disease phase.
Keywords: Pathogenesis, treatment options, vitiligo
|How to cite this article:|
Boissy RE, Dell'Anna ML, Picardo M. On the pathophysiology of vitiligo: Possible treatment options. Indian J Dermatol Venereol Leprol 2012;78:24-9
|How to cite this URL:|
Boissy RE, Dell'Anna ML, Picardo M. On the pathophysiology of vitiligo: Possible treatment options. Indian J Dermatol Venereol Leprol [serial online] 2012 [cited 2021 Jan 23];78:24-9. Available from: https://www.ijdvl.com/text.asp?2012/78/1/24/90943
| Introduction|| |
Vitiligo is an acquired depigmenting disorder usually classified as non-segmental and segmental types with a higher incidence of the non-segmental types. The definition of the two forms is still a matter of discussion, and is mainly based on clinical evidence. The cause of non-segmental vitiligo is still unknown. It seems to require the following three factors: (1) a complex of vitiligo susceptibility genes that influence the autoimmune response; (2) genetically abnormal melanocytes; and (3) an environmental or physiological factor(s) that activates the genetic program for melanocyte destruction.  The current dogma is that there are several genes affecting the immune system and the pigment system that predisposes someone to develop vitiligo. However, a precipitating factor must ellicit an interaction between the immune system and the melanocyte, resulting in the destruction of the melanocyte population in discrete areas of the skin. Regarding the segmental type, different pathogenic mechanisms have been proposed, mainly linked to mosaicism phenomenon. This review is mainly referred to the pathogenic mechanism involved in non-segmental vitiligo.
| Inflammatory Mediators|| |
It is clear that the melanocyte population in the depigmented epidermis has been depleted. Accompanying this removal there can be a subtle appearance of immunocytes in these lesions, particularly at the border between the depigmented and normal appearing skin.  The presence of inflammatory cells at the border of a vitiligo lesion can become very marked, particularly in inflammatory vitiligo, which is manifested by red, edematous, and itchy skin. Many a time, these findings are subclinical. When present, these inflammatory cells are predominantly CD4+ and CD8+ T-cells , that can express the skin homing CLA marker.  In addition, CD11+ dendritic cells, capable of antigen presentation, have been identified in close proximity to the melanocytes in perilesional skin.  Functionally, T-cells isolated from vitiligo lesions can demonstrate melanocyte-specific cytotoxicity in non-lesional skin.  However, in a significant number of lesions, immunocytes may not be detectable, especially in lesions that are dormant.
There is additional evidence for a melanocyte-specific autoimmune response mediating melanocyte removal in vitiligo. Immunotherapy for metastatic melanoma utilizes melanocyte-specific T-cells to destroy the malignant melanocytes. Tumors regress at times and some patients develop depigmentation of normal-appearing skin.  The depigmentation resembles vitiligo, although it is not known if the mechanism of destruction is identical to/or similar to that which occurs in vitiligo. In one publication, a melanoma patient treated with CD8+ T-cell clone that was reactive for melanoma antigen recognized by T-cells (MelanA/MART-1) developed multiple depigmented lesions,  demonstrating that cytotoxic CD8+ cells against melanocyte differentiation antigens can cause melanocyte destruction that results in depigmentation.
The humoral immune system also has been implicated in the etiology of vitiligo. Serum autoantibodies against many melanocyte cytoplasmic antigens have been identified in vitiligo patients.  Serum from patients with vitiligo can cause antibody-dependent cellular cytotoxicity as well as complement-dependent cytotoxicity of cultured melanocytes. , In addition, injection of the IgG fraction of serum from patients with vitiligo into the human skin grafted on nude mice results in melanocyte destruction in the graft, suggesting a pathogenetic role for autoantibodies in vitiligo. , These antibodies are indeed able to destroy the melanocytes in vitro by complement-mediated damage and antibody-dependent cytotoxicity. Moreover, the antibodies against MCHR1 (melanin concentrating hormone receptor 1), found in vitiligo sera, can stimulate it and counteract the activity of alpha melanocyte stimulating hormone (aMSH). Histological evidence of B cells or immunoglobulin deposits in the epidermis of advancing lesions of vitiligo has not been demonstrated. , It is yet to be confirmed whether these melanocyte-specific antibodies play a direct or indirect role in the etiology of vitiligo.
| Genes|| |
Genetic analysis of vitiligo, specifically with the use of genome-wide linkage and associated studies, is beginning to provide information about the genes that are associated with vitiligo.  Several recent genes identified as candidates in the etiology of vitiligo have effects on the immune response and are involved in the cause of other autoimmune disorders. One locus at chromosome 1p31.3-32.2 (labeled as an autoimmunity susceptibility locus - AIS1) contains multiple genes. Single nucleotide polymorphisms (SNPs) in one of these candidate genes (Forkhead box D3-FOXD3) co-segregated with vitiligo in the study of a single family.  FOXD3 encodes a forkhead transcription factor that is a primary regulator of melanoblast differentiation in the embryonic neural crest.  However, other vitiligo patients do not appear to have mutations of FOXD3, and other families do not show linkage to the AIS1 region of chromosome 1p,  suggesting that this mutation may be a unique isolate.
A second candidate gene is NACHT-LRR-PYD-containing protein 1 (NALP1) on chromosome 17p13. , This gene was first identified by Nath et al,  who noted that it is associated both with vitiligo and lupus erythematosus. This gene was later found to interact with a loci on chromosomes 7 and 9.  This is a very interesting gene because the NALP1 protein is a component of the inflammasome, a cytoplasmic multiprotein complex that regulates the innate immune system, mediates the maturation of proinflammatory cytokines like interleukin-1b and -18, and stimulates cellular apoptosis.  This gene and its activities could be involved in causing melanocyte destruction and thereby vitiligo.
Recently, significant associations between generalized vitiligo and SNPs at several other loci previously associated with other autoimmune disease have been detected.  The strongly associated SNPs were distributed across the major-histocompatibility-complex (MHC) loci on chromosome 6p21.3 between several MHC class I and class II encoding area. In addition, it has recently been reported that variants in protein tyrosine phosphatase, non receptor type 22 (PTPN22),, that putatively functions as a general autoimmunity susceptibility loci, and SPARC-related modular calcium binding protein 2 (SMOC2), of unknown function, may also be associated with the risk of vitiligo.
| Melanocyte as the First Player|| |
In addition to a genetic aberration in the immune system, the etiology of vitiligo appears to also have a genetic defect in the melanocyte itself. Prior studies have demonstrated that the melanocytes in the skin of vitiligo patients can exhibit morphologic abnormalities including enlargement, fragmentation, extracellular granular material, and dilated rough endoplasmic reticulum.  Several other studies have demonstrated that the melanocyte from vitiligo skin appears fragile. The inability to culture melanocytes from pigmented skin of vitiligo patients using routine procedures and the fragility of established cultures of melanocytes have been demonstrated.  The most suggestive evidence that vitiligo melanocytes possess a genetic aberration was demonstrated by a study where an isoform of tyrosinase was also identified to correlate with vitiligo by a genome-wide association study.  A more recent study assessed SNPs for genes encoding enzymes involved in melanin synthesis in patients with vitiligo and found evidence for association of tyrosinase and dopa chrome tautomerase with vitiligo susceptibility.  These studies confirm the long-held theory that an innate defect in vitiligo melanocytes exists.
| Crashing Events|| |
Despite the fact that genetic alterations in the immune system and the melanocyte may exist in vitiligo, a precipitating factor must be the basis for instigating melanocyte destruction in this post-natally acquired disease. Sometimes, occurrence of congenital vitiligo has been suggested, but until now, there is no population study confirming that. The concordance of vitiligo in monozygotic twins is only 23%, indicating that a non-genetic component also plays an important role in vitiligo.  Anecdotal correlations of personal events with the onset of vitiligo also imply the existence of a precipitating factor. These events include severe sunburn, pregnancy, physical and emotional stress/trauma, wounds or areas of microtrauma, etc.  Contact/occupational vitiligo is the most obvious form of the disease that correlates a precipitating factor (primarily phenolic and catecholic derivatives) with the onset of melanocyte destruction. , What most of these putative precipitating factors have in common is that they facilitate facultative pigmentation of the skin. Melanocyte-stimulating hormone induced by ultraviolet (UV) overexposure,  estrogens upregulated during pregnancy, , cytokines produced during emotional stress and/or physical trauma (i.e., nerve growth factor, neurotrophins, adrenocorticotrophichormone (ACTH), endorphins, etc.), ,,,, and cytokines released during wound healing, particularly at sites of microtrauma,  can all trigger facultative melanin synthesis by melanocytes. Therefore, enhanced facultative melanization could put undue intolerable stress on the vitiligo melanocyte resulting from an elevation in the cytotoxic oxidative melanin intermediates. Consistent with this is the correlation of a tyrosinase isoform with vitiligo as described above.  This isoform of tyrosinase could allow the melanocyte to present a melanocyte-specific autoantigen to the primed hyper-reactive immune system inducing autoimmunity. Alternatively, transcription and/or maintenance of this isoform of tyrosinase may render the melanocyte to be hyper-reactive to facultative stimulators of melanization and consequently increase pigment production beyond the threshold tolerated by the vitiligo melanocytes.
| The Oxidative Pathway Forwards the Destruction|| |
How can the various precipitating factors initiate the interplay between the sensitive vitiligo melanocytes and the autoimmune response leading to melanocyte removal? The induction and/or combating of oxidative stress have been implicated in numerous studies.  Disruption of the biopterin metabolic pathway and network can induce H 2 O 2 generation or impede its neutralization. , Generation of reactive oxygen species is hazardous to the cells initially causing lipid peroxidation, etc.  and ultimately inducing apoptosis.  It has recently been demonstrated that vitiligo melanocytes exhibit (1) more reactive oxygen species, (2) membrane peroxidation, (3) impaired mitochondrial electron transport chain complex 1, and (4) more readily induced apoptosis, all characteristics of cells susceptible to death by oxidative stress.  It has been demonstrated by several independent studies that the antioxidant catalase, and putatively the ability to combat oxidative stress, appears to be genetically impaired in some patients with vitiligo. Specifically, (1) levels of catalase in the epidermis of some patients with vitiligo are reduced,  (2) a variant genotype of catalase (C>T SNP in codon 419 of exon 10) has been associated with susceptibility to vitiligo,  and (3) a promoter variant of the Catalase gene (-89A>T) correlates with susceptibility to vitiligo in the Chinese population.  Many alternative cellular abnormalities have also been suggested to occur in vitiligo melanocytes such as lipid alterations in the mitochondria,  impairment in the survival/apoptosis regulation of cell survival,  and inability to be stably attached to the basement membrane.  However, a common cellular/molecular denominator among these possible inherent defects have yet to be identified. It is possible that multiple and distinct genetically determined inherent defects can perturb the melanocytes and promote apoptosis that may occur throughout the vitiligo syndrome. Regardless, cells that dysfunction and head towards apoptosis have been demonstrated to induce a consequential autoimmune response that perpetuates the disease. 
| The Cellular-Oriented Treatment|| |
Starting from the overlapping but distinct pathomechanisms, treatment should be finalized to the cellular targets and possibly related to the disease phase.
Regardless of the pathogenetic role, aberrant immune response can be counteracted, at least, at onset or during the relapse phases. High potent topical or systemic corticosteroids have been used with variable effectiveness.  Dexamethasone 10 mg divided in 2 days as pulse therapy in adults has been reported to stop rapidly progressive vitiligo, causing less severe side effects compared to the continuous regimen. Topical immunomodulators (TIMS), act both on inflammatory and differentiation processes. Tacrolimus has provided excellent repigmentation mainly when administered under occlusion (hydrocolloid dressing).  Both tacrolimus and pimecrolimus are able to modulate the maturation/activation of T cells and the migration of melanocytes and melanoblasts. This last property of the TIM may thus affect the differentiation process, probably compromised during vitiligo. Currently, tacrolimus ointment is provided as a 0.1% cream applied for at least 10 weeks.
Controversial opinion exists about the effectiveness of antioxidant molecules. The debate arises from the poor understanding of the pathogenetic role of the redox equilibrium loss, as well as from the frequent uncontrolled and miraculous suggestions. Starting from the above described and experimentally tested relevance of the cellular oxidative stress, the restoration of the redox balance has therapeutical value. A balanced pool of antioxidants should be preferred to a single molecule one. It should be orally administered during the reactivation phases and as adjuvant to the phototherapies. Arrest of the progression and repigmentation have been observed and published. 
To the best of our the knowledge, the gold standard therapy is phototherapy. The biological basis for its use, origins from the in vitro ability of UV to induce migration and differentiation of the melanocytes. Several different sources are available: UVA, BB-UVB, NB-UVB, excimer. Most of the trials conducted with NB-UVB, were able to provide up to 70% repigmentation. However, the protocols are still different among the various European and World dermatologic centers. The initial dose may be 70% of the minimum erythema dose (MED) or a defined absolute value (100-280 mJ/cm 2 ), the progressive increments range from 20 to 50%, the overall treatment ranges from 6 to 12 months. Consequently, the effectiveness is too hard to compare. 
| References|| |
|1.||Boissy RE, Spritz RA. Frontiers and controversies in the pathobiology of vitiligo: Separating the wheat from the chaff. Exp Dermatol 2009;18:583-5. |
|2.||Hann SK, Park YK, Lee KG, Choi EH, Im S. Epidermal changes in active vitiligo. J Dermatol 1992;19:217-22. |
|3.||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;148:1219-28. |
|4.||Tu CX, Gu JS, Lin XR. Increased interleukin-6 and granulocyte-macrophage colony stimulating factor levels in the sera of patients with non-segmental vitiligo. J Dermatol Sci 2003;31:73-8. |
|5.||van den Wijngaard R, Wankowicz-Kalinska A, Le Poole C, Tigges B, Westerhof W, Das P. Local immune response in skin of generalized vitiligo patients: Destruction of melanocytes is associated with the prominent presence of CLA+ T cells at the perilesional site. Lab Invest 2000;80:1299-309. |
|6.||Kroll TM, Bommiasamy H, Boissy RE, Nickoloff BJ, Mestril R, Le Poole IC. 4-Tertiary butyl phenol exposure sensitizes melanocytes to dendritic cell mediated killing. J Invest Dermatol 2005;124:798-806. |
|7.||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;129:2220-32. |
|8.||Luiten RM, Kueter EW, Mooi W, Gallee MP, Rankin EM, Gerritsen WR, et al. Immunogenicity, including vitiligo, and feasibility of vaccination with autologous GM-CSF-transduced tumor cells in metastatic melanoma patients. J Clin Oncol 2005;23:8978-91. |
|9.||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;192:1637-44. |
|10.||Kemp EH, Gavalas NG, Gawkrodger DJ, Weetman AP. Autoantibody responses to melanocytes in the depigmenting skin disease vitiligo. Autoimmun Rev 2007;6:138-42. |
|11.||Kemp EH, Wwwtman AP, Gawkrodger DG.Humoral Immunity. In: Picardo M, Taieb A, editors. Vitiligo, Berlin, Hedelberg: Springer-Verlag; 2010. p. 248-56. |
|12.||Norris DA, Kissinger GM, Naughton GM, Bystryn JC. Evidence for immunologic mechanisms in human vitiligo: Patients' sera induce damage to human melanocytes in vitro by complement-mediated damage and antibody-dependent cellular cytotoxicity. J Invest Dermatol 1988;90:783-9. |
|13.||Gilhar A, Zelickson B, Ulman Y, Etzioni A. In vivo destruction of melanocytes by the IgG fraction of serum from patients with vitiligo. J Invest Dermatol 1995;105:683-6. |
|14.||Hertz KC, Gazze LA, Kirkpatrick CH, Katz SI. Autoimmune vitiligo: Detection of antibodies to melanin-producing cells. N Engl J Med 1977;297:634-7. |
|15.||Bleehen SS. Histology of vitiligo. In: Klaus SN, editor. Pigment Cell 5: Part II of Proceedings of the Xth International Pigment Cell Conference, Cambridge, Massachusetts, 1977. Basel/New York: S. Karger; 1979. p. 54-61. |
|16.||Spritz RA. Shared genetic relationships underlying generalized vitiligo and autoimmune thyroid disease. Thyroid 2010;20:745-54. |
|17.||Alkhateeb A, Fain PR, Spritz RA. Candidate functional promoter variant in the FOXD3 melanoblast developmental regulator gene in autosomal dominant vitiligo. J Invest Dermatol 2005;125:388-91. |
|18.||Kos R, Reedy MV, Johnson RL, Erickson CA. The winged-helix transcription factor FoxD3 is important for establishing the neural crest lineage and repressing melanogenesis in avian embryos. Development 2001;128:1467-79. |
|19.||Spritz RA. Genetics. In: Picardo M, Taieb A, editors. Vitiligo. Berlin Heidelberg: Springer-Verlag; 2010. p. 155-64. |
|20.||Jin Y, Birlea SA, Fain PR, Spritz RA. Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J Invest Dermatol 2007;127:2558-62. |
|21.||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;356:1216-25. |
|22.||Nath SK, Kelly JA, Namjou B, Lam T, Bruner GR, Scofield RH, et al. Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus. Am J Hum Genet 2001;69:1401-6. |
|23.||Jin Y, Riccardi SL, Gowan K, Fain PR, Spritz RA. Fine-mapping of vitiligo susceptibility loci on chromosomes 7 and 9 and interactions with NLRP1 (NALP1). J Invest Dermatol 2010;130:774-83. |
|24.||Martinon F, Gaide O, Petrilli V, Mayor A, Tschopp J. NALP inflammasomes: A central role in innate immunity. Semin Immunopathol 2007;29:213-29. |
|25.||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;362:1686-97. |
|26.||LaBerge GS, Bennett DC, Fain PR, Spritz RA. PTPN22 is genetically associated with risk of generalized vitiligo, but CTLA4 is not. J Invest Dermatol 2008;128:1757-62. |
|27.||Laberge GS, Birlea SA, Fain PR, Spritz RA. The PTPN22-1858C>T (R620W) functional polymorphism is associated with generalized vitiligo in the Romanian population. Pigment Cell Melanoma Res 2008;21:206-8. |
|28.||Birlea SA, Gowan K, Fain PR, Spritz RA. Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. J Invest Dermatol 2010;130:798-803. |
|29.||Boissy RE. Histology of vitiliginous skin. In: Hann SK, Nordlund JJ, editors. Vitiligo: Monograph on the Basic and Clinical Science 1 st ed. Oxford, England: Blackwell Science Ltd; 2000. p. 23-34. |
|30.||Boissy RE. The intrinsic (genetic) theory for the cause of vitiligo. In: Hann SK, Nordlund JJ, editors. Vitiligo A Monograph on the Basic and Clinical Science. Oxford: Blackwell Science Ltd.; 2000. p. 123-8. |
|31.||Herbstman DM, Hou W, Garvan C, Wallace MR, McCormack WT. Association analysis of melanin biosynthesis genes in vitiligo susceptibility. Exp Dermatol 2010; In press. |
|32.||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;16:208-14. |
|33.||Boissy RE, Manga P. On the etiology of contact/occupational vitiligo. Pigment Cell Res 2004;17:208-14. |
|34.||Boissy RE. Occupational vitiligo. In: Picardo M, Taieb A, editor, Vitiligo. Berlin Heidelberg: Springer-Verlag; 2010. p. 175-80. |
|35.||Abdel-Malek Z, Suzuki I, Tada A, Im S, Akcali C. The melanocortin-1 receptor and human pigmentation. Ann N Y Acad Sci 1999;885:117-33. |
|36.||Jee SH, Lee SY, Chiu HC, Chang CC, Chen TJ. Effects of estrogen and estroen receptor in normal human melanocytes. Biochem Biophys Res Commun 1994;199:1407-12. |
|37.||Hall PF. The influence of hormones on melanogenesis. Aust J Dermatol 1969;10:125-39. |
|38.||Halaban R, Langdon R, Birchall N, Cuono C, Baird A, Scott G, et al. Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes. J Cell Biol 1988;107:1611-9. |
|39.||Peacocke M, Yaar M, Mansur CP, Chao MV, Gilchrest BA. Induction of nerve growth factor receptors on cultured human melanocytes. Proc Natl Acad Sci USA 1988;85:5282-6. |
|40.||Yaar M, Eller MS, DiBenedetto P, Reenstra WR, Zhai S, McQuiad T, et al. The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes. J Clin Invest 1994;94:1550-62. |
|41.||Imokawa G, Miyagishi M, Yada Y. Endothelin-1 as a new melanogen: Coordinated expression of its gene and the tyrosinase gene in UVB-exposed human epidermis. J Invest Dermatol 1995;105:32-7. |
|42.||Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 2004;84:1155-228. |
|43.||Quatresooz P, Hermanns JF, Paquet P, Pierard GE. Mechanobiology and force transduction in scars developed in darker skin types. Skin Res Technol 2006;12:279-82. |
|44.||Picardo M, Dell'Anna ML. Oxidative stress. In: Picardo M, Taieb A, editor, Vitiligo. Berlin Heidelberg: Springer-Verlag; 2010. p. 231-8. |
|45.||Schallreuter KU, Wood JM. Thioredoxin reductase: Its role in epidermal redox status. J Photochem Photobiol B 2001;64:179-84. |
|46.||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;122:307-13. |
|47.||Marnett LJ. Lipid peroxidation-DNA damage by malondialdehyde. Mutat Res 1999;424:83-95. |
|48.||Takahashi A, Masuda A, Sun M, Centonze VE, Herman B. Oxidative stress-induced apoptosis is associated with alterations in mitochondrial caspase activity and Bcl-2-dependent alterations in mitochondrial pH (pHm). Brain Res Bull 2004;62:497-504. |
|49.||Dell'Anna ML, Ottaviani M, Albanesi V, Vidolin AP, Leone G, Ferraro C, et al. Membrane lipid alterations as a possible basis for melanocyte degeneration in vitiligo. J Invest Dermatol 2007;127:1226-33. |
|50.||Schallreuter KU, Wood JM, Berger J. Low catalase levels in the epidermis of patients with vitiligo. J Invest Dermatol 1991;97:1081-5. |
|51.||Casp CB, She JX, McCormack WT. Genetic association of the catalase gene (CAT) with vitiligo susceptibility. Pigment Cell Res 2002;15:62-6. |
|52.||Liu L, Li C, Gao J, Li K, Zhang R, Wang G et al. Promoter variant in the catalase gene is associated with vitiligo in Chinese people. J Invest Dermatol 2010;130:2647-53. |
|53.||Dell'Anna ML, Ottaviani M, Bellei B, Albanesi V, Cossarizza A, Rossi L, 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;223:187-93. |
|54.||Moretti S, Fabbri P, Baroni G, Berti S, Bani D, Berti E, et al. Keratinocyte dysfunction in vitiligo epidermis: Cytokine microenvironment and correlation to keratinocyte apoptosis. Histol Histopathol 2009;24:849-57. |
|55.||Gauthier Y, Cario Andre M, Taieb A. A critical appraisal of vitiligo etiologic theories: Is melanocyte loss a melanocytorrhagy? Pigment Cell Res 2003;16:322-32. |
|56.||Mahoney JA, Rosen A. Apoptosis and autoimmunity. Curr Opin Immunol 2005;17:583-8. |
|57.||Gawkrodger DJ, Omerod AD, Shaw L, Mauri-Sole I, Whitton ME, Watts MJ, et al. Vitiligo: Concise evidence based guidelines on diagnosis and management. Postgrad Med J 2010;86:466-71. |
|58.||Lubaki LJ, Ghanem G, Vereecken P, Fouty E, Benammar L, Vadoud-Seyedi J, et al. Time-kinetc study of repigmentation in vitiligo patients by tacrolimus or pimecrolimus. Arch Dermatol Res 2010;302:131-7. |
|59.||Dell'Anna ML, Matrofrancesco A, Sala R, Venturini, 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;32:631-6. |
|60.||Leone G, Tanew A. UVB total body and targeted phototherapies. In: Picardo M, Taieb A, editors. Vitiligo. 11 th ed. Springer: Berlin-Heidelberg; 2010. p. 353-61. |
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