Vitiligo pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief:  Guillermo Rodriguez Nava, M.D. [2]

## Overview

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Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. [1][2] The fact that vitiligo is more prevalent in patients with certain autoimmune disorders, such as Addison's disease, hyperthyroidism, alopecia areata and pernicious anemia supports this hypothesis,[3][4][5] but it should also be recognized that the majority of patients with vitiligo do not have any autoimmune disorder.

## Immune Mechanisms

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* Both cellular immunity and humoral immunity have been linked to the pathogenesis of vitiligo.[6]
* A predominance of CD8+ T Lymphocytes and Th1 CD4+ T lymphocytes has been found in the perilesional areas[7][8] exhibiting cytotoxical activity against melanocytes.[9]
* Vitiligo patients have circulating IgG and IgA autoantibodies to melanocytes proteins as tyrosinase, TYRP 1 and 2; the melanosomal matrix protein gp100 (Pmel17) and Melan A/MART 1.[10][11] Passive immunization with monoclonal autoantibodies against the melanocyte membrane protein gp75 (TYRP1) in an animal model induced vitiligo-like lesions.[12]

## Non-immune Mechanisms

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* A genetic predisposition to an alteration of the pathway of biopterins and catechols has been observed.
* The high production of toxic metabolites, mainly 6- and 7-BH4 and noradrenaline, in combination with a redox unbalance lead to melanocyte damage.[13][14][15]
* Following melanocyte damage, these are eliminated by three possible mechanisms:[16]
* Necrosis
* Apoptosis[17]
* Detachment, so-called "melanocytorrhagy"[18][19]
* Unified theory: the alterations in the membrane of the melanocytes and the liberation of antigens due to apoptosis and necrosis could sensitize the immune cells leading to an autoimmune process.[20]

## Genetics

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Among 656 people with and without vitiligo in 114 families, several mutations (single-nucleotide polymorphisms) were identified in the NALP1 gene.[21][22] The NALP1 gene, which is on chromosome 17 located at 17p13, is on a cascade that regulates inflammation and cell death, including myeloid and lymphoid cells. NALP1 is expressed at high levels in T cells and Langerhan's cells, white cells that are involved in skin autoimmunity. Among the inflammatory products of NALP1 are caspase 1 and caspase 5, which activate the inflammatory cytokine interleukin-1β. Interleukin-1β is expressed at high levels in patients with vitiligo.

Of the 656 people, 219 had vitiligo only, 70 had vitiligo with autoimmune thyroid disease, and 60 had vitiligo and other autoimmune diseases. Addison's disease (typically an autoimmune destruction of the adrenal glands) may be associated with vitiligo as well.

In one of the mutations, the amino acid leucine in the NALP1 protein was replaced by histidine (Leu155->His). The original protein and sequence is highly conserved in evolution, and found in humans, chimpanzee, rhesus monkey, and the bush baby, which means that it's an important protein and an alteration is likely to be harmful.

The following is the normal DNA and protein sequence in the NALP1 gene:

TCA  | CTC  | CTC  | TAC  | CAA

|
|
|
|

Ser  | Leu  | Leu  | Tyr  | Gln
S  | L  | L  | Y  | Q

In some cases of vitiligo the first leucine is altered to histidine, by a Leu155→His mutation:

TCA  | CAC  | CTC  | TAC  | CAA

|
|
|
|

Ser  | His | Leu  | Tyr  | Gln
S  | H | L  | Y  | Q

(Leucine is nonpolar and hydrophobic; histidine is positively charged and hydrophilic, so it is unlikely to serve the same function.[23] [24])

The normal sequence of the DNA code for NALP1 of TCACTCCTCTACCAA is replaced in some of these vitiligo families by the sequence TCACACCTCTACCAA,[25] which respectively code for the amino acid sequence of the normal NALP1 protein SLLYQ being replaced by SHLYQ.[26]

## Microscopic Pathology

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Histological examination typically shows an absence of melanocytes in the affected areas of the skin. However, it is possible to sometimes identify degenerating melanocytes at the borders of the affected areas. In these patients, normal melanocytes may be found in normal skin areas yet, even in these regions, changes such as abnormal keratinocytes may be found, showing evidence of vacuolated cytoplasm in the basal layers of cells as well as granular extracellular materials.[27] In certain situations it is possible to identify lymphocytic infiltrates on the margin of the lesions, which is consistent with the underlying immunological mechanism, responsible for the destruction of the melanocytes.[28]

## References

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1. ↑ Gauthier Y, Cario Andre M, Taïeb A (2003). "A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocytorrhagy?". Pigment Cell Res. 16 (4): 322–32. PMID 12859615.CS1 maint: Multiple names: authors list (link)
2. ↑ Dell'anna ML, Picardo M (2006). "A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo". Pigment Cell Res. 19 (5): 406–11. doi:10.1111/j.1600-0749.2006.00333.x. PMID 16965269.
3. ↑ Shahla Babaee Nejad, Hamideh Herizchi Qadim, Leila Nazeman, Roohollah Fadaii & Mohamad Goldust (2013). "Frequency of autoimmune diseases in those suffering from vitiligo in comparison with normal population". Pakistan journal of biological sciences: PJBS. 16 (12): 570–574. PMID 24494526. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
4. ↑ Daniel Holthausen Nunes & Ligia Maria Hademann Esser (2011). "Vitiligo epidemiological profile and the association with thyroid disease". Anais brasileiros de dermatologia. 86 (2): 241–248. PMID 21603806. Unknown parameter `|month=` ignored (help)
5. ↑ Kirsty J. MacLean & Michael J. Tidman (2013). "Alopecia areata: more than skin deep". The Practitioner. 257 (1764): 29–32. PMID 24383154. Unknown parameter `|month=` ignored (help)
6. ↑ Michelsen D (2010). "The Double Strike Hypothesis of the vitiligo pathomechanism: new approaches to vitiligo and melanoma". Med Hypotheses. 74 (1): 67–70. doi:10.1016/j.mehy.2009.08.008. PMID 19748188.
7. ↑ Steitz J, Brück J, Lenz J, Büchs S, Tüting T (2005). "Peripheral CD8+ T cell tolerance against melanocytic self-antigens in the skin is regulated in two steps by CD4+ T cells and local inflammation: implications for the pathophysiology of vitiligo". J Invest Dermatol. 124 (1): 144–50. doi:10.1111/j.0022-202X.2004.23538.x. PMID 15654968.CS1 maint: Multiple names: authors list (link)
8. ↑ Lang KS, Caroli CC, Muhm A, Wernet D, Moris A, Schittek B; et al. (2001). "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. 116 (6): 891–7. doi:10.1046/j.1523-1747.2001.01363.x. PMID 11407977.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
9. ↑ van den Boorn JG, Konijnenberg D, Dellemijn TA, van der Veen JP, Bos JD, Melief CJ; et al. (2009). "Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients". J Invest Dermatol. 129 (9): 2220–32. doi:10.1038/jid.2009.32. PMID 19242513.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
10. ↑ Kemp EH, Gavalas NG, Gawkrodger DJ, Weetman AP (2007). "Autoantibody responses to melanocytes in the depigmenting skin disease vitiligo". Autoimmun Rev. 6 (3): 138–42. doi:10.1016/j.autrev.2006.09.010. PMID 17289548.CS1 maint: Multiple names: authors list (link)
11. ↑ Ali R, Ahsan MS, Azad MA, Ullah MA, Bari W, Islam SN; et al. (2010). "Immunoglobulin levels of vitiligo patients". Pak J Pharm Sci. 23 (1): 97–102. PMID 20067874.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
12. ↑ Hara I, Takechi Y, Houghton AN (1995). "Implicating a role for immune recognition of self in tumor rejection: passive immunization against the brown locus protein". J Exp Med. 182 (5): 1609–14. PMC 2192219. PMID 7595233.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
13. ↑ Cucchi ML, Frattini P, Santagostino G, Orecchia G (2000). "Higher plasma catecholamine and metabolite levels in the early phase of nonsegmental vitiligo". Pigment Cell Res. 13 (1): 28–32. PMID 10761993.CS1 maint: Multiple names: authors list (link)
14. ↑ Schallreuter KU, Moore J, Wood JM, Beazley WD, Peters EM, Marles LK; et al. (2001). "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. 116 (1): 167–74. doi:10.1046/j.1523-1747.2001.00220.x. PMID 11168813.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
15. ↑ Schallreuter KU, Wood JM, Berger J (1991). "Low catalase levels in the epidermis of patients with vitiligo". J Invest Dermatol. 97 (6): 1081–5. PMID 1748819.CS1 maint: Multiple names: authors list (link)
16. ↑ Maria Lucia Dell'anna & Mauro Picardo (2006). "A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo". Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society. 19 (5): 406–411. doi:10.1111/j.1600-0749.2006.00333.x. PMID 16965269. Unknown parameter `|month=` ignored (help)
17. ↑ R. M. van den Wijngaard, J. Aten, A. Scheepmaker, I. C. Le Poole, A. J. Tigges, W. Westerhof & P. K. Das (2000). "Expression and modulation of apoptosis regulatory molecules in human melanocytes: significance in vitiligo". The British journal of dermatology. 143 (3): 573–581. PMID 10971331. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
18. ↑ Y. Gauthier, M. Cario-Andre, S. Lepreux, C. Pain & A. Taieb (2003). "Melanocyte detachment after skin friction in non lesional skin of patients with generalized vitiligo". The British journal of dermatology. 148 (1): 95–101. PMID 12534601. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
19. ↑ Yvon Gauthier, Muriel Cario Andre & Alain Taieb (2003). "A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocytorrhagy?". Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society. 16 (4): 322–332. PMID 12859615. Unknown parameter `|month=` ignored (help)
20. ↑ Tara M. Kroll, Hemamalini Bommiasamy, Raymond E. Boissy, Claudia Hernandez, Brian J. Nickoloff, Ruben Mestril & I. Caroline Le Poole (2005). "4-Tertiary butyl phenol exposure sensitizes human melanocytes to dendritic cell-mediated killing: relevance to vitiligo". The Journal of investigative dermatology. 124 (4): 798–806. doi:10.1111/j.0022-202X.2005.23653.x. PMID 15816839. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
21. ↑ Gregersen PK (2007). "Modern genetics, ancient defenses, and potential therapies". N. Engl. J. Med. 356 (12): 1263–6. doi:10.1056/NEJMe078017. PMID 17377166.
22. ↑ Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA (2007). "NALP1 in vitiligo-associated multiple autoimmune disease". N. Engl. J. Med. 356 (12): 1216–25. doi:10.1056/NEJMoa061592. PMID 17377159.CS1 maint: Multiple names: authors list (link)
23. ↑ List of Amino Acids and Their Abbreviations
24. ↑ The Genetic Code (DNA)
25. ↑ Ensembl Transcript Report Ensembl Transcript ID: NST00000262467
26. ↑ Ensembl Protein Report Ensembl Peptide: ID ENSP00000262467
27. ↑ Soutor, Carol (2013). Clinical dermatology. New York: McGraw-Hill Education/Lange Medical Books. ISBN 978-0-07-177296-9.
28. ↑ Goldsmith, Lowell (2012). Fitzpatrick's dermatology in general medicine. New York: McGraw-Hill Medical. ISBN 0071669043.

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