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Clinical Updates

James J Nordlund, MD

Not Just Skin Deep: The Complicated Pathogenesis of Vitiligo

James Nordlund

Wednesday, June 10, 2009

Vitiligo is a chronic acquired disorder that is characterized by white patches on the skin caused by the destruction of epidermal melanocytes. Melanocytes are the production factory for melanin, and they are destroyed and missing in vitiliginous skin.1,2 Merkel cells are absent in white skin,3-5 and keratinocytes also give evidence of injury.6

Depigmented skin is functionally different from normal-appearing skin.7 It does not react to contact sensitization nor react to contact allergens normally.8-10 Normal white skin is susceptible to skin cancers, both of keratinocytic and melanocyte origin. Vitiligo skin is white but is resistant to carcinogenesis, and only a few cases of skin cancers of keratinocytic origin have been reported in vitiligo skin.11,12 This is in marked contrast to albino skin, in which squamous cell carcinomas are common, although melanomas are very rare.13-15 Vitiligo skin is not susceptible to forming melanomas, because it has no melanocytes.

The normal-appearing skin of patients with vitiligo also has aberrant response to injury.6 The keratinocytes are surrounded by extracellular granular material, thought possibly to be a remnant from injury to the keratinocytes.6 Vitiligo, like other skin disorders, exhibits the Koebner phenomenon or the isomorphic response.16,17 Minor injuries, such as an abrasion to the knees, cat scratches or even sunburn can cause the injured normal-appearing skin to depigment.

The causes of vitiligo are not known, although much information has been gathered about factors that contribute to melanocyte destruction. It has been suggested that melanocytes are destroyed by apoptosis rather than necrosis.18,19 There are two factors underlying the destruction of melanocytes: an enhanced susceptibility of vitiliginous melanocytes to injury and apoptosis, and an aberrant or too vigorous immune response. These two factors probably have their origin in genes that predispose to vitiligo.


A number of epidemiological studies have suggested that vitiligo has a polygenic origin, probably resulting from mutations in a set of three genes or, less likely, four genes.20-22

The prevalence of vitiligo in the general population is about 0.38, or one per 250 individuals.23 In the primary families of patients with vitiligo, the prevalence is about 6-7% 20,21,24, a twenty-fold increase from that observed in the general population, an observation suggestive of a genetic diathesis. There is an approximately 23% concordance in identical twins, additional support for a genetic predisposition to vitiligo.25

One early candidate gene, VIT126, has been implicated in causing depigmentation. VIT1 has been relabeled F-box protein 11 (FBXO11) and is located on chromosome 2p21.27 It codes for an arginine methyltransferase that is also involved in middle ear function. In vitiligo melanocytes, there is a reduced expression of this gene. There are several other genes associated with vitiligo and other forms of autoimmunity.22 Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is located on chromosome 1p13. PTPN22 exhibits regulatory activity for both T- and B-lymphocytes and is associated with rheumatoid arthritis, lupus erythematosus and diabetes mellitus type 2. It has also been associated with vitiligo.

A third gene of interest is the AlS1 locus on chromosome 1p31.3-p32.2.28 More detailed studies of this region identified another gene, forkhead box D3 (FOXD3), which codes for an embryonic transcription factor that is involved in the regulation, differentiation and development of melanoblasts and some mesodermal tissues.29 A British kinship with a familial form of depigmentation has an aberrant form of this gene and has an atypical type of leukoderma. Other kinships with vitiligo do not show linkage to this locus.27

In 2001, Nath30 and his colleagues identified a gene labeled SLEV1 for systemic lupus erythematosus vitiligo. They identified patients with both lupus and vitiligo. The gene was located on chromosome 17p13. In 2007, the gene was rediscovered and renamed NALP1.31 The gene is associated with a variety of autoimmune disorders, including thyroiditis, diabetes mellitus and rheumatoid arthritis, disorders that can occur in some patients with vitiligo. It is normally expressed in high levels in immune cells, such as Langerhans cell and T-lymphocytes, and modulates and regulates their response to bacterial and viral antigens. It recruits capase 1 and capase 5 into inflammasomes and can induce apoptosis31, the mechanism by which melanocytes are destroyed in vitiligo.19

The Immune Response

The role of the immune system in causing vitiligo has been a subject of study for decades. There have been many reports from investigators seeking a link between cytotoxic antibodies and melanocytes.32-35 In general, the identified antibodies are usually non-specific or are not directed at surface antigens.36

Other investigators have studied cellular immune responses to melanocyte antigens.37-39 Depigmentation is often observed in patients with metastatic melanoma40-42. The association of melanoma and depigmentation suggests that the host immunity induced by the malignancy can attack normal epidermal melanocytes, destroying them and producing depigmentation. The development of depigmentation in association with metastatic melanoma seems to signal a better prognosis for prolonged survival.41


Fontana-Masson silver stains for melanin show a loss of pigment from the white skin. Dopa stains carried out on an epidermal sheet show absence of dendritic cells containing tyrosinase from the white skin.2 Electron microscopy confirms the absence of melanocytes from white skin.

A biopsy taken from the edge of spreading vitiligo and stained by hematoxylin and eosin stain (H&E) shows a sparse mononuclear infiltrate in the epidermis and dermis. On some occasions, the spreading of vitiligo can be symptomatic (e.g. causing itchiness) and is accompanied by an erythematous and slightly raised border.43 There is a marked intense lymphocytic infiltrate at the border of these lesions.44


There are Langerhans cells that line up at the base of the membrane of vitiliginous skin, seemingly replacing melanocytes.45 Analysis of the infiltrates, in both inflammatory and non-inflammatory vitiligo, shows the consistent presence of macrophages, dendritic cells, and CD4+ and CD8+ T-lymphocytes in the infiltrate.36 These cellular changes are accompanied by increased expression of interferon-γ, HLA-DR and ICAM-1.36

Melanocyte Reactive T-Lymphocytes

Patients with vitiligo do have melanocyte reactive T-cells in their circulation46, and these cells can express cytotoxic activity against autologous melanocytes.38,47 The antigens against which they are sensitized include tyrosinase, MART-1 and gp100.36,47

Therapeutic Modalities

Current therapies are all immunomodulators of one type or another. Studies have shown that topical steroids are one of the more effective treatments.48-51 Other treatments include psoralen plus ultraviolet A (PUVA), a known immune suppressor.50, 52-54 PUVA has been replaced by narrow-band ultraviolet light.50,55,56 Ultraviolet light in the UVB range is a well-known immunosuppressant.

In recent years, calcineurin inhibitors, such as  tacrolimus and pimecrolimus, have been used successfully to treat vitiligo.49,57-61 That vitiligo responds favorably to immunosuppressants suggests a role for the immune system in causing melanocyte destruction, which is the mechanism for depigmentation.

Chemical Melanocytotoxicity

It has been recognized that some chemicals, such as monobenzyl ether of hydroquinone (monobenzone), can cause skin depigmentation that resembles vitiligo.9,62,63 This chemical is used to depigment patients with vitiligo that is too extensive to repigment.9,63 The chemical structure of this compound resembles, to some degree, tyrosine, the substrate for melanin synthesis. It is thought that monobenzone interferes with normal synthesis of melanin and produces radical oxygens that induce apoptosis in the melanocytes. The addition of these substituted phenolic agents to cultures of normal and vitiligo melanocytes and to control cultures confirms that vitiligo melanocytes are highly susceptible to injury from these agents in comparison with various controls.64 It seems probable that tyrosine hydroxylase 1 activates melanin formation in melanocytes, which incorporates these phenolic derivatives that ultimately lead to melanocyte destruction.36,64


Much more must be learned before vitiligo is resolved as a significant disorder. The most important goal is to find a medication that safely and permanently halts the progression of melanocyte destruction. We can clearly see that vitiligo is a group of disorders for which there will be several or many different genetic bases.


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