Not Just Skin Deep: The Complicated Pathogenesis of Vitiligo
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
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
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
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
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
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
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
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
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
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
- Le Poole IC, van den Wijngaard RM, Westerhof W, Dutrieux RP,
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- Bose SK. Absence of Merkel cells in lesional skin of vitiligo
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- Bose SK. Probable mechanisms of loss of Merkel cells in
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- Bose SK. Absence of Merkel cells in lesional skin of vitiligo.
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