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Pathogenesis of vitiligo - An update

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Review Article
Pathogenesis of vitiligo: An update
ABSTRACT
Vitiligo is the most common depigmentary disorder that has been affecting human lives across centuries. Despite its high prevalence, not
much can be said precisely about its pathogenesis. Over the years, several theories based on a lot of research have been put forward and
many more are coming up each day. This article aims to summarise the various theories put forward so far and highlight the Recent
updates in each of them.
Keywords: Pathogenesis, update, vitiligo
INTRODUCTION
Vitiligo is a commonly acquired depigmentary disorder of
skin, also known as swetakusta in Indian literature.
Clinically, it is characterized by development of
depigmented macules and patches secondary to selective
destruction of melanocytes.[1] Clinically, two major subtypes
of vitiligo are well recognized: non-segmental and
segmental. Non-segmental vitiligo (NSV) is the more
common subtype, having asymmetrical, non-dermatomal
distribution usually with a gradual onset.[2] Segmental
vitiligo (SV) is less common and is characterized by a
unilateral dermatomal distribution which usually has an
early rapid onset and stabilizes in a limited location once
fully developed.[2] The prevalence of vitiligo is high
ranging from 0.005 to 0.38% cases worldwide.[3-5] Gujarat,
located on the western coast of the Indian Peninsula, has
been reported to have a prevalence of 8.8%, the highest in
the world.[5,6] Despite its high prevalence and old history,
its etiopathogenesis is complex and enigmatic. Most of
the currently available evidence supports the occurrence
of an autoimmune phenomenon in patients with an
underlying genetic predisposition.[7] However, with
further advancement and research in understanding the
pathogenesis of this psychologically devastating disease,
newer insights into its etiopathogenesis keep emerging.
For this review, we searched PubMed, Google and Google
Scholar with keywords including ‘vitiligo’, ‘pathogenesis’,
‘vitiligo pathogenesis latest’, ‘epidemiology’ and
‘etiopathogenesis’. All types of studies including reviews,
in vivo / in vitro experimental studies, animal studies and
observational studies published in standard peer-reviewed
journals were included. This review aims to discuss the
various known as well as newer emerging theories in the
pathogenesis of vitiligo. To make the review more
interesting, the data until 2011 has been placed under
‘What is known’ category, and the data from studies
published in the last 5 years has been placed under the
‘Recent updates’ category. Because NSV is a more common
form of vitiligo, most of the experimental studies and
theories discussed in this review pertain to pathogenesis
of NSV. However, wherever a difference in the pathogenesis
of the two types as been suggested in literature, a mention
has been made in the text.
Genetics
What is known?
Familial clustering is seen in vitiligo. Various studies have
found that the frequency of vitiligo among first-degree
AMANJOT K. ARORA, MUTHU S. KUMARAN
Department of Dermatology, Venereology and Leprology,
Postgraduate Institute of Medical Education and Research,
Chandigarh, India
Address for correspondence: Dr. Muthu Sendhil Kumaran, MD,
DNB, Associate Professor, Department of Dermatology, Venereology
and Leprology, Post Graduate Institute of Medical Education and
Research, Sector-12, Chandigarh - 160 012, India.
E-mail: [email protected]
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DOI:
10.4103/2349-5847.219673
How to cite this article: Arora AK, Kumaran MS. Pathogenesis of vitiligo: An
update. Pigment Int 2017;4:65-77.
© 2017 Pigment International | Published by Wolters Kluwer - Medknow
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Arora and Kumaran: Pathogenesis of vitiligo: An update
relatives varies from 0.14% to as high as 20%.[8-10] Such
figures suggest a definite genetic component.
Nevertheless, only 23% concordance has been observed
amongst monozygotic twins, which suggests that a
significant non-genetic component exists in the
pathogenesis of vitiligo.[8] As vitiligo is a polygenic
disease, several candidate genes including major
histocompatibility complex (MHC), angiotensin-converting
enzyme (ACE), catalase (CAT), cytotoxic T lymphocyte
antigen-4 (CTLA-4), catechol-O-methyltransferase (COMT),
estrogen receptor (ESR), mannan-binding lectin (MBL2),
protein tyrosine phosphatase, non-receptor type 22
(PTPN22), human leukocyte antigen (HLA), NACHT
leucine-rich repeat protein 1 (NALP1), X-box binding
protein 1 (XBP1), forkhead box P1 (FOXP1) and
interleukin-2 receptor A (IL-2RA), that are involved in the
regulation of immunity have been tested for genetic
association with generalized vitiligo.[11,12] In patients with
various vitiligo-associated autoimmune/auto-inflammatory
syndromes, HLA haplotypes, especially HLA-A2, −DR4,
−DR7 and −DQB1*0303, have been frequently found to
play an important role[13,14] At the same time, in patients
with vitiligo alone, PTPN22, NALP1 and XBP1 have been
found to play a causal role.[15-17]
Genome-wide linkage analysis has revealed autoimmune
susceptibility (AIS) loci associated with vitiligo. AIS1 was
discovered to be located on chromosome 1p31.3–p32.2,[18]
AIS2 on chromosome 7 and AIS3 on chromosome 8.[19] AIS1
and AIS2 linkages were found to occur in families with
vitiligo along with other autoimmune diseases, while AIS3
was found in the non-autoimmune family subgroup. Another
gene, that is, systemic lupus erythematosus vitiligo-related
gene (SLEV1) located on chromosome 17, was found to be
associated with generalized vitiligo present in association
with other concomitant autoimmune diseases.[19]
Recent updates
In a recent study, gene expression profiling was performed
in patients with SV and NSV to analyze the changes in gene
expression in patients with vitiligo and compare the two
groups with each other as well as healthy individuals (HI).[20]
High-throughput whole genome expression microarrays
were used to assay the gene expression profiles among
HI, SV and NSV. In this study, they found that in patients
with SV with HI as a control, the differently expressed
genes included the ones involved in the adaptive
immune response, cytokine–cytokine receptor interaction,
chemokine signalling, focal adhesion and sphingolipid
metabolism. On the other hand, the differently expressed
genes in patients with NSV mainly controlled the innate
immune system, autophagy, apoptosis, melanocyte biology,
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ubiquitin-mediated proteolysis and tyrosine metabolism.
Thus, they concluded that different genetic pathomechanisms were involved in the two distinct subtypes of
vitiligo. In another study from China, the C allele of
rs35652124 located on the promoter region of nuclear
factor E2-related factor 2 (Nrf2) gene was found to have a
protective effect against vitiligo.[21] Lately, the role of
microRNAs (miRNAs) and toll-like receptors (TLRs) in the
pathogenesis of vitiligo has been explored.[22,23] In a study
by Šahmatova et al., miR-99b, miR-125b, miR-155 and miR199a-3p levels were found to be increased while that of miR145 was found to be decreased in the skin of patients with
vitiligo. MiRNAs (miR-155) when over-expressed lead to the
inhibition of melanogenesis-associated genes and altered
interferon-regulated genes in the melanocytes and
keratinocytes.[22] Traks et al. recently established the role
of TLRs and vilitgo in their study, wherein they found that
single nucleotide polymorpisms (SNPs) in TLR7 were
associated with vitiligo making them a future target for
targeted therapies.[23] Recently, Shen et al. also reviewed the
various key loci that have been implicated in the
pathogenesis of vitiligo, and interested readers can refer
them.[24] Thereupon, the data available so far suggest that
vitiligo has a polygenic inheritance with no single gene
dictating its pathogenesis.
AUTOIMMUNE HYPOTHESIS
Autoimmunity has long been suspected to play a significant
role in the pathogenesis of vitiligo. This has been
substantiated by multiple studies published in the
literature so far. Both cellular and humoral immunity have
been found to be of etiological significance in the
pathogenesis of vitiligo.
Cellular Immunity
What is known?
As far as cellular immunity is concerned, the main culprits
are the CD8+ cytotoxic T-cells. Perilesional skin biopsies
have shown epidermotropic cutaneous lymphocyte antigen
positive lymphocytes with an increased CD8+/CD4+ ratio,
substantiating the role of cytotoxic T-cells in the
pathogenesis of vitiligo.[25,26] These T-cells have been
shown to bring about degenerative changes in
melanocytes and vacuolization of basal cells in the
normal-appearing perilesional skin in patients with
actively spreading lesions.[27] An increased expression of
CD25 and MHC II (specifically HLA-DR) and ability to secrete
interferon gamma (IFN γ) has been noted in these T-cells
which lead to increased expression of intercellular adhesion
molecule-1 and, consequently, increased T-cell migration to
the skin leading to a vicious cycle.[25,26]
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Arora and Kumaran: Pathogenesis of vitiligo: An update
Also, high frequencies of Melan-A-specific CD8+ T-cells have
been found in patients with vitiligo, and their number may
correlate with disease extent.[28-30] Another subset of
T-cells, called the follicular T helper (Tfh) cells, has been
described lately in the pathogenesis of vitiligo.[31,32] The Tfh
cells secrete interleukin (IL) 21 IL-21 which brings about
B-cell activation, thereby, playing a pivotal role in
autoimmune diseases such as vitiligo. They are also key
players in cytotoxic responses as they promote an increase
in CD8+ T-cells and prolong their cytotoxic responses.[31,32]
Recent updates
Interferon γ (IFN γ) has been recently identified as a part of
the ‘signature cytokine profile’ implicated in the
pathogenesis of vitiligo. In an engineered mouse model
of vitiligo, Harris and co-workers found IFNs to play a central
role in the spread of vitiligo lesions by bringing about an
increased expression of CXCL10, which subsequently
regulates the invasion of epidermal and follicular tissues
by CD8+ T-cells.[33] Similar results were seen in an avian
model, in which an increased expression of IFN γ correlated
well with the progression of vitiligo.[34]
IL-17 and T helper type 17 (Th17) cells, which elaborate this
cytokine, have been increasingly recognized to play an
important role in autoimmunity. Singh et al. recently
reviewed their role in vitiligo and found increased levels
of IL-17 in the blood as well as the tissue samples of
patients with vitiligo.[35] These findings were further
substantiated by Zhou et al.[36] and Bharadwaj et al.,[37]
who found that the levels of Th17 cells correlated well with
disease activity in generalized vitiligo. The latter also found
significant increase in the expression of IL-1β and
transforming growth factor-beta (TGF-β) in patients with
active NSV.[37]
In a recent study, serum levels of IL-33 were found to be
significantly increased in patients with vitiligo and showed
positive correlation with disease activity. This study
suggested a possible etiologic role of IL-33 in the
pathogenesis of vitiligo and concluded it to be a target
for future therapies.[38]
In recent times, various studies have highlighted the pivotal
role of regulatory T-cells (Tregs) in the pathogenesis of
vitiligo.[39] Tregs are known to fight against autoimmunity
and their levels have been reported to be lower in patients
with vitiligo,[40,41] especially, in the lesional and perilesional
skin.[42] Not only are they decreased in number but they also
have impaired functioning.[39] Both TGF-β and IL 10, which
are physiological inducers of Tregs, have been found to be
decreased in active vitiligo lesions.[43,44]
Humoral Immunity
What is known?
Various subsets of antibodies are seen in patients with
vitiligo and are categorized as those against cell surface
pigment cell antigens, intracellular pigment cell antigens
and non-pigment cell antigens.[45] Certain antigens namely
VIT 40/75/90, named after their respective weights, have
been identified in around 83% patients with vitiligo.
Although VIT 90 is found exclusively on pigment cells,
VIT 40 and VIT 75 are considered common to both
pigment and non-pigment cells. Non-specific antibodies
against these antigens have been found in patients with
vitiligo.[46] As melanocytes are much more sensitive to
immune-mediated injury, it is probable that minimal
injury from non-specific antibodies may induce lethal
harm to melanocytes, but not to the surrounding cells.[47]
Antibodies against tyrosinase and tyrosinase-related
proteins 1 and 2 (TRP-1 and TRP-2), SOX9 and SOX 10
(transcription factors involved in the differentiation of
cells derived from the neural crest) have also been
detected in patients with autoimmune polyendocrine
syndrome type 1 (APS1) and in patients with vitiligo
without any concomitant disease.[48-50]
Recent updates
In a recent study, 15 out of 19 patients with unstable vitiligo
were found to be positive for antibodies against
melanocytes.[51] Anti-melanocyte antibodies have been
found to localize in the cytoplasm of melanocytes.[52] In
another study, antibodies against membrane and
cytoplasmic antigens were discovered in patients with
vitiligo and, using protein mass spectrometry, these
membrane antigens were identified to be Lamin A/C and
Vimentin X.[52] Thus, the role of anti-melanocyte antibodies
in the pathogenesis of vitiligo cannot be refuted.
Oxidative stress
What is known?
The oxidative stress theory of vitiligo suggests that the main
culprit in the pathogenesis of vitiligo is the intra-epidermal
accumulation of reactive oxygen species (ROS), the most
notorious of which is H2O2 whose concentration may reach
upto one milimole.[53-55] At this concentration, H2O2 leads to
changes in the mitochondria and, consequently, apoptosis/
death of the melanocytes.[56,57]
Alterations in the markers of redox status are commonly
seen in patients with vitiligo.[58] Important markers of
interest are malondialdehyde (MDA), selenium, vitamins,
glutathione peroxidase (GPx), superoxide dismutase (SOD)
and CAT.[58,59] MDA is a product of lipid peroxidation and an
indicator of oxidative stress.[58,59] Selenium is required for
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GPx activity and is a major antioxidant present in the
erythrocytes. SOD scavenges superoxide radicals and
reduces their toxicity (converts O2– to O2 and H2O2), and
CAT converts H2O2 to O2 and H2O.[58,59] Significantly
higher levels of SOD, decreased erythrocyte GPx activity,
low levels of enzyme CAT and vitamins C and E have been
detected both in the epidermis and in the serum of
patients with vitiligo[60-63] Ines et al. found that SOD
activity was increased in both stable and active disease,
while MDA and selenium levels were increased most notably
in active disease only. The erythrocyte CAT activity and
serum vitamin A and E levels were not significantly
different from controls.[64] The researchers insisted that
enhanced SOD activity could result in the accumulation
of H2O2. Additionally, CAT and GPx are downstream
enzymes that detoxify H2O2, and GPx levels were found
to be lower in patients with vitiligo, thereby, compounding
H2O2 accumulation.[64] In a later study, it was found that
SOD, GPx and MDA levels were increased in active
and stable disease jointly, with higher increases
consistently present in the active group. On the contrary,
CAT activity was notably more decreased in the active
group than in stable disease.[65] The authors suggested
that increase in SOD activity ultimately resulted in H2O2
accumulation (as it catalyses a reversible reaction) that
is not broken down by CAT, because its levels are lower
than normal.[65]
SNPs interfering with the CAT enzyme’s subunit assembly
and function, have been found more frequently in patients
with vitiligo.[66] In addition, H2O2 accumulation brings
about degradation of the active site of CAT enzyme,
thereby making it unsuitable to function.[67] Furthermore,
deranged melanin synthesis pathways involving 6-biopterin
lead to increased synthesis of ROS and subsequent
oxidative injury to melanocytes.[68-70]
A new theory, called the haptenation theory, has been
proposed to establish the pathogenic role of oxidative
stress in vitiligo.[71] According to this hypothesis, high
levels of H2O2 lead to increased levels of tyrosinase
enzyme and its activity which, because of a genetic
polymorphism specific to ‘vitiligo’ melanocytes, is capable
of binding to a variety of substrates such as noradrenalin
(during severe mental stress and bereavement), triiodothyronine and estrogen, thereby, generating
orthoquinone metabolites. These metabolites act as
putative haptogenic substrates for tyrosinase and convert
the tyrosinase enzyme into a neoantigen, which eventually
acts as an autoantigen for the immune system.[71] Thus, an
autoimmune reaction is triggered which brings about
depigmentation by selective destruction of melanocytes
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containing the autoantigen in the form of altered
tyrosinase enzyme.[71]
Recent updates
In a recent study, Zalaie contradicted the aforementioned
findings by spectrometrically measuring H2O2 in the lesional
and non-lesional skin of patients with vitiligo of skin Type V
and VI.[2] They concluded that the epidermal H2O2 levels
were not increased but rather decreased in patients with
NSV contrary to the previous belief.[2]
In another study, melanocytes cultured from patients with
vitiligo were found to demonstrate certain changes in their
cellular machinery as a result of sustained but sub-lethal
oxidative stress.[72] These changes included alterations in
the signal-transduction pathways such as mitogen-activated
protein kinase hyperactivation and increased sensitivity to
apoptosis inducers, as well as increased expression of IL-6,
matrix metalloproteinase-3 and insulin-like growth
factor-binding protein-3 and −7.[72] Picardo et al.[73] named
this conglomerate of cellular changes as ‘senescence
phenotype’, because it resembled the cytokine milieu seen
in neurodegenerative diseases.
Recent research has pointed out the importance of ‘Nrf2antioxidant response element (ARE) pathway’ in regulating
vitiligo of the skin[74-76] The Nrf2-ARE is one of the major
ROS scavenging pathways that prevent oxidative damage by
the induction of downstream antioxidant genes such as
heme oxygenase-1 (HO-1).[77] An in vitro study revealed
decreased Nrf2 nuclear translocation and transcription in
vitiligo melanocytes with resultant decrease in HO-1
expression and aberrant redox balance. In an in vitro
study, aspirin was found to dramatically induce NRF2
nuclear translocation and enhance ARE-luciferase activity,
thereby inducing the expression of HO-1 in human
melanocytes and protecting human melanocytes against
H2O2-induced oxidative stress.[77]
A fresh theory unifying the etiological role of oxidative
stress and autoimmunity in vitiligo has been proposed, as
per which, both the factors coexist in patients with vitiligo
but might play different roles in initiation or perpetuation of
vitiligo.[78] This theory proposed that in patients with recent
onset vitiligo, lipid peroxidation levels, indicative of
oxidative stress, were increased while anti-melanocyte
antibody levels, indicative of autoimmune process, were
increased in patients with long standing vitiligo. Thus, they
concluded that oxidative stress plays a pivotal role in
initiating vitiligo and the resultant accumulation of ROS
damages the melanocytes as well as alters the structure of
important melanogenic proteins such as tyrosinase, thereby,
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Arora and Kumaran: Pathogenesis of vitiligo: An update
making them antigenic. These neoantigens subsequently
incite an immune response that sustains the disease
process.[78]
Researchers have reported a significant association
between a specific polymorphism of forkhead box class
O (FOXO) proteins and vitiligo.[79] Decreased levels of
FOXO3a protein have been found in patients with active
vitiligo which result in impaired antioxidant mechanism
causing tissue injury and eventually vitiligo.[79]
Autocytotoxicity
What is known?
Toxic metabolites, both intracellular, such as those formed
during melanin synthesis, and extracellular, such as
phenols or quinones, may accumulate and damage the
melanocytes of genetically susceptible individuals
bringing about autocytotoxic injury to the melanocytes.
It has been shown that tyrosine upon entering the
melaninogenic pathways produces certain electrically
unstable by-products, which have the potential to
damage other cellular substrates resulting in death of
the melanocytes.[80]
Recent updates
In a recent study, Kim et al. investigated the role of high
mobility group box 1 (HMGB1) in the pathogenesis of
vitiligo.[81] HMGB1 is a non-histone deoxyribonucleic acid
(DNA)-binding protein that is secreted from the
keratinocytes following exposure to ROS or ultraviolet B
(UVB) light. It participates in a number of physiological and
pathological processes, including cytokine production, cell
proliferation, angiogenesis, cellular differentiation and cell
death. In this study, Kim et al. treated the melanocytes with
recombinant HMGB1 (rHMGB1) and studied its effects on
melanocyte survival.[81] They found that rHMGB1 increased
the expression of cleaved caspase 3 and decreased melanin
production as well as the expression of melanogenesisrelated molecules in treated melanocytes leading to
apoptosis and disappearance of the melanocytes. In the
same study, it was found that patients with active
vitiligo showed significantly higher blood levels of
HMGB1 (vs. healthy controls). In addition, greater
expression of HMGB1 was observed in the vitiliginous
skin (vs. uninvolved skin). Thus, HMGB1 could initiate
autocytotoxic injury to the melanocytes secondary to
increased oxidative stress or UV light exposure.[81]
Melanocytorrhagy
What is known?
Theory of melanocytorrhagy proposes that NSV is a primary
melanocytorrhagic disorder with altered melanocyte
responses to friction which induces their detachment,
apoptosis and subsequent transepidermal loss.[82] This
theory adequately explains the Koebner’s phenomenon
because it proposes that weakly anchored melanocytes
upon facing minor friction and/or other stress undergo
separation from the basement membrane, migrate upward
across the epidermis and are eventually lost to the
environment resulting in vitiligo at the sites of trauma.[83]
Kumar et al. found that the melanocytes were poorly
attached to Type IV collagen in patients with unstable
vitiligo, whereas the attachment was fairly firm in
patients with a stable disease.[84] More importantly, they
demonstrated that in patients with unstable vitiligo, the
dendrites of perilesional melanocytes were small, clubbed
and retracted which were unable to adhere melanocytes
to the basement membrane and the surrounding
keratinocytes, thereby, rendering them more prone to
transepidermal loss.[84]
Tenascin, an extracellular matrix molecule that inhibits the
adhesion of melanocytes to fibronectin, has been found to be
elevated in vitiliginous skin contributing to the loss of
melanocytes or ineffective repopulation.[85] This results in
focal gaps and impaired formation of basement membrane
resulting in weakening of the basal attachment of melanocytes
and subsequent chronic melanocyte loss known as
melanocytorrhagy.[85] It has been proposed that during
their transepidermal migration, damaged melanocytes
could induce an immune response, thereby, perpetuating
vitiligo.[85]
Recent updates
In a recent study by Kumar et al., alterations in the nuclear
receptor protein ‘liver X receptor alpha (LXR α)’ was found to
play a crucial role in bringing about melanocytorrhagy in
patients with NSV. They reported an increased expression
of LXR-α, a promoter of apoptosis, in the perilesional skin of
patients with NSV.[86] In the same study, treatment with LXR-α
agonist, 22(R)-hydroxycholesterol, was found to significantly
decrease melanocyte adhesion and proliferation.[86] Thus,
they concluded that a higher expression of LXR-α in the
melanocytes of the perilesional skin significantly decreased
the adhesion and proliferation and increased the apoptosis of
melanocytes.
DEFICIENCY OF SURVIVAL SIGNALS
As per this theory, a deficiency of survival signals in the
vitiliginous skin leads to apoptosis of melanocytes. In
the normal epidermis, stem cell factors released from the
neighbouring keratinocytes regulate melanocyte growth
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Arora and Kumaran: Pathogenesis of vitiligo: An update
and survival by binding to membrane tyrosine kinase
receptor c-kit.[87] As such, it is possible that a
significantly decreased number of c-kit receptors
observed in the perilesional melanocytes[87] and lower
expression of stem cell factor from the surrounding
keratinocytes[88] may contribute to the death of
melanocytes.
Neurohumoral hypothesis: psycho-neuro-endocrineimmune connection in vitiligo
What is known?
There is enough scientific evidence that supports the view
that psychological stressors and nervous pathways
have an impact on the release of neuropeptides (NPs),
various cell behaviours and expression of innate and
adaptive immunity in the skin. Evidence in support of
the neurohumoral pathogenesis of vitiligo includes
common origin of both the melanocytes and nerves
from the neural crest cells, the usual presence of SV in a
dermatomal fashion, alterations in perspiration and
nerve structure in vitiliginous skin and expression of
specific neuropeptides in patients with vitiligo.[89,90]
Stress is known to induce the production of various NPs
in the skin such as neuropeptide Y (NPY).[91,92]
Immunohistochemical stains have also shown an increase
in NPY, both within and around a vitiliginous patch.[93] The
release of this neuropeptide from nerve fibres is
suspected to initiate a cascade of reactions leading to
the destruction of melanocytes, probably, mediated by
mast cells and granulocytes.[93] This theory is of major
interest when applied to SV. Vitiligo lesions also exhibit
increased levels of norepinephrine and low levels of
acetylcholine esterase activity.[94,95] An increased level of
neurotransmitters may be directly cytotoxic to cells or may
have an indirect effect by causing constriction of supplying
blood vessels, thereby causing hypoxia and subsequently
cell death.[92,93] Increased levels of homovanillic and
vanillylmandelic acids in the 24-hour urine samples of
patients with recent onset or progressive disease
support the role of stress and the resultant increase in
levels of catecholamines in initiating and perpetuating
vitiligo.[92]
Recent updates
Lately, Shaker et al. estimated the gene expression of
corticotropin releasing hormone (CRH) and corticotropin
releasing hormone receptor 1 (CRHR 1) in both the lesional
and non-lesional skin in a sample of patients with vitiligo
and assessed its association with psychological stress as
measured by the social readjustment stress scale.[96] They
found a significant increase in the expression of CRH and
CRHR-1 in both the lesional and non-lesional skin of patients
70
with vitiligo and a significant direct association with
stress.[96]
Normally, CRH-R1 is known to increase the expression of
proopiomelanocortin (POMC) and induce the production of
adrenocorticotrophic hormone through the activation of
cyclic adenosine monophosphate-dependent pathway(s) in
an attempt to bring about increased pigmentation.[97]
In addition, the melanocytes respond with enhanced
production of cortisol and corticosterone, which is
dependent upon POMC activity, to suppress an immune
response.[97] Thus, the aforementioned study, shows that the
upregulation of CRH and CRHR-1 might be a form of systemic
compensation in patients with vitiligo so as to restore normal
pigmentation in vitiligo lesions, however, a defective
melanogenesis pathway in vitiligo lesions might still lead to
failure of repigmentation.
Vitamin D deficiency
What is known?
1,25-dihydroxyvitamin D3 or vitamin D is a fat-soluble
vitamin, which is obtained by humans through diet and is
synthesized in the skin from 7-dehydrocholesterol under the
influence of UV light. It regulates calcium and bone
metabolism, controls cell proliferation and differentiation
and exerts immunoregulatory activities.[98]
Vitamin D has a nuclear receptor called vitamin D receptor
(VDR). VDRs are present in the cells involved in calcium and
bone metabolism, and also in the keratinocytes, melanocytes,
fibroblasts and immune system cells of the skin.[98] Vitamin D
exerts a significant effect on the melanocytes and
keratinocytes via various mechanisms. In vitro studies
have shown that vitamin D3 increases melanogenesis
and tyrosinase content of cultured human melanocytes and
protects the melanocytes from UVB-induced apoptosis, thus,
contributing to repigmentation in vitiligo macules.[98,99]
Evidence supporting the role of vitamin D in inducing
repigmentation in vitiligo skin comes from various studies
in which vitamin D analogues, including calcipotriol and
tacalcitol, have been shown to enhance repigmentation in
patients with vitiligo.[100-102] In addition, vitamin D has been
shown to exert immunomodulatory effects by suppressing the
levels of proinflammatory cytokines such as IL-6, IL-8, tumour
necrosis factor (TNF)-α and TNF-γ.[103]
Recent updates
In a recent investigation by Ustun et al., insufficient
(<30 ng/ml) or very low (<15 ng/ml) levels of vitamin D
were observed in majority of patients, although the
difference was not significant when 41 control patients
were compared to 25 patients with vitiligo.[104] Another
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Arora and Kumaran: Pathogenesis of vitiligo: An update
study investigated 40 patients with vitiligo and 40 age- and
gender-matched controls wherein significantly lower serum
vitamin D levels were seen in the patients in relation to the
controls.[105]
In a recent systematic review and meta-analyses by Upala
et al., it was concluded that a significantly lower concentration
of serum 25-hydroxyvitamin D was seen in patients with
vitiligo compared with healthy controls.[106]
The following reasons have been theorized behind
decreased vitamin D levels in vitiligo patients: (i)
consumption of vitamin D in the autoimmune process
and (ii) decreased sun exposure by patients in an attempt
to prevent sunburn. The former was supported by a study by
Saleh et al., who found that patients with vitiligo and
autoimmune diseases have lower serum 25(OH)D levels
than patients with vitiligo without autoimmune diseases,
though, the difference was not statistically significant.[105]
On the contrary, recent studies by Karagün et al.,[107]
Karagüzel et al.,[108] and Khurrum et al.,[109] could not find
any statistically significant difference in vitamin D levels
between patients and healthy controls. Nonetheless,
Karagüzel et al. concluded that after six months of
treatment, lesion size decreased in patients who received
combination treatment with topical tacrolimus 0.1% and
vitamin D daily (P < 0.001); while the lesion size
increased in patients who received only topical therapy
(P < 0.01), thereby, substantiating the role of vitamin D
supplementation in patients with vitiligo.[108]
Hyperhomocystinemia
What is known?
Vitamin B12 and folic acid are important cofactors required
by the enzyme homocysteine (Hcy) methyltransferase for
the regeneration of methionine from Hcy in the activated
methyl cycle.[110] Consequently, a nutritional deficiency in
either of these two vitamins results in an increase in Hcy
levels and a decrease in methionine levels in the
circulation.[111,112] Reduced levels of vitamin B12 and folic
acid have been reported in patients with vitiligo.[113-115]
Moreover, it has been noted that homocystinuria is
associated with fair skin and hair, a phenomenon often
described as ‘pigmentary dilution’.[116]
Low CATactivity is detected in patients with vitiligo, which is
known to affect Hcy metabolism.[117] In addition, it has been
suggested that an increase in local Hcy levels interferes with
normal melanogenesis and plays a role in the pathogenesis
of vitiligo by inhibiting the action of histidase and tyrosinase
enzymes in the skin.[118] In a pilot study by Shaker and
El-Tahlawi, involving 26 patients with vitiligo, it was found
that the mean serum Hcy level in the patient group was
significantly higher than in the control group (P <
0.001).[119] The mean Hcy level in patients with
progressive disease was significantly higher than those in
the control group (P < 0.001). In patients with stable
disease, the mean Hcy level was higher, but not
significantly, (P > 0.05), whereas in patients with
regressive disease, the mean Hcy level was almost the
same as that of the controls (P > 0.05).[119]
Several theories back up the possible effects of elevated Hcy
on melanocytes in vitiliginous skin. (i) The production of
toxic ROS by Hcy oxidation adds to the oxidative stress in
vitiligo that may contribute to the destruction of the
melanocytes in vitiligo skin.[120,121] The fact that folic
acid has an antioxidant effect in vitiligo backs up
this hypothesis.[122] (ii) Hcy inhibits tyrosinase enzyme
probably by interacting with copper at the active site
of the enzyme.[123] (iii) Other harmful effects of
homocysteinemia may be due to the reaction of Hcy with
proteins forming disulphides and the conversion of Hcy to
highly reactive thiolactone, which could react with
the proteins forming NH–CO– adducts, thus, affecting
the body’s proteins and enzymes.[124] However, some
researchers did not find a significant difference in levels
between patients with vitiligo and controls.[125,126]
Recent updates
In the recent years, there was a surge of studies that
supported the role of elevated levels of Hcy in the
etiopathogenesis of vitligo.[127-130] However, the major
drawback of all the studies discussed so far was that they
were performed on a small number of participants. Finally,
Alghamdi et al.[130] and Chen et al.[131] published large
studies, which included 306 and 2000 participants,
respectively. Alghamadi et al. included 153 patients with
vitiligo and 153 age- and sex-matched healthy controls and
recorded that Hcy and vitamin B12 levels were not
significantly different in patients with vitiligo from those
in healthy controls.[130] Chen et al. conducted a study
involving 1000 patients with vitiligo and 1000 age- and
sex-matched controls and found that patients with vitiligo
had higher levels of serum Hcy as well as lower activity
concentrations of methylenetetrahydrofolate reductase
(MTHFR) gene than the controls.[131] Thus, the findings of
these two large studies further added to the conflict. In a
recent study, Anbar et al., found significantly increased Hcy
level in patients’ lesional-induced bulla, although no
differences were seen in the serum levels between the
cases and the controls.[132] They suggested the possibility
that Hcy is produced locally in the lesions, and as such,
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Arora and Kumaran: Pathogenesis of vitiligo: An update
needs a larger lesional surface area to have a detectable level
in the serum. Thus, they concluded that larger the surface
area affected higher the serum Hcy levels. This reinforced
the conclusions drawn by Silverberg and Silverberg, who
reported elevated levels of serum Hcy in cases with
extensive vitiligo and recommended it as a severity
marker on the initial examination of patients with
vitiligo.[133] In a recent study conducted in India, serum
Hcy levels were found to be higher than the western
reference standards in both cases and controls.[134] This
could partly be explained by a predominantly vegetarian
Indian population included in the study, whose diet is
deficient in vitamin B12 and partly by genetic
polymorphisms in the MTHFR gene.The authors did not
notice any significant difference in the Hcy levels between
cases and controls and suggested that serum Hcy may not be
a reliable marker in the Indian population probably because
of differences in dietary habits.[134]
ROLE OF TUMOUR NECROSIS FACTOR ALPHA
Tumour necrosis factor-alpha (TNF-α) is one of the major
cytokines implicated in the pathogenesis of vitiligo.
TNF-α has been shown to inhibit melanocyte
Figure 1: Proposed patho-mechanisms behind the convergence theory. Convergence theory proposes that the various triggers, perhaps, work in
combination to bring about onset of vitiligo. (I) Genetic theory: In a genetically predisposed person, various environmental triggers such as UV radiation,
stress and ROS bring about the onset of vitiligo. (II) Neurohumoral hypothesis: Stress brings about an increased secretion of catecholamines and
neuropeptides leading to increased production of free radicals, which bring about damage to melanocytes and generation of neoantigens, thereby,
triggering immune response. (III) Autocytotoxic hypotheses: Exposure to UV radiation leads to spontaneous production of ROS and increased HMGB1
(high-mobility group box 1) protein level, which brings about activation of caspases, and subsequent loss of melanocytes. (IV) Autoimmune hypothesis:
Various triggers bring about synthesis of neoantigens, which initiate an autoimmune phenomenon. (V) Melanocytorrhagy: ROS, structural alterations in
melanocytes and alterations in tenascin lead to loss of adhesion of melanocytes to the basement membrane which results in transepidermal elimination
of melanocytes on exposure to mild trauma
72
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Arora and Kumaran: Pathogenesis of vitiligo: An update
Table 1: A summary of the major theories implicated in the pathogenesis of vitiligo and its Recent updates
Theory
Genetic theory
Autoimmune
hypothesis
Oxidative stress
hypothesis
Autocytotoxic
hypothesis
Neurohumoral hypothesis
What
is
known?
Several candidate genes,
MHC, ACE, CAT, CTLA-4,
COMT, ESR, MBL2, PTPN22,
HLA, NALP1, XBP1, FOXP1
and IL-2RA, have been
associated with generalized
vitiligo
*SV: Various new pathogenic
genes have been identified
separately for SV and NSV.
Melanocyte-specific
CD8+ T-cells and
follicular T helper (Tfh)
cells bring about
cytotoxic and
autoimmune responses
against the melanocytes
*The role of IFN γ, IL-17,
Th-17 cells, IL-33 and
Treg cells is being singly
recognized in vitiligo.
An alteration of the
redox status of skin and
blood stream of patients
with vitiligo is well
known
Environmental exposures
and melanin synthesis
pathways lead to
autocytotoxic damage to
melanocytes
Psychological stressors and
nervous pathways have an
impact on and bring about
the release of neuropeptides,
which eventually generate
melanotoxic by-products
*
*ROS and UVB bring about
the secretion of HMGB1, a
non-histone DNA-binding
protein, from the
keratinocytes which leads
to increased production of
caspases and subsequent
apoptosis of melanocytes
A significant increase in the
expression of CRH and
CRHR-1 in the lesional and
non-lesional skin of patients
with vitiligo has been
reported as a form of
systemic compensation to
restore normal pigmentation
in vitiligo lesions which,
however, fails because of
defective melanogenesis
pathway in vitiligo lesions
*
*Newer anti-melanocyte
antibodies have been
found in high titres in
patients with NSV
What
is
new?
The role of microRNAs
(miRNAs) and Toll-like
receptors (TLRs) has been
put forward
Recent studies have
found that the epidermal
H2O2 level is not
increased but rather
decreased in patients
with NSV
*A decreased activity of
Nrf2 ARE and FOXO3a
protein leading to
impaired antioxidant
mechanism has been
seen in patients with
vitiligo
differentiation from stem cells, hamper melanocyte function
and destroy melanocytes through induction of various
apoptotic pathways.[135] However, the use of anti-TNF-α
agents has been considered to have mixed results. There
is increasing data on the occurrence of vitiligo as a side
effect of anti-TNF-α therapy used for a variety of
autoimmune diseases such as psoriasis or chronic
inflammatory rheumatic diseases.[136-138] On the other
hand, TNF-α inhibition has been found to halt disease
progression in patients with progressive vitiligo by
quashing cell-mediated immunity.[139] These two strikingly
different effects of anti TNF-α therapy can be explained by
different effects of various anti TNF-α agents on T reg
production and activation and on Th1/Th2 cytokine
balance. For example, in ankylosing spondylitis infliximab
reduces and etanercept enhances IFN-γ production.[139] In
addition, the co-occurrence of vitiligo with various
inflammatory diseases (including psoriasis, inflammatory
bowel disease, rheumatoid arthritis, ankylosing
spondylitis) is well described, therefore, the development
or worsening of skin depigmentation may be coincidental
and related to the underlying disease. Thus, it has been
suggested that etanercept should be considered the
preferred anti-TNF-α agent in patients at risk of
developing vitiligo to mitigate the risk of this adverse
event during therapy for other conditions.[139]
THE CONVERGENCE THEORY
The convergence theory states that all the aforementioned
theories, namely genetic, neurohumoral, autocytoxic, autoimmunity, melanocytorrhagy, altered cellular environment
and impaired melanocyte migration, each contribute to the
pathogenesis of vitiligo and none are mutually exclusive.[140,141]
This theory has been summarized in Figure 1. Table 1
summarizes the various theories implicated in the
pathogenesis of vitiligo and Recent updates in each of the
proposed theories.
CONCLUSION
The cause of vitiligo still remains unknown, although, it is
clear that several different pathophysiological processes
may be involved. The best-supported hypothesis so far is
the autoimmune hypothesis followed by the oxidative
stress theory. Newer theories, such as melanocytorrhagy,
decreased melanocyte survival and the role of HMGB-1
DNA-binding protein, homocysteine and vitamin D
deficiency have recently been put forward. Because all
of these theories seem plausible, it is likely that
vitiligo may indeed include an array of disorders with
different pathophysiological background yet a common
phenotype.
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Arora and Kumaran: Pathogenesis of vitiligo: An update
Financial support and sponsorship
Nil.
18.
19.
Conflicts of interest
There are no conflicts of interest.
20.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
74
Glassman SJ. Vitiligo, reactive oxygen species and T-cells. Clin Sci
(Lond) 2011;120:99-120.
Zailaie MZ. Epidermal hydrogen peroxide is not increased in lesional
and non-lesional skin of vitiligo. Arch Dermatol Res 2017;309:31-42.
Lu T, Gao T, Wang A, Jin Y, Li Q, Li C. Vitiligo prevalence study in
Shaanxi Province, China.Int J Dermatol 2007;46:47-51.
Howitz J, Brodthagen H, Schwartz M, Thomsen K. Prevalence of
vitiligo. Epidemiological survey on the Isle of Bornholm, Denmark.
Arch Dermatol 1977;113:47-52.
Das SK, Majumder PP, Chakraborty R, Majumdar TK, Haldar B.
Studies on vitiligo. I. Epidemiological profile in Calcutta, India. Genet
Epidemiol 1985;2:71-8.
Dwivedi M, Laddha NC, Shajil EM, Shah BJ, Begum R. The ACE
gene I/D polymorphism is not associated with generalized vitiligo
susceptibility in Gujarat population. Pigment Cell Melanoma Res
2008;21:407-8.
Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: A
comprehensive overview Part I. Introduction, epidemiology,
quality of life, diagnosis, differential diagnosis, associations,
histopathology, etiology, and work-up. J Am Acad Dermatol
2011;65:473-91.
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.
Nath SK, Majumder PP, Nordlund JJ. Genetic epidemiology of
vitiligo: Multilocus recessivity cross-validated. Am J Hum Genet
1994;55:981-90.
Majumder PA. Genetics and prevalence of vitiligo vulgaris. In: Hann
SK, Nordlund J, editors. Vitiligo: A Monograph on the Basic and
Clinical Science. Oxford: Blackwell Science Ltd.; 2000.
Spritz RA. The genetics of generalized vitiligo: Autoimmune
pathways and an inverse relationship with malignant melanoma.
Genome Med 2010;19;2:78.
Spritz RA. The genetics of generalized vitiligo. Curr Dir Autoimmun
2008;10:244-57.
Zhang XJ, Chen JJ, Liu JB. The genetic concept of vitiligo. J Dermatol
Sci 2005;39:137-46.
Liu JB, Li M, Chen H, Zhong SQ, Yang S, Du WD, et al. Association
of vitiligo with HLA-A2: A meta-analysis. J Eur Acad Dermatol
Venereol 2007;21:205-13.
Canton I, Akhtar S, Gavalas NG, Gawkrodger DJ, Blomhoff A,
Watson PF, et al. A single-nucleotide polymorphism in the gene
encoding lymphoid protein tyrosine phosphatase (PTPN22)
confers susceptibility to generalised vitiligo. Genes Immun
2005;6:584-7.
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.
Ren Y, Yang S, Xu S, Gao M, Huang W, Gao T, et al. Genetic
variation of promoter sequence modulates XBP1 expression and
genetic risk for vitiligo. PLoS Genet 2009;5:e1000523.
Alkhateeb A, Stetler GL, Old W, Talbert J, Uhlhorn C, Taylor M,
et al. Mapping of an autoimmunity susceptibility locus (AIS1) to
chromosome 1p31.3–p32.2. Hum Mol Genet 2002;11:661-7.
Spritz RA, Gowan K, Bennett DC, Fain PR. Novel vitiligo
susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3),
confirmation of SLEV1 on chromosome 17, and their roles in an
autoimmune diathesis. Am J Hum Genet 2004;74:188-91.
Wang P, Li Y, Nie H, Zhang X, Shao Q, Hou X, et al. The changes of
gene expression profiling between segmental vitiligo, generalized
vitiligo and healthy individual. J Dermatol Sci 2016;84:40-9.
21.
Song P, Li K, Liu L, Wang X, Jian Z, Zhang W, et al. Genetic
polymorphism of the Nrf2 promoter region is associated with vitiligo
risk in Han Chinese populations. J Cell Mol Med 2016;20:1840-50.
22.
Šahmatova L, Tankov S, Prans E, Aab A, Hermann H, Reemann P,
et al. MicroRNA-155 is Dysregulated in the Skin of Patients with
Vitiligo and Inhibits Melanogenesis-associated Genes in Melanocytes
and Keratinocytes. Acta Derm Venereol 2016;96:742-7.
Traks T, Keermann M, Karelson M, Rätsep R, Reimann E, Silm H,
et al. Polymorphisms in Toll-like receptor genes are associated with
vitiligo. Front Genet 2015;6:278.
Shen C, Gao J, Sheng Y, Dou J, Zhou F, Zheng X, et al. Genetic
susceptibility to Vitiligo: GWAS approaches for identifying vitiligo
susceptibility Genes and Loci. Front Genet 2016;7:3. Published online
2016 Feb 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740779/.
doi: 10.3389/fgene.2016.00003.
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.
Badri AM, Todd PM, Garioch JJ, Gudgeon JE, Stewart DG, Goudie
RB. An immunohistological study of cutaneous lymphocytes in
vitiligo. J Pathol 1993;170:149-55.
Hann SK, Park YK, Lee KG, Choi EH, Im S. Epidermal changes in
active vitiligo. J Dermatol 1992;19:217-22.
Ogg GS, Rod Dunbar P, Romero P, Chen JL, Cerundolo V.
High frequency of skin-homing melanocyte-specific cytotoxic T
lymphocytes in autoimmune vitiligo. J Exp Med 1998;188:
1203-8.
Palermo B, Campanelli R, Garbelli S, Mantovani S, Lantelme E,
Brazzelli V, et al. Specific cytotoxic T lymphocyte responses against
Melan-A/MART1, tyrosinase and gp100 in vitiligo by the use of
major histocompatibility complex/peptide tetramers: The role of
cellular immunity in the etiopathogenesis of vitiligo. J Invest
Dermatol 2001;117:326-32.
Lang KS, Caroli CC, Muhm A, Wernet D, Moris A, Schittek B, et al.
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 2001;116:
891-7.
Allard EL, Hardy MP, Leignadier J, Marquis M, Rooney J, Lehoux D,
et al. Overexpression of IL-21 promotes massive CD8+ memory T
cell accumulation. Eur J Immunol 2007;37:3069-77.
Liu S, Lizée G, Lou Y, Liu C, Overwijk WW, Wang G, et al. IL-21
synergizes with IL-7 to augment expansion and anti-tumor function of
cytotoxic T cells. Int Immunol 2007;19:1213-21.
Harris JE, Harris TH, Weninger W, Wherry EJ, Hunter CA, Turka
LA, et al. A mouse model of vitiligo with focused epidermal
depigmentation requires IFN-g for autoreactive CD8+ T-cell
accumulation in the skin. J Invest Dermatol 2012;132:1869-76.
Shi F, Erf GF. IFN-g, IL-21, and IL-10 co-expression in evolving
autoimmune vitiligo lesions of Smyth line chickens. J Invest Dermatol
2012;132:642-9.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
Pigment International | Volume 4 | Issue 2 | July-December 2017
[Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131]
Arora and Kumaran: Pathogenesis of vitiligo: An update
35.
Singh RK, Lee KM, Vujkovic-Cvijin I, Ucmak D, Farahnik B,
Abrouk M, et al. The role of IL-17 in vitiligo: A review.
Autoimmun Rev 2016;15:397-404.
36.
Zhou L, Shi YL, Li K, Hamzavi I, Gao TW, Huggins RH, et al.
Increased circulating Th17 cells and elevated serum levels of TGFbeta and IL-21 are correlated with human non-segmental vitiligo
development. Pigment Cell Melanoma Res 2015;28:324-9.
Bhardwaj S, Rani S, Srivastava N, Kumar R, Parsad D. Increased
systemic and epidermal levels of IL-17A and IL-1β promotes
progression of non-segmental vitiligo. Cytokine 2017;91:153-61.
doi: 10.1016/j.cyto.2016.12.014.
Vaccaro M, Cicero F, Mannucci C, Calapai G, Spatari G, Barbuzza O,
et al. L 33 circulating serum levels are increased in patients with nonsegmental generalized vitiligo. Arch Dermatol Res 2016;308:527-30.
Dwivedi M, Kemp EH, Laddha NC, Mansuri MS, Weetman AP,
Begum R. Regulatory T cells in vitiligo: Implications for pathogenesis
and therapeutics. Autoimmun Rev 2015;14:49-56.
Lili Y, Yi W, Ji Y, Yue S, Weimin S, Ming L. Global activation of
CD8+ cytotoxic T lymphocytes correlates with an impairment in
regulatory T cells in patients with generalized vitiligo. PLoS One
2012;7. doi: 10.1371/journal.pone.0037513.e37513.
Dwivedi M, Laddha NC, Arora P, Marfatia YS, Begum R. Decreased
regulatory T-cells and CD4+/CD8+ ratio correlate with disease onset
and progression in patients with generalized vitiligo. Pigment Cell
Melanoma Res 2013;26:586-91.
Abdallah M, Lotfi R, Othman W, Galal R. Assessment of tissue
FoxP3+, CD4+ and CD8+ T-cells in active and stable nonsegmental
vitiligo. Int J Dermatol 2014;53:940-6.
Shi F, Erf GF. IFN-g, IL-21, and IL-10 co-expression in evolving
autoimmune vitiligo lesions of Smyth line chickens. J Invest Dermatol
2012;132:642-9.
Khan R, Gupta S, Sharma A. Circulatory levels of T-cell cytokines
(interleukin [IL]-2, IL-4, IL-17, and transforming growth factor-β) in
patients with vitiligo. J Am Acad Dermatol 2012;66:510-1.
Bystryn JC. Serum antibodies in vitiligo patients. Clin Dermatol
1989;7:136-45.
Cui J, Arita Y, Bystryn JC. Characterization of vitiligo antigens.
Pigment Cell Res 1995;8:53-9.
Norris DA, Capin L, Muglia JJ, Osborn RL, Zerbe GO, Bystryn JC,
et al. Enhanced susceptibility of melanoctyes to different
immunologic effector mechanisms in vitro: Potential mechanisms
for postinflammatory hypopigmentation and vitiligo. Pigment Cell
Melanoma Res 1988;1:113-23.
Baharav E, Merimski O, Shoenfeld Y, Zigelman R, Gilbrud B,
Yecheskel G, et al. Tyrosinase as an autoantigen in patients with
vitiligo. Clin Exp Immunol 1996;105:84-8.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
Okamoto T, Irie RF, Fujii S, Huang SK, Nizze AJ, Morton DL, et al.
Anti-tyrosinase-related protein-2 immune response in vitiligo patients
and melanoma patients receiving active specific immunotherapy.
J Invest Dermatol 1998;111:1034-9.
Hedstrand H, Ekwall O, Olsson MJ, Landgren E, Kemp EH, Weetman
AP, et al. The transcription factors SOX9 and SOX10 are vitiligo
autoantigens in autoimmune polyendocrine syndrome type I. J Biol
Chem 2001;276:35390-5.
Zhu MC, Ma HY, Zhan Z, Liu CG, Luo W, Zhao G. Detection of
auto antibodies and transplantation of cultured autologous
melanocytes for the treatment of vitiligo. Exp Ther Med 2017;13:
23-8.
Zhu MC, Liu CG, Wang DX, Zhan Z. Detection of serum antimelanocyte antibodies and identification of related antigens in
patients with vitiligo. Genet Mol Res 2015;14:160-73.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
Schallreuter KU, Moore J, Wood JM, Beazley WD, Peters EM,
Marles LK, et al. Epidermal H2O2 accumulation alters
tetrahydrobiopterin (6BH4) recycling in vitiligo: Identification of a
general mechanism in regulation of all 6BH4-dependent processes?
J Invest Dermatol 2001;116:167-74.
Schallreuter KU, Moore J, Wood JM, Behrens-Williams S, Panske A,
Harari M, et al. In vivo and in vitro evidence for hydrogen peroxide
(H2O2) accumulation in the epidermis of patients with vitiligo and its
successful removal by a UVB-activated pseudocatalase. J Invest
Dermatol Symp Proc 1999;4:91-6.
Schallreuter KU, Moore J, Behrens-Williams S, Behrens-Williams S,
Panske A, Harari M, et al. Rapid initiation of repigmentation of
vitiligo with dead sea limatotherapy in combination with
pseudocatalase (PC-KUS). Int J Dermatol 2002;41:482-7.
Dell’Anna ML, Urbanelli S, Mastrofrancesco A, Camera E, Iacovelli
P, Leone G, et al. Alterations of mitochondria in peripheral blood
mononuclear cells of vitiligo patients. Pigment Cell Res 2003;16:
553-9.
Swalwell H, Latimer J, Haywood RM, Birch-Machin MA.
Investigating the role of melanin in UVA/UVB- and hydrogen
peroxide-induced cellular and mitochondrial ROS production and
mitochondrial DNA damage in human melanoma cells. Free Radic
Biol Med 2011;52:626-34.
Yildirim M, Baysal V, Inaloz HS, Can M. The role of oxidants and
antioxidants in generalized vitiligo at tissue level. J Eur Acad
Dermatol Venereol 2004;18:683-6.
Latha B, Babu M. The involvement of free radicals in burn injury: A
review. Burns 2001;27:309-17.
Khan R, Satyam A, Gupta S, Sharma VK, Sharma A. Circulatory
levels of antioxidants and lipid peroxidation in Indian patients with
generalized and localized vitiligo. Arch Dermatol Res 2009;301:
731-7.
Arican O, Kurutas EB. Oxidative stress in the blood of patients with
active localized vitiligo. Acta Dermatovenerol Alp Pannonica Adriat
2008;17:12-6.
Sravani PV, Babu NK, Gopal KV, Rao GR, Rao AR, Moorthy B,
et al. Determination of oxidative stress in vitiligo by measuring
superoxide dismutase and catalase levels in vitiliginous and nonvitiliginous skin. Indian J Dermatol Venereol Leprol 2009;75:
268-71.
63.
Dammak I, Boudaya S, Ben Abdallah F, Turki H, Attia H, Hentati B.
Antioxidant enzymes and lipid peroxidation at the tissue level in
patients with stable and active vitiligo. Int J Dermatol 2009;48:
476-80.
64.
Ines D, Sonia B, Riadh BM, Amel el G, Slaheddine M, Hamida T,
et al. A comparative study of oxidant-antioxidant status in stable
and active vitiligo patients. Arch Dermatol Res 2006;298:
147-52.
Dammak I, Boudaya S, Ben Abdallah F, Turki H, Attia H, Hentati B.
Antioxidant enzymes and lipid peroxidation at the tissue level in
patients with stable and active vitiligo. Int J Dermatol 2009;48:
476-80.
Casp CB, She JX, McCormack WT. Genetic association of the
catalase gene (CAT) with vitiligo susceptibility. Pigment Cell Res
2002;15:62-6.
65.
66.
67.
68.
Aronoff S. Catalase: Kinetics of photooxidation. Science 1965;150:
72-3.
Schallreuter KU, Wood JM, Pittelkow MR, Buttner G, Swanson N,
Korner C, et al. Increased monoamine oxidase A activity in the
epidermis of patients with vitiligo. Arch Dermatol Res 1996;288:
14-8.
Pigment International | Volume 4 | Issue 2 | July-December 2017
75
[Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131]
Arora and Kumaran: Pathogenesis of vitiligo: An update
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
Schallreuter KU, Wood JM, Ziegler I, Lemke KR, Pittelkow MR,
Lindsey NJ, et al. Defective tetrahydrobiopterin and catecholamine
biosynthesis in the depigmentation disorder vitiligo. Biochim Biophys
Acta 1994;1226:181-92.
Beazley WD, Gaze D, Panske A, Panzig E, Schallreuter KU. Serum
selenium levels and blood glutathione peroxidase activities in vitiligo.
Br J Dermatol 1999;141:301-3.
Westerhof W, Manini P, Napolitano A, D’Ischia M. The haptenation
theory of vitiligo and melanoma rejection: A close-up. Exp Dermatol
2011;20:92-6.
Bellei B, Pitisci A, Ottaviani M, Ludovici M, Cota C, Luzi F, et al.
Vitiligo: A possible model of degenerative diseases. PLoS One
2013;8:e59782.
Picardo M, Dell’Anna ML, Ezzedine K, Hamzavi I, Harris JE,
Parsad D, et al. Vitiligo. Nat Rev Dis Primers 2015;1:15011.
Qiu L, Song Z, Setaluri V. Oxidative stress and vitiligo: The Nrf2ARE signaling connection. J Invest Dermatol 2014;134:2074-6.
Jian Z, Li K, Liu L, Zhang Y, Zhou Z, Li C, et al. Heme oxygenase-1
protects human melanocytes from H2O2-induced oxidative stress via
the Nrf2-ARE pathway. J Invest Dermatol 2011;131:1420-7.
Jian Z, Li K, Song P, Zhu G, Zhu L, Cui T, et al. Impaired activation of
the Nrf2-ARE signaling pathway undermines H2O2-induced
oxidative stress response: A possible mechanism for melanocyte
degeneration in vitiligo. J Invest Dermatol 2014;134:2221-30.
Jian Z, Tang L, Yi X, Liu B, Zhang Q, Zhu G, et al. Aspirin induces
Nrf2-mediated transcriptional activation of haem oxygenase-1 in
protection of human melanocytes from H2O2-induced oxidative
stress. J Cell Mol Med 2016;20:1307-18.
Laddha NC, Dwivedi M, Mansuri MS, Singh M, Gani AR, Yeola AP,
et al. Role of oxidative stress and autoimmunity in onset and
progression of vitiligo. Exp Dermatol 2014;23:352-3.
Ozel Turkcu U, Solak Tekin N, Gokdogan Edgunlu T, Karakas Celik
S, Oner S. The association of FOXO3A gene polymorphisms with
serum FOXO3A levels and oxidative stress markers in vitiligo
patients. Gene 2014;536:129-34.
Hann SK, Chun W. Autocytotoxic hypothesis for the destruction of
melanocytes as the cause of vitiligo. In: Hann SK, Nordlund J, editors.
Vitiligo. Oxford: Blackwell Science Ltd.; 2000.
Kim JY, Lee EJ, Seo J, Oh SH. Impact of HMGB1 on melanocytic
survival and its involvement in the pathogenesis of vitiligo. Br
J Dermatol 2017;176:1558-68. doi: 10.1111/bjd.15151.
82.
Kumar R, Parsad D. Melanocytorrhagy and apoptosis in vitiligo:
Connecting jigsaw pieces. Indian J Dermatol Venereol Leprol
2012;78:19-23.
83.
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.
Kumar R, Parsad D, Kanwar AJ. Role of apoptosis and
melanocytorrhagy: A comparative study of melanocytes adhesion
in stable and unstable vitiligo. Br J Dermatol 2011;164:187-91.
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;137:171-8.
Kumar R, Parsad D, Kanwar AJ, Kaul D. Altered levels of LXR-a:
Crucial implications in the pathogenesis of vitiligo. Exp Dermatol
2012;21:853-8.
Kitamura R, Tsukamoto K, Harada K, Shimizu A, Shimada S,
Kobayashi T, et al. Mechanisms underlying the dysfunction of
melanocytes in vitiligo epidermis: Role of SCF/KIT protein
interactions and the downstream effector, MITF-M. J Pathol
2004;202:463-75.
84.
85.
86.
87.
76
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
Lee AY, Kim NH, Choi WI, Youm YH. 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.
Lotti T, Zanardelli M, D’Erme AM. Vitiligo: What’s new in the
psycho-neuro-endocrine-immune connection and related treatments.
Wien Med Wochenschr 2014;164:278-85.
Orecchia GE. Neural pathogenesis. In: Hann S, Nordlund J, editors.
Vitiligo. Oxford: Blackwell Science Ltd.; 2000.
Al’Abadie MS, Senior HJ, Bleehen SS, Gawkrodger DJ.
Neuropeptide and neuronal marker studies in vitiligo. Br
J Dermatol 1994;131:160-5.
Morrone A, Picardo M, de Luca C, Terminali O, Passi S, Ippolito F.
Catecholamines and vitiligo. Pigment Cell Res 1992;5:65-9.
Le Poole IC, van den Wijngaard RM, Smit NP, Oosting J, Westerhof
W, Pavel S. Catechol-O-methyltransferase in vitiligo. Arch Dermatol
Res 1994;286:81-6.
Schallreuter KU, Wood JM, Pittelkow MR, Buttner G, Swanson N,
Korner C, et al. Increased monoamine oxidase A activity in the
epidermis of patients with vitiligo. Arch Dermatol Res 1996;288:
14-8.
Iyengar B. Modulation of melanocytic activity by acetylcholine. Acta
Anat 1989;136:139-41.
Shaker OG, Eltahlawi SM, Tawfic SO, Eltawdy AM, Bedair NI.
Corticotropin-releasing hormone (CRH) and CRH receptor 1 gene
expression in vitiligo. Clin Exp Dermatol 2016;41:734-40.
Slominski A, Zmijewski M, Zbytek B, Tobin DJ, Theoharides TC,
Rivier J, et al. Key role of CRF in the skin stress response system.
Endocrine Rev 2013;34:827-84.
Lips P. Vitamin D physiology. Prog Biophys Mol Biol 2006;92:4-8.
Adorini L, Penna G. Control of autoimmune diseases by the vitamin D
endocrine system. Nat Clin Pract Rheumatol 2008;4:404-12.
Birlea SA, Costin GE, Norri DA. New insights on therapy with
vitamin D analogs targeting the intracellular pathways that control
repigmentation in human vitiligo. Med Res Rev 2009;29:514-46.
Parsad D, Saini R, Verma N. Combination of PUVAsol and topical
calcipotriol in vitiligo. Dermatology 1998;197:167-70.
Oh SH, Kim T, Jee H, Do JE, Lee JH. Combination treatment of nonsegmental vitiligo with a 308-nm xenon chloride excimerlaser and
topical high-concentration tacalcitol: A prospective, single-blinded,
paired, comparative study. J Am Acad Dermatol 2011;65:428-30.
Koizumi H, Kaplan A, Shimizu T, Ohkawara A. 1,
25-Dihydroxyvitamin D3 and a new analogue, 22-oxacalcitriol,
modulate proliferation and interleukin-8 secretion of normal
human keratinocytes. J Dermatol Sci 1997;15:207-13.
Ustun I, Seraslan G, Gokce C, Motor S, Can Y, Ugur Inan M, et al.
Investigation of vitamin D levels in patients with vitiligo vulgaris.
Acta Dermatovenerol Croat 2014;22:110-3.
Saleh HM, Abdel Fattah NS, Hamza HT. Evaluation of serum
25-hydroxyvitamin D levels in vitiligo patients with and without
autoimmune diseases. Photodermatol Photoimmunol Photomed
2013;29:34-40.
Upala S, Sanguankeo A. Low 25-hydroxyvitamin D levels are
associated with vitiligo: A systematic review and meta-analysis.
Photodermatol Photoimmunol Photomed 2016;32:181-90.
Karagün E, Ergin C, Baysak S, Erden G, Aktaş H, Ekiz Ö. The role of
serum vitamin D levels in vitiligo. Postepy Dermatol Alergol
2016;33:300-2.
Karagüzel G, Sakarya NP, Bahadır S, Yaman S, Ökten A. Vitamin D
status and the effects of oral vitamin D treatment in children with
vitiligo: A prospective study. Clin Nutr ESPEN 2016;15:28-31.
Pigment International | Volume 4 | Issue 2 | July-December 2017
[Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131]
Arora and Kumaran: Pathogenesis of vitiligo: An update
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
Khurrum H, AlGhamdi KM. The relationship between the serum level
of vitamin D and vitiligo: A controlled study on 300 subjects. J Cutan
Med Surg 2016;20:139-45.
Mudd SH, Levy HL, Skorby LF. Disorders of transsulfuration. In:
Scriver CR, Beudet AL, Sly WS, Valle D, editors. The Metabolic and
Molecular Basis of Inherited Disease. 7th ed. New York: McGrawHill; 1995. p. 1279-327.
Guttormsen AB, Schneede J, Ueland PM, Refsum H. Kinetics of total
plasma homocysteine in subjects with hyperhomocysteinemia due to
folate or cobalamin deficiency. Am J Clin Nutr 1996;64:194-202.
Minet JC, Bissé E, Aebischer CP, Beil A, Wieland H, Lütschg J.
Assessment of vitamin B12, folate and vitamin B6 status and relation
to sulfur amino acid metabolism in neonates. Am J Clin Nutr
2000;72:751-7.
Montes LF, Dias ML, Lajous J, Garcia NJ. Folic acid and vitamin B12
in vitiligo: A nutritional approach. Cutis 1992;50:39-42.
Kim SM. Serum levels of folic acid and vitamin B12 in Korean
patients with vitiligo. Yonsei Med J 1999;40:195-8.
El-Batawi MM, El-Tawil NE, El-Tawil AE. Serum levels of vitamin
B12 and folic acid in Egyptian patients with vitiligo. Egypt J Derm
Androl 2001;21:77-80.
Brenton DP, Cusworth DC, Dent CE, Jones EE. Homocystinuria.
Clinical and dietary studies.Q J Med 1966;35:325-46.
Goth L, Rass P, Pay A. Catalase enzyme mutations and their
association with diseases. Mol Diagn 2004;8:141-9.
Kurbanov Kh, Burobin VA, Berezov TT. Histidase activity of the skin
in relation to the state of melanogenesis. Bull Exp Biol Med
1974;78:898-900.
Shaker OG, El-Tahlawi SM. Is there a relationship between
homocysteine and vitiligo? A pilot study. Br J Dermatol 2008;159:
720-4.
Guilland JC, Favier A, Potier de Courcy G, Galan P, Hercberg S.
Hyperhomocysteinemia: An independent risk factor or a simple
marker of vascular disease? 1. Basic data. Pathol Biol (Paris)
2003;51:101-10. [In French].
Ortonne J-P. Vitiligo and other disorders of hypopigmentation. In:
Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. New York:
Mosby; 2003. p. 947-73.
Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease:
Cause or effect? Am J Clin Nutr 2000;72:315-23.
Reish O, Townsend D, Berry SA, Tsai MY, King RA. Tyrosinase inhibition
due to interaction of homocyst(e)ine with copper: The mechanism for
reversible hypopigmentation in homocystinuria due to cystathionine betasynthase deficiency. Am J Hum Genet 1995;57:127-32.
Ramakrishnan S, Sulochana KN, Lakshmi S, Selvi R, Angayarkanni
N. Biochemistry of homocysteine in health and diseases. Indian J
Biochem Biophys 2006;43:275-83.
Balci DD, Yonden Z, Yenin JZ, Okumus N. Serum homocysteine,
folic acid and vitamin B12 levels in vitiligo. Eur J Dermatol
2009;19:382-3.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
Yasar A, Gunduz K, Onur E, Calkan M. Serum homocysteine, vitamin
B12, folic acid levels and methylenetetrahydrofolate reductase
(MTHFR) gene polymorphism in vitiligo. Dis Markers 2012;33:
85-9.
Singh S, Singh U, Pandey SS. Increased level of serum homocysteine
in vitiligo. J Clin Lab Anal 2011;25:110-2.
Karadag AS, Tutal E, Ertugrul DT, Akin KO, Bilgili SG. Serum
holotranscobalamine, vitamin B12, folic acid and homocysteine
levels in patients with vitiligo. Clin Exp Dermatol 2012;37:62-4.
Ataş H, Cemil BÇ, Gönül M, Baştürk E, Çiçek E. Serum levels of
homocysteine, folate and vitamin B12 in patients with vitiligo before
and after treatment with narrow band ultraviolet B phototherapy and
in a group of controls. J Photochem Photobiol B 2015;148:174-80.
Alghamdi KM, Moussa Na KM, Huma K. Is there a real relationship
between serum level of homocysteine and vitiligo? A controlled study
on 306 subjects. J Cutan Med Surg 2014;18:5-7.
Chen JX, Shi Q, Wang XW, Guo S, Dai W, Li K, et al. Genetic
polymorphisms in the methylenetetrahydrofolate reductase gene
(MTHFR) and risk of vitiligo in Han Chinese population: A genotypephenotype correlation study. Br J Dermatol 2014;170:1092-9.
Anbar T, Zuel-Fakkar NM, Matta MF, Arbab MM. Elevated
homocysteine levels in suction-induced blister fluid of active
vitiligo lesions. Eur J Dermatol 2016;26:64-7.
Silverberg JI, Silverberg NB. Serum homocysteine as a biomarker of
vitiligo vulgaris severity: A pilot study. J Am Acad Dermatol
2011;64:445-7.
Gupta S, D’souza P, Dhali TK, Arora S. Serum homocysteine and
total antioxidant status in vitiligo: A case control study in Indian
population. Indian J Dermatol 2016;61:131-6.
Toussirot É, Aubin F. Paradoxical reactions under TNF-a blocking
agents and other biological agents given for chronic immunemediated diseases: An analytical and comprehensive overview.
RMD Open 2016;2:e000239. doi: 10.1136/rmdopen-2015-000239.
Ramírez-Hernández M, Marras C, Martínez-Escribano JA.
Infliximab-induced vitiligo. Dermatology 2005;210:79-80.
Toussirot E, Salard D, Algros MP, Aubin F. Occurrence of vitiligo in a
patient with ankylosing spondylitis receiving adalimumab. Ann
Dermatol Venereol 2013;140:801-2.
Posada C, Flórez A, Batalla A, Alcázar JJ, Carpio D. Vitiligo during
treatment of Crohn’s disease with adalimumab: Adverse effect or
co-occurrence? Case Rep Dermatol 2011;3:28-31.
Webb KC, Tung R, Winterfield LS, Gottlieb AB, Eby JM, Henning
SW, et al. Tumour necrosis factor-a inhibition can stabilize disease in
progressive vitiligo. Br J Dermatol 2015;173:641-50.
Namazi MR. Neurogenic dysregulation, oxidative stress, autoimmunity,
and melanocytorrhagy in vitiligo: Can they be interconnected? Pigment
Cell Res 2007;20;360-3.
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;2:145-53.
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