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Pathogenesis of vitiligo - An update

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Review Article
Pathogenesis of vitiligo: An update
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
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.
What is known?
Familial clustering is seen in vitiligo. Various studies have
found that the frequency of vitiligo among first-degree
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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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,
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.
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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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
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
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]
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]
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
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
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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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
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
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
with vitiligo and a significant direct association with
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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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
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]
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]
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
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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
Genetic theory
Oxidative stress
Neurohumoral hypothesis
Several candidate genes,
and IL-2RA, have been
associated with generalized
*SV: Various new pathogenic
genes have been identified
separately for SV and NSV.
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
Environmental exposures
and melanin synthesis
pathways lead to
autocytotoxic damage to
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
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
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 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.
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
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Arora and Kumaran: Pathogenesis of vitiligo: An update
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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