Transcript association studies in vitiligo

Vitiligo Part 2
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UV radiation of the skin
causes increased DNA
damage and thus activity of
p53 in the keratinocytes of the
skin. This causes (amongst
others) the production of Kitl
(Kit ligand, binds to the Kit
receptor) and POMC
(Proopiomelanocortin) which
is later processed to ACTH
(Adrenocorticotropic hormone)
and the different MSH-forms
(Melanocyte-stimulating
hormone). These act on the
MC1R (Melanocortin 1
receptor) on the surface of the
melanocytes and induce
pigmentatio
In the melanocytes the binding
of these ligands activates
different signal transduction
pathways which all finally lead
to the activation of the
transcription factor MITF
(Microphtalmia-associated
transcription factor) which
then upregulates the
transcription of tyrosinase.
Biology of Melanocyte
VITILIGO GENETICS
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Most human diseases result from an interaction between genetic variants and environmental factors, and to
establish the actual contribution of genetic factors is the first step of genetic studies that evaluate complex
diseases. In general terms, the scrutiny of complex diseases genetic components begins through observational
studies, such as: analyzes of pools of familial cases, comparative studies of concordance rates of disease
occurrence among monozygotic (MZ) and dizygotic (DZ) twins and complex segregation analyzes (CSA).
However, these studies do not provide information on the exact nature of the genetic component in question, as
the location and identity of the involved genes. In order to advance it is necessary to perform different studies
involving molecular genetic markers, as it is done in linkage and association analysis.
Genetic epidemiological studies have demonstrated that vitiligo can be considered a complex genetic disease
because:
(i) the disease varies in symptom severity and age of onset, which hinders the definition of the appropriate
phenotype and the selection of the optimum study population; early age of onset was associated with familial
occurrence of generalized vitiligo. In addition, early onset vitiligo is associated with more severe disease;
(ii) the etiological mechanisms of the disease can vary; vitiligo's etiopathogenesis has not yet been fully clarified,
and several theories have been proposed;
(iii ) complex genetic diseases are often oligogenic or even polygenic and each gene contributes to a fraction of
the overall relative risk; linkage analysis performed using vitiligo phenotype identified susceptible loci located on
chromosomes 1, 4, 6, 7 , 8, 17 & 22 co-segregating with the disease. For these regions, some genes consistently
associated with vitiligo have been reported, such as NLRP1 (17p13) and XBP1 (22q12).
The involvement of genetic factors in the susceptibility to vitiligo became evident in familial studies, which
demonstrated that vitiligo segregates with a complex standard of multifactorial and polygenic inheritance .
Additional evidence for a genetic susceptibility component in vitiligo has been gathered from (complex segregation
analsis) CSA, the main statistical tool used to determine, from familial information, the inheritance model that best
explains the pattern of segregation on a particular phenotype
LINKAGE STUDIES IN VITILIGO
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Linkage analysis is a tool that allows the screening of the entire human genome, using multigenerational families
in order to identify genomic regions that harbor loci responsible for the observed phenotype, even without prior
assumptions about the disease pathogenesis. The principle of linkage analysis is based on the premise that if a
polymorphic marker is near the locus that harbors the disease predisposing gene, they will co-segregate in
families over generations, more intensively than expected under the hypothesis of aleatory transmission expected
in an independent heritage of unconnected loci.
The first evidence of linkage was between vitiligo associated with systemic lupus erythematosus (SLE) and
chromosome 17p13 markers, a locus denominated by authors as SLEV1, in 16 Euro-American families affected
by both diseases. This result suggests the existence of a probable common genetic autoimmunity determinant of
vitiligo and SLE in these families. A subsequent independent study detected linkage between 1p31 locus, termed
by the authors "AIS1" (Autoimmunity Susceptibility Locus 1) and vitiligo in a large multigenerational family
presenting multiple cases of vitiligo and Hashimoto's thyroiditis. In a subsequent complementary study, in which
the original collection of families was expanded to a total of 102 pedigrees, additional evidence of the connection
with vitiligo was detected on chromosomes 7 and 8. Furthermore, the evidence of linkage to
17p13 locus previously described was confirmed. Thus, the suggestive linkage signal to four loci on chromosomes
9, 13, 19 and 22 was detected. The authors suggest that linkage signals detected for chromosomes 7q and 17p
seem to derive primarily from families segregating vitiligo and epidemiologically related autoimmune diseases. On
the other hand, the linkage signal detected for chromosome 8p derived from families that segregate only
vitiligo. More recently, a genomic scan conducted in Chinese multiplex families affected by generalized vitiligo
identified the connection between the disease and markers of region 4q13-q21, 22q12 and 6p21-p22.
Linkage analyzes performed in populations with different ethnic backgrounds, using generalized vitiligo as
phenotype, showed that the main susceptibility locus co-segregating with the disease is not the same in each
population, except for 22q11. This suggests that different genes may be involved in the pathogenesis of vitiligo in
different populations around the world, characterizing a polygenic disease. The exact definition of the gene or
genes involved in controlling the phenotype in question depends on further studies, usually association ones,
involving target genes located in genomic regions identified in the linkage analysis.
Association between vitiligo and other disorders
Pathogeneses of vitiligo
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What Causes
Low Stomach
Acid?
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@Aging
@Low thyroid or
thyroid dysfunction
@Adrenal
fatigue/insufficiency
@H. Pylori infection
@Medications
@Poor diet
@Stress
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NUTRITIONAL SUPPLEMENTATION FOR VITILIGO
ASSOCIATION STUDIES IN VITILIGO
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There are two main design types of association studies: population-based and family-based. Population-based
studies (case-control) primarily compare the allele frequencies of a genetic marker among affected and
unaffected individuals (controls); a particular allele is considered associated with the studied phenotype when it
occurs with different frequencies amongst the groups. The big challenge in this type of study is the correct
selection of the population segment and the sample size, in order to have sufficient power to detect the genetic
effect, if it really exists. Family-based association studies use the basic trio design, consisting of two parents and
an affected offspring. The analysis assesses the frequency with which a particular allele is transmitted from a
heterozygous parent to the affected child: a deviation in the expected aleatory transmission, according to the first
law of Mendel, suggests an association. It is important to emphasize that, association studies have greater power
to detect moderate to weak genetic effects when compared to linkage studies, which makes them ideal for fine
mapping of previously detected chromosomal regions connected with the disease.
Currently, over 50 candidate genes were already investigated in association studies for susceptibility to vitiligo.
However, few genes, including DDR1, XBP1, NLRP1, PTPN22 and COMT, were consistently associated with the
disease, either by being located in a region previously identified in a linkage study (positional) or by having been
replicated in populations of different geographic regions,. In addition to the genes listed above, an evidence of
association with vitiligo phenotypes was found for markers of ACE, AIRE, CD4, COX2, ESR1, EDN1, FAS,
FOXD3, FOXP3, IL1 - RN, IL - 10, MBL2, MC1R, MYG1, Nrf2, PDGFRA, PRO2268, SCF, SCGF, TXNDC5,
UVRAG and VDR genes, but these associations were not replicated in independent populations.Nevertheless,
several genetic studies for CAT and CTLA - 4 genes in populations of different ethnic origins, have produced
conflicting results. In general, associations between variants of HLA genes with susceptibility to vitiligo,
considering different ethnic groups, have not been consistent, however, there are notable exceptions, such as the
association signs observed for HLA - A2, HLA - DR4 and HLA - DR7 alleles
Candidate genes identified from linkage genomic scans generated interesting results. The first was NLRP1,
located in chromosome region 17p13, which encodes an innate immune system regulatory protein. NLRP1 gene
polymorphisms were first investigated and associated to American families affected with generalized vitiligo and
autoimmune diseases epidemiologically associated to vitiligo; later, the association signal was replicated in
independent case-control populations from Romania and Jordan, using the generalized vitiligo phenotype
ASSOCIATION STUDIES IN VITILIGO
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Successful fine mapping of 22q12 locus identified XBP1 gene associated with
vitiligo. XBP1 encodes a transcription factor that regulates the expression of MHC class II genes.
The identification of genetic variant rs2269577, located in XBP1 gene promoter region associated
with vitiligo per se, was possible due to the progressive realization of association analyzes in three
independent population samples, both case-control and families. Furthermore, a functional study
showed high expression of XBP1 in the injured skin of patients who carry the risk allele C of
rs2269577 polymorphism. Interestingly, the same risk allele of variant rs2269577 was replicated in
a European population in a case-control association study.
Another approach is the selection of genes involved in important biological pathways in the
disease pathogenesis, as is the case with DDR1 gene, located on chromosome region 6p21.
DDR1 gene encodes a transmembrane tyrosine kinase receptor; mutations in this gene can lead
to alterations in melanocyte adhesion to basal membrane via integrin CCN3. Association between
DDR1 gene polymorphisms and vitiligo per se has been reported in a population from southern
Brazil. Interestingly, the association signal observed was strongly dependent on age, suggesting a
more pronounced genetic effect in patients affected with vitiligo that were aged ≤ 18 and 25. It is
important to note that, one study in a Korean population sample replicated the association
between vitiligo and DDR1 variants, although the statistical signal has not withstood correction for
multiple testing. Another independent study failed to replicate the same association; however, the
authors did not evaluate the population sample stratified by age of vitiligo onset. Recent functional
studies have shown that the decreasing of melanocyte adhesion in the basal lamina is due in part
to decreased expression of DDR1
GENOME WIDE ASSOCIATION STUDIES - GWAS
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GENOME WIDE ASSOCIATION STUDIES - GWAS
GWAS involve hundreds of thousands of genetic markers, enough for complete genome coverage, which are
tested in combination to determine their association with a particular disease. This method is free of functional or
positional hypotheses, since the only goal in selecting the collection of markers to be tested is to achieve the most
substantial coverage possible, including all genes in the genome that are investigated in a single experiment.
Thus, GWAS allow the identification of genes previously unsuspected of participating in the pathogenesis control
of the studied disease.
The first GWAS in vitiligo was conducted in a genetically isolated population sample under strong founder effect
(thus presenting lower genetic variability) in northwestern Romania, with a high prevalence of generalized vitiligo,
the authors found an association between the disease and SMOC2 gene marker rs13208776 (p=3.13×10); yet,
this finding was not replicated. Subsequently, two independent GWAS for generalized vitiligo, conducted in
Caucasian and Chinese samples, found many signs of vitiligo associated with polymorphisms of several loci,
including the MHC. Only 2 of these signals for LPP and IKZF4 genes were replicated in population samples
different from the original ones.
Genome-wide linkage study is a method, when executed correctly, identifies genetic loci of vitiligo in multiplex
families. These studies help to determine the position of the genetic marker inherited together with a specific
disease. Genome-wide linkage studies in the Caucasian population multiplex vitiligo families identified additional
linkage signals on chromosomes 7, 8, 9, 11, 13, 17, 19, and 22
. In addition, this parallels with the genetic linkage studies of vitiligo in Chinese Han population which detected
linkage signals on chromosomes 1, 4, 6, 14, and 22. .Normally, genetic loci discovered through genome-wide
linkage studies encompass several megabases. The diversity of proposed regions has created a challenge in fine
mapping.
Genome-wide association studies is a high through put technology, capable of “pin-pointing” disease-causing
genes. Since 2005, GWAS has been proved to be the most powerful and efficient study design thus far in
identifying genetic variants that are associated with complex diseases. More than 1000 types of complex diseases
and traits have been investigated by this approach. Since 2010, several GWASs have been performed in patients
with vitiligo in various ethnic populations .these studies have confirmed genetic associations of almost 40 genes
and loci with vitiligo during the past 5 years .Recently, Next-Generation DNA Re-Sequencing and exome
sequencing analysis have also been used for identifying variants of genes for vitiligo
Multiple vitiligo genes have been identified, some linked to the melanocyte, others to
immune system regulation, and some identifying association with other autoimmune
diseases
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A summary of
loci associated
with vitiligo
through GWAS,
GWAS-MA
studies up to
2015-10.
Front. Genet., 01
February 2016
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Vitiligo risk loci
involved in pathways
and shared with
other autoimmune
diseases
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Front. Genet., 01 February
2016
Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo
Susceptibility Genes and Loci
Front. Genet., 01 February 2016
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Vitiligo is an autoimmune disease
with a strong genetic component,
characterized by areas of
depigmented skin resulting from
loss of epidermal melanocytes.
Genetic factors are known to play
key roles in vitiligo through
discoveries in association studies
and family studies. Previously,
vitiligo susceptibility genes were
mainly revealed through linkage
analysis and candidate gene
studies. Recently, our
understanding of the genetic basis
of vitiligo has been rapidly
advancing through genome-wide
association study (GWAS). More
than 40 robust susceptible loci
have been identified and
confirmed to be associated with
vitiligo by using GWAS. Most of
these associated genes participate
in important pathways involved in
the pathogenesis of vitiligo. Many
susceptible loci with unknown
functions in the pathogenesis of
vitiligo have also been identified,
indicating that additional molecular
mechanisms may contribute to the
risk of developing vitiligo
The reported genes and loci on
the chromosomes associated
with vitiligo through GWAS and
GWAS meta-analysis up to
2015-10. All of the marked
regions and genes on the
chromosomes achieved genomewide significance (p < 5E-8) in at
least one study. .
ETIOPATHOGENESIS
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The etiopathogenesis of vitiligo has not been fully elucidated and several theories have been proposed. Among those, the autoimmune
hypothesis is currently the most accepted by experts. Besides this theory, others have been intensively studied, such as epidermal
adhesion defect, biochemical and neural hypotheses. This article will discuss the adhesion defect, autoimmune and biochemical theories.
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I. AUTOIMMUNE THEORY
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The initial perception that autoimmunity was involved in patients with non-segmental vitiligo was based on the frequent co-occurrence of
autoimmune diseases in these patients and their relatives, such as lupus erythematosus, psoriasis, alopecia areata, halo nevi and mainly
autoimmune thyroid diseases, besides the favorable response to immunosuppressive therapies such as photochemotherapy with UVA
(PUVA) and topical and oral corticosteroids .In this regard, it has been determined that therapy with systemic corticosteroids decreased
antibody mediated cytotoxicity against melanocytes in patients with vitiligo.
Vitiligo is accompanied by abnormal humoral and cellular immunity and high levels of serum circulating autoantibodies have been
detected in 5 to 10% of patients, predominantly of the IgG class and particularly anti-tyrosinase one and two (TRP-1 and TRP-2), however
the role of anti-melanocyte antibodies in vitiligo pathogenesis remains uncertain and it has been suggested that their presence may be
secondary to keratinocyte and melanocyte damages.
Melanocytes are capable of presenting antigens in the presence of MHC class II, which would allow HLA-DR+ cells present in the
perilesional vitiligo area to present antigens in response to trauma or local inflammation, in the latter case leading to autoimmune
destruction of melanocytes. Several studies have demonstrated the presence of CD4+ and CD8+ lymphocytic infiltrates in the dermoepidermal junction in perilesional vitiligo skin.
Interestingly, melanocyte-specific cytotoxic T lymphocytes were associated with disease activity. More recently, an in vitro study showed
that cytotoxic T lymphocytes infiltrated in common vitiligo perilesional area destroyed neighboring melanocytes.
Melanocytes and melanoma cells share differentiation antigens, and based on the number of cases observed in humans and mice, the
spontaneous development of vitiligo in patients with melanoma has been considered as a sign of good prognosis for this tumor. In this
regard, various studies about vitiligo's immunology are derived from the study of melanoma and melanoma vaccines; for example,
immunotherapy against antigens such as gp100 and tyrosinase may lead to cytotoxic T lymphocytes infiltration both in the specific
melanoma area as in vitiligo lesions.
The mechanism of self-tolerance loss, which magnifies the autoreactive cytotoxic lymphocytes actions in the destruction of melanocytes,
is still unknown; a recent study showed evidence of functional defects in peripheral regulatory T cells (TREGs) in half of the patients
tested with unstable vitiligo.
It has also been found in segmental vitiligo, whose pathogenesis was primarily linked to sympathetic nerves dysfunction, evidence that
immune-mediated cellular responses including CD8+ T lymphocytes is involved in the early stages of this type of disease, moreover, in
the same study flow cytometry detected a high expression level of IFN-γ in injured skin.
A profile of Th-1 cytokines, Interferon-g, TNF-a and recently IL-8, has been well described in vitiligo skin areas both segmental and nonsegmental. Besides Th-1 response, many evidences of Th-17 influence have been reported in vitiligo, with IL17+ lymphocytes infiltration
in dermal areas on the border of vitiligo lesions being demonstrated by immunohistochemistry and immunofluorescence; in addition, an
increased expression of IL-17A and IL-1 b was also found on the edges of lesions. An increase of IL-17 in the serum of patients affected
by vitiligo was recently described
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What is Non-Segmental Vitiligo?
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Non-Segmental Vitiligo (NSV) is a condition
that causes depigmentation of parts of the
skin. It's generalized and symmetrical. It
occurs when melanocytes, the cells
responsible for skin pigmentation, detach
from the basal membrane and exfoliate in the
upper epidermis (melanocytorrhagy).
Basically, NSV is a genetic predisposition to
dysfunctional melanocyte adhesion, and it
can be triggered by an internal or external
"severe" event. Shifting the contemporary
research paradigm, new studies point to the
fact that NSV is not caused by a
dysfunctional immune system.
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Melanocytes have 2 adhesion mechanisms:
Integrin alpha5-beta1 (main one) and
CCN3→DDR1→Colagen-IV (contingency).
The latter seems to work partially or is faulty
in a genetically NSV predisposed person.
The former mechanism is easily affected by
physical traumas, oxidative stress, and
stress hormones in any person, specially in
NSV sufferers. This will be explained in detail
in the "How Does NSV Present in Patients"
section ahead.
This occurs because melanocytes will be
potentially detached based on the mimetism
theory called "Koebner response" or
"isomorphic response". So, the main
adhesion mechanism (integrin) will be
constantly threatened due to (1) friction and
trauma in certain regions like knees, elbows,
A genetically NSV predisposed person may live a whole hands, feet, wrists, around the eyes,
forehead and around the mouth (see picture
life without triggering the disease. However, once the below) where white patches appear, it can be
it is usually facilitated by (2) oxidative
Vitiligo is triggered it becomes hard to cure, but not said
stress, and accelerated by (3) stress
hormones.
impossible.
Could (endoplasmic reticulum) ER Stress Be A Major Link Between Oxidative
Stress And Autoimmunity In Vitiligo
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Vitiligo has been found to be associated with a number of other autoimmune
diseases . Vitiligo is a multifactorial polygenic disorder with a complex
pathogenesis . In vitiligo patients, skin melanocytes are partially or completely
lost, and several theories have been put forward to explain the etiology of the
disease such as oxidative stress, autoimmune, neural and genetic
hypotheses . Melanocyte death may occur due to intrinsic and/or extrinsic
factors . Histological investigations have demonstrated presence of
inflammatory infiltrate of mononuclear cells in the upper dermis and at the
dermal-epidermal junction of peri-lesional skin of Non-Segmental Vitiligo
(NSV) patients . The initiation mechanism of this microinflammatory reaction
is still not clear, nevertheless local triggers are reported to signal the innate
immune system of skin that trigger adaptive immune responses targeting
melanocytes . There is wide range of evidence that show vitiligo to be a
systemic rather than a local disorder. Impairment of humoral and cellmediated immunity has been recognized in vitiligo patients . Moreover,
increased local and systemic cytokine expression has also been observed in
vitiligo patients . Many studies have addressed the key role of oxidative
stress in melanocyte death and anti-melanocyte immune responses;
however, the relationship between them remains unclear. Recently, we have
reported a positive correlation between increased Lipid Peroxidation (LPO)
levels and presence of circulating anti-melanocyte antibodies in vitiligo
patients . Reactive Oxygen Species (ROS) are produced as byproducts of
melanogenesis controlled by various antioxidant enzymes . Oxidative stress
is considered to be the initial triggering event in the pathogenesis of
melanocyte destruction . Vitiligo is accompanied by oxidative stress
characterized by overproduction and accumulation of H2O2 and melanocyte
destruction . For the interconnection between, oxidative stress and
autoimmunity it has been suggested that oxidative stress may have a role in
vitiligo onset, while autoimmunity contributes towards the disease
progression . Furthermore, Toosi et al. demonstrated accumulation of
misfolded proteins and activation of Unfolded Protein Response (UPR) in the
endoplasmic reticulum due to redox disruptions caused by oxidative stress.
Protein misfolding in the ER has been reported to contribute to the
pathogenesis of many human diseases (Table 1). Though unfolded proteins
have the potential to bring about ER homeostasis restoration and cell survival
by the activation of Inositol-Requiring Enzyme-1 (IRE1), Protein Kinase RNA
(PKR)-like ER kinase (PERK) and Activating Transcription Factor-6 (ATF6)
pathways, persistent stress conditions can on the other hand trigger
apoptosis . Furthermore, inhibited UPR can contribute to the activation of
autoimmune response by way of generation of self-altered antigens during
degradation of misfolded proteins, besides release of neo-antigens by
apoptotic cells, and altered immune-tolerance mechanisms in cells with an
anomalous UPR [
II. ADHESION DEFECT THEORY
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It has been suggested that adhesion defects are involved in the disappearance of melanocytes in vitiligo
lesions. The main clinical sign reinforcing this theory is the occurrence of koebnerization or Köebner phenomenon
(appearance of vitiligo after an acute or chronic trauma), which may be present in up to 31% of Caucasian patients
with common vitiligo.
In one of the earliest studies that attempted to identify adhesion defects in the genesis of vitiligo, an
immunohistochemical analysis was performed and demonstrated that tenascin protein, which can interfere with
melanocyte adhesion, was over-expressed in damaged skin compared to the healthy skin of the same patients.
Experimental study with patients of the generalized subgroup (which included common, acrofacial and universal
types) demonstrated that these patients presented melanocyte detachment after mechanical rubbing of the
unaffected skin. This observation led to the proposal of a new theory that non-segmental vitiligo is a
melanocytorrhagic primary disorder, i.e., there would probably occur an acute loss of melanocytes (because most
patients have a sudden onset of lesions), with an altered response of melanocytes to friction and possibly other
types of stress, which would induce cell detachment and subsequent transepidermal loss. In this context, the
authors of this theory speculated that an autoimmune phenomenon might be triggered by antigen release and
recognition of affected melanocytes by dendritic cells or memory T cells during trans-epidermal migration, thereby
exacerbating the detachment and loss of more melanocytes.
Alterations in the main protein that adheres melanocytes to the epidermis basal layer, DDR1 (Discoidin Domain
Receptor-1) have been implicated as one of the aggravating factors in the loss of melanocytes. Initially, genetic
association studies have found evidence of a connection between non-segmental vitiligo and DDR1 gene alleles,
which was more evident in vitiligo patients with the onset of disease before 25 years of age.
Functional studies attempting to explain the involvement of DDR1 and CCN3 protein (which controls the adhesion
of DDR1 to epidermis basal layer observed that perilesional melanocytes did not express CCN3, moreover, the
silencing of CCN3 in melanocytes induced a significant inhibition of their adhesion to collagen IV. In this same
study, it was demonstrated that the expression of DDR1 in lesional skin was decreased compared to perilesional
skin in most patients, and collagen IV expression was diminished in all affected individuals. In this same research
line, a recent study confirmed the decreased expression of DDR1 in all lesional epidermis, whereas epidermal
expression of DDR1 was secondary only to expression in keratinocytes and not in epidermis basal layer, where
melanocytes are located. This study hypothesized that the vitiligo is a condition in which all the epidermis is
affected and not only melanocytes.
III. VITILIGO'S BIOCHEMICAL THEORY
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The hypothesis that vitiligo could be caused by a metabolic pathway dysfunction, not necessarily related to
melanocytes, which would lead to the production of toxic metabolites such as catecholamines, oquinones and
reactive oxygen species, has been widely investigated.
The involvement of oxidative stress damage to melanocytes is supported by evidence suggesting an imbalance
between the oxidant/antioxidant systems in the epidermis of patients with vitiligo. It has been demonstrated that
melanocytes on the lesion borders of vitiligo patients showed increased sensitivity to oxidative stress when in
culture. Schallreuter et al. observed in vivo that patients with vitiligo can accumulate a concentration of H2O2 over
10-3 M in their epidermis. Different possible sources of endogenous production of H2O2 in the epidermis of vitiligo
patients have been described, including an increase in monoamine oxidase A (MAO-A), increased activity of
NADPH-oxidase and imbalance in (6R)-L-erythro 5,6,7,8-tetrahydrobiopterin (6-BH4)
synthesis/recycling/regulation. One of the likely consequences of increased 6-BH4 production observed in the
epidermis of affected patients is the inhibition of phenylalanine hydroxylase enzyme, responsible for producing Ltyrosine from L-phenylalanine, leading to low levels of tyrosine and therefore, a defect in melanin synthesis.
Patients with vitiligo have a low level/activity of enzymatic and non-enzymatic antioxidants such as catalase,
glutathione peroxidase and vitamin E, possibly increasing H2O2 toxicity. The results obtained for the levels of
superoxide dismutase antioxidant were conflicting amongst studies. Further evidence on the involvement of
oxidative stress in the disease pathogenesis is the suspension of the depigmentation process and skin color
recovering with the removal of epidermal H2O2 by Narrow-Band-UVB 311nm activated pseudocatalase.
Studies have reported the involvement of the adrenergic and cholinergic systems in vitiligo pathogenesis.
Acetylcholinesterase (AChE) is an important enzyme in promoting and maintaining oxidative stress, being
inactivated by oxidation of Trp,432 Trp,435Met436 residues by H2O2. Interestingly, AChE activity is low in vitiligo
skin lesions during depigmentation, but it returns to normal when the damaged skin starts repigmentation.Picardo
et al. showed that abnormal catecholamine release by autonomic nerve terminations could result in excessive
production of toxic radicals in the melanocyte microenvironment. Furthermore, high levels of catecholamine
metabolites in the urine of patients with vitiligo during the active phase of disease have been reported, when
compared with age-matched controls.
Keratinocytes (K)-melanocytes (M) intercellular pathways affected by
inflammatory hyper-response and ROS-related altered gene expression
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Different pathways for melanocyte loss:
(i) Generation of ROS by various
metabolic processes. (ii) Imbalance in
ROS generation and antioxidant
system leads to accumulation of free
radicals resulting in oxidative stress.
This accumulation causes DNA
damage, synthesis of defective proteins
and membrane disintegration which
provokes immune system resulting in
autoimmunity. (iii) Increased
catecholamines inhibits mitochondrial
calcium uptake which results in
generation of free radicals. (iv)
Exposure to UV radiation leads to
spontaneous production of quinones in
melanocytes which in turn results into
ROS generation
Keratinocytes (K)-melanocytes (M)
intercellular pathways affected by
inflammatory hyper-response and
ROS-related altered gene expression.
The numerical reduction of
melanocytes and the resulting loss of
function is the primary cause of skin
depigmentation observed in vitiliginous
lesions.
Vitiligo: interplay between oxidative stress and immune system
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. Interplay of genes,
environment and immune
system in precipitation of
vitiligo: interaction of genes
with environment and
immune system leads to
vitiligo. Susceptible genes
under the effect of
environmental trigger like:
generation of ROS by
various environmental
sources (UV and ionizing
radiations, air and water
pollution, heavy metals etc.)
and repeated mechanical
traumas can result into
aberrant immunological
responses (i.e. cellular and
humoral immune response)
resulting into autoimmunity
Could (endoplasmic reticulum) ER Stress Be A Major Link Between Oxidative
Stress And Autoimmunity In Vitiligo?
Pigmentary Disorders 1:123 ,2O14
Oxidative stress
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Oxidative stress is an imbalance between the production of oxygen and the
body’s ability to detoxify and repair the damage caused at the cellular
level. Oxidative stress can damage every cell component, including proteins,
lipids and DNA.
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Neuronal
hypothesis for
segmental vitiligo
(upper left),
somatic mosaicism
hypothesis for
segmental vitiligo
(upper right),
microvascular skinhoming hypothesis
for segmental
vitiligo (lower left),
and three-step
theory of several
pathophysiological
mechanisms
leading to clinical
outcome of
segmental vitiligo
(lower right). NPY,
neuropeptide Y;
VIP, vasoactive
intestinal peptide.
Neuronal Mechanisms
The British Journal of Dermatology. 2012;166(2):240
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For many years it has been stated that segmental vitiligo has a dermatomal distribution.
Therefore, neuronal mechanisms have been suggested to play a role in the pathogenesis of this
unilateral type of vitiligo ( upper left). Clinical observations have been reported in which the skin
became white in areas corresponding to local neurological damage (e.g. subacute encephalitis,
spinal cord tumour or following trauma). Physiological abnormalities associated with sympathetic
nerve function (acetylcholine activity, neuropeptide distribution and catecholamine metabolism)
were described in lesional segmental vitiligo skin. It was demonstrated an increased cutaneous
blood flow compared with the contralateral normal skin and a significantly increased α- and βadrenoceptor response in segmental vitiligo lesions. However, the detection of disturbed
neuropeptides is not specific for segmental vitiligo. The nerve fibre density and secretion of
neuropeptides [e.g. nerve growth factor (NGF), calcitonin gene-related peptide] were also found to
be elevated in psoriatic lesions. In alopecia areata, substance P fibres are increased in early
lesions and a role for NGF in the induction of the catagen phas. The central nervous system
(CNS) and immune system interrelate with each other to establish a homeostatic balance. The
CNS dampens excessive inflammatory responses by producing anti-inflammatory catecholamines
and the inflammation is locally regulated by secretion of neuropeptides. As such, the current
evidence supporting the neural hypothesis might also be explained as a bystander effect of
inflammation instead of a triggering factor..
Neuronal hypothesis for segmental vitiligo (upper left), somatic mosaicism hypothesis for
segmental vitiligo (upper right), microvascular skin-homing hypothesis for segmental vitiligo (lower
left), and three-step theory of several pathophysiological mechanisms leading to clinical outcome
of segmental vitiligo (lower right). NPY, neuropeptide Y; VIP, vasoactive intestinal peptide.
Moreover, with respect to the distribution pattern of segmental vitiligo, it is striking that the
distribution of segmental vitiligo lesions is in most cases not dermatomal.
Somatic Mosaicism
The British Journal of Dermatology. 2012;166(2):240
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When lesions are present along the lines of Blaschko, it has been suggested that they reflect an underlying
mosaicism of different cell lines ( upper right). A mosaic distribution pattern is observed in several pigmentation
disorders such as Blaschkoid hypopigmentations, McCune–Albright syndrome, epidermal naevi, naevus
depigmentosus and several autosomal dominant skin conditions (e.g. incontinentia pigmenti).[20] The lines of
Blaschko represent the migration pattern of skin cells during embryogenesis. They are considered to follow the
dorsoventral development of cellular components of the skin. Although this is mainly described (and sometimes
genetically proven) in monogenetic skin diseases, a linear or segmental arrangement along the lines of Blaschko
has also been noted in polygenetic diseases such as psoriasis. Happle[21] suggested to use the term 'isolated
segmental manifestation' and 'superimposed segmental manifestation' in polygenic disorders with lesions along
the lines of Blaschko. The isolated type occurs in an otherwise 'healthy person' in whom the predisposing factors
are selectively present in the affected segment. The superimposed type occurs in a heterozygote individual often
at an earlier age of onset, where segmental lesions precede the milder nonsegmental lesions, and family members
can be affected by the nonsegmental form. Such cases may be best explained by an early postzygotic event in the
form of loss of heterozygosity involving one of the genes predisposing to the disorder. It has been hypothesized
that the mixed type of vitiligo (combination of segmental and nonsegmental vitiligo) could also represent a
superimposed form of a segmental mosaicism.
The concept of isolated and superimposed segmental vitiligo is, however, still a theory and convincing data at the
molecular level are still missing. Nevertheless, several clinical observations support the theory of mosaicism in
segmental vitiligo, such as the observation that a family history for generalized vitiligo has been reported in up to
16% of patients with segmental vitiligo, and typically not within their offspring. Furthermore, the superior long-term
take of epidermal cellular grafting in segmental vitiligo lesions compared with the moderate to limited results in
patients with generalized and mixed vitiligo, respectively, might be explained by the theory of mosaicism.[22] It
indicates that the transplanted cells of autologous donor skin are genetically affected as well in the generalized
and mixed type of vitiligo, and not in the isolated type of segmental vitiligo.
In contrast, based on evaluations of the distribution patterns of segmental vitiligo lesions, a minor part of the
lesions fits more or less within the described Blaschko lines.
Microvascular Skin Homing
The British Journal of Dermatology. 2012;166(2):240
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It has also been suggested that the midline delineation in unilateral lesions could
represent the migration pattern of cytotoxic T cells from specific regional lymph nodes
along the efferent microvascular system via homing receptors ( lower left). It has
been reported that these homing receptors could have a unique unilateral homing
code. With respect to this, the typical observation of halo naevi in patients with
segmental vitiligo may indicate a causal relation. In our experience patients most
often mention that the appearance of halo naevi occurs prior to the development of
the segmental vitiligo lesions. This points towards the possible theory of clonal
expansion of melanocyte-specific T lymphocytes in the regional lymph node. We
described the early clinical, histopathological and immunophenotypic sequences of
segmental vitiligo appearing in a patient with additional halo naevi. This was the first
report providing evidence that a melanocyte-specific CD8+ T-lymphocyte-mediated
immune response was involved in the early phases of segmental vitiligo.
However, the theory of skin-homing receptors explaining entirely the specific disease
pattern of segmental vitiligo seems unlikely as no inflammatory skin disease has been
described showing a similar pattern. Melanoma-associated depigmentation after
vaccination follows a more generalized vitiligo-like pattern although the vaccine is
often delivered by subcutaneous or intradermal injection. In theory, the tumourspecific T cells drain to the regional lymph nodes which could, according to the theory
of unilateral skin homing, also lead to a more segmental vitiligo pattern.
Genome
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Scientists compared the genomes (entire set of genes) of groups of people with and without vitiligo. They found more than 10 genes associated with vitiligo. As we might
have guessed, some of these genes are involved in the immune system. And some with melanocytes.
It is important to mention that people with vitiligo don't have genes that other people don't have. There is no vitiligo gene. These folks just have different versions of these
10 genes that we all share.
Different versions mean different instructions. Which means a slightly different protein may get made.
These slightly different proteins may look or act differently than the ones made by people without vitiligo. And something about these differences causes the destruction of
melanocytes.
Let's discuss two of the identified genes and see how they might cause vitiligo. These two give a nice overview of how the immune system can get confused.
MHC. The MHC (major histocompatibility) genes play an important role in the immune system. They label cells so the immune system can either pass by or attack.
For example, when bacteria infect a cell, MHC can display bits of bacterial proteins on the outside of the cell. Sort of like a red flag. When the immune system sees this, it
attacks any cell that has the red flag. This includes the bacteria.
People with vitiligo have a different version of one of these MHC genes. The idea is that this MHC sees something about a melanocyte as a red flag. This makes the
immune system think that the melanocyte is an invader.
So the immune system attacks and destroys the melanocytes. The end result is vitiligo.
TYR. The TYR gene makes a protein called TYR. This protein helps make the pigment melanin in melanocytes.
People with vitiligo have a different version of the TYR gene. What scientists think is happening is that the immune system attacks the melanocytes because this TYR
protein looks suspiciously like a red flag. A case of mistaken identity that leads to the destruction of melanocytes which leads to vitiligo.
So things can go wrong on either end. Sometimes a gene in an immune cell makes it attack the melanocyte. And sometimes a gene in the melanocyte makes the immune
system attack it.
Many of the other genes that scientists found act similarly. Some work in the immune system and others in melanocytes.
They also found other genes that weren't so easy to explain. Once they figure those out, scientists will learn a lot about vitiligo. And a lot about melanocytes and the
immune system.
These diseases happen when your immune system mistakenly attacks some part of your own body. In vitiligo, the
immune system may destroy the melanocytes in the skin. It is also possible that one or more genes may make a
person more likely to get the disorder.
Some researchers think that the melanocytes destroy themselves. Others think that a single event such as
sunburn or emotional distress can cause vitiligo. But these events have not been proven to cause vitiligo
People with certain autoimmune diseases (such as hyperthyroidism) are more likely to get vitiligo than people who don’t have any autoimmune diseases. Scientists do not
know why vitiligo is connected with these diseases. However, most people with vitiligo have no other autoimmune disease.
Scientists have gained a better understanding of vitiligo in recent years, especially through gene research. Current research includes studies to investigate:
-How trauma or stress to the skin can trigger vitiligo or the development of new white patches.
-New treatments and better understanding of vitiligo using a mouse model.
-Genes that may cause or contribute to having vitiligo.
-Analysis of genes already known to be linked to vitiligo.
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What Causes
Low Stomach
Acid?
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@Aging
@Low thyroid or
thyroid dysfunction
@Adrenal
fatigue/insufficiency
@H. Pylori infection
@Medications
@Poor diet
@Stress
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Vitiligo Classification
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Much has been discovered in recent years about the pathophysiology of the disease,
pointing clinical findings to three main factors: 1) adhesion deficit throughout the
epidermis, not only affecting the adhesion of melanocytes, but also
keratinocytes; 2) increased local oxidative stress; 3) T lymphocyte-mediated
cytotoxicity against melanocytes
Vitiligo Classification
Types
Subtypes
Non-segmental vitiligo
Acrofacial
Mucosal (more than one site affected)
Generalized or Common Universal
Mixed (associated with segmental vitiligo)
Rare forms
Segmental
Unisegmental, bisegmental or multisegmental
Unclassified or indeterminate Focal
Mucosal (only one site affected)
Adapted from: Revised classification / nomenclature of vitiligo and related issues: the
Vitiligo Global Issues Consensus Conference - 2012.
Vitiligo developing within congenital melanocytic nevus
Journal of Dr. NTR University of Health Sciences 2016 : 5 : 1 : 67
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Giant melanocytic nevus with hypertrichosis and depigmented patches within the nevus on the left thigh
(posterior aspect)
Congenital
melanocytic
showing loss of melanocytes
nevus
Vitiligo developing within congenital melanocytic nevus
Journal of Dr. NTR University of Health Sciences 2016 : 5 : 1 : 67
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Nevus with vitiligo focus, nevoid cells within the dermal tissue
Epidermis showing transition of loss of melanocytes,
dermis showing nevus cells
HISTOPATHOLOGY of vitiligo
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Melanocytes are derived from neural crest cells. Neurons, glial cells, cardiac cells, craniofacial
tissue and adrenal medulla are also originated from such pluripotent cells. Melanocyte precursors,
known as melanoblasts, migrate, proliferate and differentiate en route to their destination in the
basal epidermis and hair follicles.
Epidermal melanocytes and keratinocytes form structural and functional units, known as
epidermal melanin units, in which every melanocyte carries its melanosomes through dendrites to
approximately 36 associated keratinocytes. Skin pigmentation results of this close interaction
between melanocytes that produce melanosomes and keratinocytes that receive
them. Melanocytes are located in the basal layer of the epidermis at a ratio of one to every 5 basal
keratinocytes.
The maintenance of this balance occurs through controlled induction of melanocyte division. To
proliferate, the melanocyte will detach from the basement membrane and from keratinocytes, then
retract its dendrites, divide, migrate through the basement membrane and re-attach itself to the
matrix and keratinocytes to form a new epidermal melanin unit.
Keratinocytes act on melanocytes by producing several factors that regulate their survival. They
create the necessary microenvironment for the proliferation, differentiation and melanocyte
migration.
The fundamental histopathological difference between skin with normal coloration and skin with
vitiligo is the absence of functioning melanocytes on the latter. Although there may be viable
melanocytes in the altered skin, they are usually absent, which can be verified by FontanaMasson staining, specific for melanin or by dihydroxyphenyl alanine technique for the
demonstration of tyrosinase. Techniques that use autoantibodies to identify melanocytic lineage
and electron microscopy, also demonstrate that the achromic patches of vitiligo are devoid of
melanocytes. Other stains that may be useful are: DOPA, which detects active melanocytes and
HMB-45, Mel-5, NKI/beteb that detect active and inactive melanocytes.
Inflammatory changes were found more frequently in early lesions. When present, the identified
inflammatory cells were mostly CD4+ and CD8+ lymphocytes.
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vitiligo, 10x, stained for
melanin. Note that melanin
(tiny, dark spots) is absent
on the basal layer of the
epidermis although it is
preserved around the hair
follicle.
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Microscopically lesions
have no melanocytes and
there is a loss of melanin
pigment in the epidermis.
These findings are often
subtle, so that microscopic
appearance of vitiligo falls
under the differential of
‘histologically normalappearing skin’. The
absence of melanocytes
can be confirmed by
immunohistochemistry and
lack of melanin by special
stains. Notice in the
accompanying
photomicrograph, melanin
(tiny, dark spots) is absent
on the basal layer of the
epidermis although it is
preserved around the hair
follicle.
HISTOPATHOLOGY of vitiligo
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Vitiligo. Note the absence of basal melanocytes
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Vitiligo. S-100 protein stains show the
absence of basal melanocytes.
Melanin granules in the skin of a vitiligo patient. Zone of depigmented
skin Fontana-Masson staining, ×200.
Melanin granules in the skin of a vitiligo patient. Marginal zone.
Fontana-Masson staining, ×200.
Inflammatory vitiligo with raised borders and psoriasiform histopathology
Dermatology Online Journal 11 (3): 13
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Psoriasiform changes in raised border of a vitiligo lesion
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@Histological features of vitiligo that on
the edge of the skin lesions by
(reflectance confocal microscopy) RCM
can be seen highly refractile
inflammatory cells showed (H and E,
×400): Hypopigmentation, lymphocytes
infiltration
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@ Histological features of vitiligo that
on the edge of the skin lesions by RCM
can be seen highly refractile
inflammatory cells showed (H and E,
×400): Hypopigmentation, no
lymphocytic infiltration
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Reflectance
confocal microscopy
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Vitiligo is a depigmentation disorder affecting between 1%
to 2% of the general population. The disease is caused by
the absence of melanin in the skin and hair follicles. Vitiligo
is easy to be diagnosed, but difficult to be treated. It can be
divided into two stages clinically: An active stage and a
stable stage. As different stages require different
treatments: The stable stage is eligible to surgical
treatments and phototherapies, while the active stage is
likely to respond to steroids, phototherapy/chemotherapy,
and immunosuppressants as these drugs are used to arrest
the disease progression; therefore, it is important to
discriminate these two stages. At present, parameter of
vitiligo stage judgment includes VIDA score, Kobner
Phenomenon, and Wood's lamp examination. But these
parameter have their own limitations and rely mostly on
subjective judgments. Therefore, it is necessary to
introduce more objective methodologies in order to improve
the accuracy of staging. In vivo RCM is a real-time
repetitive imaging tool that provides non-invasive images at
a nearly histological resolution.
A commercially available in vivo RCM device, was used for
imaging. The instrument operated with a diode laser at an
830 nm wavelength and a laser power < 35 mW at tissue
level. This system provided high-resolution images
(approximately 1-2 μm in the lateral dimension and 4-5 μm
in the axial ones) to a depth of 200 to 350 μm in vivo (from
the epidermis down to the superficial reticular dermis)
Description of characteristics under RCM
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Reflectance confocal microscopy imaging of lesional skin in vitiligo: The rings lost their integrity and
existence of remaining pigment at the dermo-epidermal junction level (b) RCM imaging of lesional skin in
vitiligo: Complete loss of pigment at the dermo-epidermal junction level
Description of characteristics under RCM
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(a) RCM imaging of lesional skin in vitiligo: Clear border (b) RCM imaging of lesional skin in vitiligo:
Unclear border
Description of characteristics under RCM
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Highly refractile
inflammatory cells
could be seen at the
edge of the lesions
Description of characteristics under RCM
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RCM imaging of lesional
skin in vitiligo: Dendritic
and highly refractile
melanocytes can be seen
in the lesional area
Differential diagnosis
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Conditions with similar symptoms include the following:
Pityriasis alba
Tuberculoid leprosy
Postinflammatory hypopigmentation
Tinea versicolor
Albinism
Piebaldism
Idiopathic guttate hypomelanosis
Progressive macular hypomelanosis
Primary adrenal insufficiency
Differential diagnoses of vitiligo
Differential
diagnosis of
childhood vitiligo
IJDVL2012 : 78 : 1 : 30
VITILIGO TREATMENT
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The goal of vitiligo treatment is to control the autoimmune damage to melanocytes and stimulate their migration from surrounding skin and
adnexal reservoirs. Treatment may be divided into pharmacological, surgical and physical, which can sometimes be combined.
Pharmacological Treatment
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Topical
Systemic
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Physical Treatment
Surgical Treatment
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1.Pharmacological Treatment
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Corticosteroids
Topical corticosteroid therapy is considered a first-line treatment of vitiligo, since it is low-cost and easy to apply. It is limited by the risk of
local adverse effects, such as atrophy, striae and telangiectasias and also systemic side effects. Thus, the use of high-potency topical
corticosteroids is more suitable to treat small affected areas, being more effective on the face, elbows and knees.
Although studies recommend the use of highpower topical corticosteroids in localized vitiligo, its use should be limited to 2-4 months
periods, as low power corticosteroids or the use of other immunomodulators should be considered in order to decrease the risk of adverse
events. If no clinical response is seen with topical corticosteroids in 3 to 4 months, their application should be suspended.
Calcineurin Inhibitors
Initially used in transplant patients, calcineurin inhibitors are immunosuppressants, the first of which, cyclosporine, is not used topically
due to the lack of good cutaneous absorption. Subsequently, tacrolimus and pimecrolimus, other calcineurin inhibitors, demonstrated
good absorption when used topically.
Corticosteroids inhibit collagen synthesis, leading to an increased risk of skin atrophy, especially during prolonged use. An advantage of
calcineurin inhibitors is that neocollagenesis does not depend from calcineurin; hence there is no risk of atrophy.
Topical tacrolimus is a calcineurin inhibitor that controls the activity of T lymphocytes through the inhibition of proinflammatory cytokines,
blocking the transcription of the IL-2 genes which are important for the proliferation of cytotoxic T lymphocytes, and also inhibiting the
transcription and production of IL-4, IL5, IL-10, IFN-γ and TNF-α. .
Calcineurin inhibitors have demonstrated efficacy similar to topical corticosteroids, without the risk of cutaneous atrophy in the long-term
use.
Calcipotriol and betamethasone dipropionate
The use of calcipotriol combined with topical corticosteroids has been reported in the literature. The use of vitamin D analogues has been
associated with narrow-band UVB and Excimer LASER
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Topical treatment
Systemic Treatment
• Systemic corticosteroid therapy
• Systemic corticosteroid therapy is used in cases
of disseminated vitiligo lesions with rapid
progression. Decreased complement-mediated
cytotoxicity and levels of antibodies against
melanocyte surface have been described in
patients with unstable vitiligo responsive to
systemic corticosteroids.
• The use of systemic corticosteroids in
minipulses has been used in order to minimize
adverse events inherent to the treatment.
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2- Physical Treatment
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2- Physical Treatment
Ultraviolet (UV) radiation, both in UVA and UVB spectrum, has been used in the treatment of vitiligo. Its effect is
not yet fully understood. It can induce immunosuppression by inhibiting melanocyte destruction or stimulating the
increase in their numbers and migratory capacity.
Narrow band UVB - NBUVB
An effective and safe therapeutic modality, treatment with narrowband UVB (311nm) is considered a first-line
option for vitiligo. It dispenses the combined use of an oral psoralen, thus freeing patients of ocular and
gastrointestinal adverse events related to this drug.
Phototherapy with UVA and psoralens (PUVA therapy)
Photochemotherapy is a therapeutic method that consists in the use of a drug that enhances the effects of light.
Psoralens are the most commonly used drugs in the treatment of vitiligo, in the forms 8methoxypsoralen, 5methoxypsoralen or trimethylpsoralen which may be used in their oral and topical presentations.
The most frequent short-term adverse events are cutaneous and ocular phototoxicities, nausea and headache
while long-term side effects, such as photoaging and increased risk of skin cancer, especially squamous cell
carcinoma are dose-related.
Topical PUVA therapy can be used in localized forms of vitiligo in adults and children over 2 years old. Due to the
lower doses of UVA used and small absorption of topical psoralen it is considered a safer option.
The better results achieved with NBUVB as well as its greater safety profile when compared to UVA phototherapy,
are causing the latter to be less used.
Monochromatic Excimer light
The combination of monochromatic excimer light with xenon chloride gas emits light with a wavelength of 308nm.
There are two forms of producing this light; the excimer LASER that produces a coherent and monochromatic light
and the excimer lamp that produces a non-directional and non-coherent light of 308nm. These treatment forms
differ from NBUVB in their mode of application, as they may be applied in a more localized fashion in the lesions.
3 - Surgical therapy
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Surgical melanocyte transplantation is an important therapeutic option available for patients with stable disease
who failed to respond to classical therapies. It is indicated even for traditionally refractory areas such as distal
extremities, elbows, knees, nipples, eyelids and lips. Furthermore, the appropriate choice of patients, with the
exclusion of those presenting Koebner phenomenon and active disease is essential to prevent achromic lesions in
the donor areas and achieve better results in the receiving areas
Punch Grafting (PG) is the easiest and lowest cost technique, although it is generally limited to treating small
areas. The recipient area is prepared by performing multiple punches of equal size or 0.25 to 0.5 mm smaller than
those extracted from the donor area.
Larger grafts often produce a cosmetically undesirable effect, known as cobblestoning (cobblestone appearance).
This side effect usually resolves spontaneously or with treatments like electrofulguration. Punch grafting is able to
produce excellent repigmentation and good cosmetic results.
Suction blister epidermal grafting (SBEG) is a technique for obtaining thin skin grafts through dermoepidermal
separation caused by prolonged suction applied in the donor area. The recipient area is prepared by dermabrasion
or laser application (Erbium:YAG or CO2). Although SBEG is a time consuming technique restricted to treating
small areas, it can provide good therapeutic results with minimal chances of producing unsightly scars in the donor
area.
Split-thickness skin grafts also have good repigmentation rates, and also the advantage of treating large areas
with a single procedure. The graft is obtained with the aid of a dermatome, although this procedure requires skill
and experience. Furthermore, the incompatibility of colors in the receiving area and scarring in the donor area are
potential side effects of this technique.
Autologous non-cultured epidermal cell suspension (NCECS) grafting, a cellular transplantation technique, has the
advantage of treating a receiving area about 10 times larger than the donor area, with excellent color
compatibility. In this procedure, a skin fragment is obtained by shaving biopsy and the epidermis is separated from
the dermis using a trypsin solution. After several additional steps, a suspension of keratinocytes and melanocytes
is obtained and transplanted to the scarified skin in the receiver area.
Cell culture has also been used as a means of increasing the number of viable cells and treat even larger areas
using less donor tissue. However, this method is costly and requires the support of a tissue culture
laboratory. Furthermore, the use of some mitogens present in the culture medium raised questions about the
safety of the procedure
Induction of vitiligo after imiquimod treatment of condylomata acuminata
Diseases BMC series 201414:329
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Loss of melanocytes and melanin granules. a. Normal stratum corneum, stratum granulosum, and stratum
spinosum, with loss of melanocytes and melanin granules in the basal layer. Dermis showing no abnormalities
(H&E ×100). b. loss of melanocytes and melanin granules in the basal layer
Induction of vitiligo after imiquimod
treatment of condylomata acuminata
• Vitiligo patches
involving the glans
penis, shaft of the
penis, and scrotum
after the use of
imiquimod 5%.
• a. Vitiligo on the
patient’s penis,some
remaining pigmented
areas within
the vitiligo. plaques .
• b. vitiligo on the
patient’s scrotum.
BMC Infectious
•
Diseases BMC series 201414:329
Induction of vitiligo after imiquimod treatment of condylomata acuminata
Diseases BMC series 201414:329
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Absence of melanin granules. a. Absence of melanin granules in epidermis. Normal dermis.
(Masson-Fontana stain for melanin ×100). b. Absence of melanin granules in epidermal basal cell
layer. (Masson-Fontana stain for melanin ×200).
Induction of vitiligo after imiquimod treatment of condylomata acuminata
Diseases BMC series 201414:329
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Normal skin (control):
normal of melanocytes and
melanin granules. a.
presence of melanocytes and
melanin granules in epidermis.
Normal dermis (MassonFontana stain for melanin
×100). b. presence of
melanocytes and melanin
granules in epidermal basal
cell layer. (MassonFontana stain for melanin
×200).
Various treatment modalities for
childhood vitiligo IJDVL2012 : 78 : 1 :
30
DOES YOUR VITILIGO MAKE
YOU DREAD THE SUN?
• or does spring bring new hope?
UV photograph of a hand with vitiligo
UV photograph of a foot with vitiligo
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Vitiligo is a
chronic skin condition
characterized by portions of
the skin losing their pigment.
It occurs when skin pigment
cells die or are unable to
function. Aside from cases
of contact with certain
chemicals, the cause of
vitiligo is unknown.
Research suggests vitiligo
may arise from autoimmune,
genetic, oxidative stress,
neural, or viral causes.
Vitiligo is typically classified
into two main categories:
segmental and nonsegmental vitiligo. Half of
those affected show the
disorder before age 20,
though most develop it
before age 40
The Role of Photolabile Dermal Nitric Oxide Derivates
in Ultraviolet Radiation (UVR)-Induced Cell Death
Int. J. Mol. Sci. 2013, 14(1), 191-204
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Human skin is exposed to solar
ultraviolet radiation comprising
UVB (280–315 nm) and UVA
(315–400 nm) on a daily basis.
Within the last two decades, the
molecular and cellular response
to UVA/UVB and the possible
effects on human health have
been investigated extensively. It
is generally accepted that the
mutagenic and carcinogenic
properties of UVB is due to the
direct interaction with DNA. On
the other hand, by interaction
with non-DNA chromophores as
endogenous photosensitizers,
UVA induces formation of
reactive oxygen species (ROS),
which play a pivotal role as
mediators of UVA-induced
injuries in human skin
UV Radiation and the Skin
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UV radiation (UV) is classified as a
“complete carcinogen” because it is both a
mutagen and a non-specific damaging
agent and has properties of both a tumor
initiator and a tumor promoter. In
environmental abundance, UV is the most
important modifiable risk factor for skin
cancer and many other environmentallyinfluenced skin disorders. However, UV
also benefits human health by mediating
natural synthesis of vitamin D and
endorphins in the skin, therefore UV has
complex and mixed effects on human
health. Nonetheless, excessive exposure
to UV carries profound health risks,
including atrophy, pigmentary changes,
wrinkling and malignancy. UV is
epidemiologically and molecularly linked to
the three most common types of skin
cancer, basal cell carcinoma, squamous
cell carcinoma and malignant melanoma,
Genetic factors also influence risk of UVmediated skin disease. Polymorphisms of
the melanocortin 1 receptor (MC1R) gene,
in particular, correlate with fairness of skin,
UV sensitivity, and enhanced cancer risk.