[Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Review Article Pathogenesis of vitiligo: An update ABSTRACT Vitiligo is the most common depigmentary disorder that has been affecting human lives across centuries. Despite its high prevalence, not much can be said precisely about its pathogenesis. Over the years, several theories based on a lot of research have been put forward and many more are coming up each day. This article aims to summarise the various theories put forward so far and highlight the Recent updates in each of them. Keywords: Pathogenesis, update, vitiligo INTRODUCTION Vitiligo is a commonly acquired depigmentary disorder of skin, also known as swetakusta in Indian literature. Clinically, it is characterized by development of depigmented macules and patches secondary to selective destruction of melanocytes.[1] Clinically, two major subtypes of vitiligo are well recognized: non-segmental and segmental. Non-segmental vitiligo (NSV) is the more common subtype, having asymmetrical, non-dermatomal distribution usually with a gradual onset.[2] Segmental vitiligo (SV) is less common and is characterized by a unilateral dermatomal distribution which usually has an early rapid onset and stabilizes in a limited location once fully developed.[2] The prevalence of vitiligo is high ranging from 0.005 to 0.38% cases worldwide.[3-5] Gujarat, located on the western coast of the Indian Peninsula, has been reported to have a prevalence of 8.8%, the highest in the world.[5,6] Despite its high prevalence and old history, its etiopathogenesis is complex and enigmatic. Most of the currently available evidence supports the occurrence of an autoimmune phenomenon in patients with an underlying genetic predisposition.[7] However, with further advancement and research in understanding the pathogenesis of this psychologically devastating disease, newer insights into its etiopathogenesis keep emerging. For this review, we searched PubMed, Google and Google Scholar with keywords including ‘vitiligo’, ‘pathogenesis’, ‘vitiligo pathogenesis latest’, ‘epidemiology’ and ‘etiopathogenesis’. All types of studies including reviews, in vivo / in vitro experimental studies, animal studies and observational studies published in standard peer-reviewed journals were included. This review aims to discuss the various known as well as newer emerging theories in the pathogenesis of vitiligo. To make the review more interesting, the data until 2011 has been placed under ‘What is known’ category, and the data from studies published in the last 5 years has been placed under the ‘Recent updates’ category. Because NSV is a more common form of vitiligo, most of the experimental studies and theories discussed in this review pertain to pathogenesis of NSV. However, wherever a difference in the pathogenesis of the two types as been suggested in literature, a mention has been made in the text. Genetics What is known? Familial clustering is seen in vitiligo. Various studies have found that the frequency of vitiligo among first-degree AMANJOT K. ARORA, MUTHU S. KUMARAN Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Address for correspondence: Dr. Muthu Sendhil Kumaran, MD, DNB, Associate Professor, Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh - 160 012, India. E-mail: [email protected] Access this article online Quick Response Code Website: www.pigmentinternational.com This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work noncommercially, as long as the author is credited and the new creations are licensed under the identical terms. For reprints contact: [email protected] DOI: 10.4103/2349-5847.219673 How to cite this article: Arora AK, Kumaran MS. Pathogenesis of vitiligo: An update. Pigment Int 2017;4:65-77. © 2017 Pigment International | Published by Wolters Kluwer - Medknow 65 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update 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, 66 ubiquitin-mediated proteolysis and tyrosine metabolism. Thus, they concluded that different genetic pathomechanisms were involved in the two distinct subtypes of vitiligo. In another study from China, the C allele of rs35652124 located on the promoter region of nuclear factor E2-related factor 2 (Nrf2) gene was found to have a protective effect against vitiligo.[21] Lately, the role of microRNAs (miRNAs) and toll-like receptors (TLRs) in the pathogenesis of vitiligo has been explored.[22,23] In a study by Šahmatova et al., miR-99b, miR-125b, miR-155 and miR199a-3p levels were found to be increased while that of miR145 was found to be decreased in the skin of patients with vitiligo. MiRNAs (miR-155) when over-expressed lead to the inhibition of melanogenesis-associated genes and altered interferon-regulated genes in the melanocytes and keratinocytes.[22] Traks et al. recently established the role of TLRs and vilitgo in their study, wherein they found that single nucleotide polymorpisms (SNPs) in TLR7 were associated with vitiligo making them a future target for targeted therapies.[23] Recently, Shen et al. also reviewed the various key loci that have been implicated in the pathogenesis of vitiligo, and interested readers can refer them.[24] Thereupon, the data available so far suggest that vitiligo has a polygenic inheritance with no single gene dictating its pathogenesis. AUTOIMMUNE HYPOTHESIS Autoimmunity has long been suspected to play a significant role in the pathogenesis of vitiligo. This has been substantiated by multiple studies published in the literature so far. Both cellular and humoral immunity have been found to be of etiological significance in the pathogenesis of vitiligo. Cellular Immunity What is known? As far as cellular immunity is concerned, the main culprits are the CD8+ cytotoxic T-cells. Perilesional skin biopsies have shown epidermotropic cutaneous lymphocyte antigen positive lymphocytes with an increased CD8+/CD4+ ratio, substantiating the role of cytotoxic T-cells in the pathogenesis of vitiligo.[25,26] These T-cells have been shown to bring about degenerative changes in melanocytes and vacuolization of basal cells in the normal-appearing perilesional skin in patients with actively spreading lesions.[27] An increased expression of CD25 and MHC II (specifically HLA-DR) and ability to secrete interferon gamma (IFN γ) has been noted in these T-cells which lead to increased expression of intercellular adhesion molecule-1 and, consequently, increased T-cell migration to the skin leading to a vicious cycle.[25,26] Pigment International | Volume 4 | Issue 2 | July-December 2017 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update 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 Pigment International | Volume 4 | Issue 2 | July-December 2017 67 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update 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 68 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, Pigment International | Volume 4 | Issue 2 | July-December 2017 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update making them antigenic. These neoantigens subsequently incite an immune response that sustains the disease process.[78] Researchers have reported a significant association between a specific polymorphism of forkhead box class O (FOXO) proteins and vitiligo.[79] Decreased levels of FOXO3a protein have been found in patients with active vitiligo which result in impaired antioxidant mechanism causing tissue injury and eventually vitiligo.[79] Autocytotoxicity What is known? Toxic metabolites, both intracellular, such as those formed during melanin synthesis, and extracellular, such as phenols or quinones, may accumulate and damage the melanocytes of genetically susceptible individuals bringing about autocytotoxic injury to the melanocytes. It has been shown that tyrosine upon entering the melaninogenic pathways produces certain electrically unstable by-products, which have the potential to damage other cellular substrates resulting in death of the melanocytes.[80] Recent updates In a recent study, Kim et al. investigated the role of high mobility group box 1 (HMGB1) in the pathogenesis of vitiligo.[81] HMGB1 is a non-histone deoxyribonucleic acid (DNA)-binding protein that is secreted from the keratinocytes following exposure to ROS or ultraviolet B (UVB) light. It participates in a number of physiological and pathological processes, including cytokine production, cell proliferation, angiogenesis, cellular differentiation and cell death. In this study, Kim et al. treated the melanocytes with recombinant HMGB1 (rHMGB1) and studied its effects on melanocyte survival.[81] They found that rHMGB1 increased the expression of cleaved caspase 3 and decreased melanin production as well as the expression of melanogenesisrelated molecules in treated melanocytes leading to apoptosis and disappearance of the melanocytes. In the same study, it was found that patients with active vitiligo showed significantly higher blood levels of HMGB1 (vs. healthy controls). In addition, greater expression of HMGB1 was observed in the vitiliginous skin (vs. uninvolved skin). Thus, HMGB1 could initiate autocytotoxic injury to the melanocytes secondary to increased oxidative stress or UV light exposure.[81] Melanocytorrhagy What is known? Theory of melanocytorrhagy proposes that NSV is a primary melanocytorrhagic disorder with altered melanocyte responses to friction which induces their detachment, apoptosis and subsequent transepidermal loss.[82] This theory adequately explains the Koebner’s phenomenon because it proposes that weakly anchored melanocytes upon facing minor friction and/or other stress undergo separation from the basement membrane, migrate upward across the epidermis and are eventually lost to the environment resulting in vitiligo at the sites of trauma.[83] Kumar et al. found that the melanocytes were poorly attached to Type IV collagen in patients with unstable vitiligo, whereas the attachment was fairly firm in patients with a stable disease.[84] More importantly, they demonstrated that in patients with unstable vitiligo, the dendrites of perilesional melanocytes were small, clubbed and retracted which were unable to adhere melanocytes to the basement membrane and the surrounding keratinocytes, thereby, rendering them more prone to transepidermal loss.[84] Tenascin, an extracellular matrix molecule that inhibits the adhesion of melanocytes to fibronectin, has been found to be elevated in vitiliginous skin contributing to the loss of melanocytes or ineffective repopulation.[85] This results in focal gaps and impaired formation of basement membrane resulting in weakening of the basal attachment of melanocytes and subsequent chronic melanocyte loss known as melanocytorrhagy.[85] It has been proposed that during their transepidermal migration, damaged melanocytes could induce an immune response, thereby, perpetuating vitiligo.[85] Recent updates In a recent study by Kumar et al., alterations in the nuclear receptor protein ‘liver X receptor alpha (LXR α)’ was found to play a crucial role in bringing about melanocytorrhagy in patients with NSV. They reported an increased expression of LXR-α, a promoter of apoptosis, in the perilesional skin of patients with NSV.[86] In the same study, treatment with LXR-α agonist, 22(R)-hydroxycholesterol, was found to significantly decrease melanocyte adhesion and proliferation.[86] Thus, they concluded that a higher expression of LXR-α in the melanocytes of the perilesional skin significantly decreased the adhesion and proliferation and increased the apoptosis of melanocytes. DEFICIENCY OF SURVIVAL SIGNALS As per this theory, a deficiency of survival signals in the vitiliginous skin leads to apoptosis of melanocytes. In the normal epidermis, stem cell factors released from the neighbouring keratinocytes regulate melanocyte growth Pigment International | Volume 4 | Issue 2 | July-December 2017 69 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update and survival by binding to membrane tyrosine kinase receptor c-kit.[87] As such, it is possible that a significantly decreased number of c-kit receptors observed in the perilesional melanocytes[87] and lower expression of stem cell factor from the surrounding keratinocytes[88] may contribute to the death of melanocytes. Neurohumoral hypothesis: psycho-neuro-endocrineimmune connection in vitiligo What is known? There is enough scientific evidence that supports the view that psychological stressors and nervous pathways have an impact on the release of neuropeptides (NPs), various cell behaviours and expression of innate and adaptive immunity in the skin. Evidence in support of the neurohumoral pathogenesis of vitiligo includes common origin of both the melanocytes and nerves from the neural crest cells, the usual presence of SV in a dermatomal fashion, alterations in perspiration and nerve structure in vitiliginous skin and expression of specific neuropeptides in patients with vitiligo.[89,90] Stress is known to induce the production of various NPs in the skin such as neuropeptide Y (NPY).[91,92] Immunohistochemical stains have also shown an increase in NPY, both within and around a vitiliginous patch.[93] The release of this neuropeptide from nerve fibres is suspected to initiate a cascade of reactions leading to the destruction of melanocytes, probably, mediated by mast cells and granulocytes.[93] This theory is of major interest when applied to SV. Vitiligo lesions also exhibit increased levels of norepinephrine and low levels of acetylcholine esterase activity.[94,95] An increased level of neurotransmitters may be directly cytotoxic to cells or may have an indirect effect by causing constriction of supplying blood vessels, thereby causing hypoxia and subsequently cell death.[92,93] Increased levels of homovanillic and vanillylmandelic acids in the 24-hour urine samples of patients with recent onset or progressive disease support the role of stress and the resultant increase in levels of catecholamines in initiating and perpetuating vitiligo.[92] Recent updates Lately, Shaker et al. estimated the gene expression of corticotropin releasing hormone (CRH) and corticotropin releasing hormone receptor 1 (CRHR 1) in both the lesional and non-lesional skin in a sample of patients with vitiligo and assessed its association with psychological stress as measured by the social readjustment stress scale.[96] They found a significant increase in the expression of CRH and CRHR-1 in both the lesional and non-lesional skin of patients 70 with vitiligo and a significant direct association with stress.[96] Normally, CRH-R1 is known to increase the expression of proopiomelanocortin (POMC) and induce the production of adrenocorticotrophic hormone through the activation of cyclic adenosine monophosphate-dependent pathway(s) in an attempt to bring about increased pigmentation.[97] In addition, the melanocytes respond with enhanced production of cortisol and corticosterone, which is dependent upon POMC activity, to suppress an immune response.[97] Thus, the aforementioned study, shows that the upregulation of CRH and CRHR-1 might be a form of systemic compensation in patients with vitiligo so as to restore normal pigmentation in vitiligo lesions, however, a defective melanogenesis pathway in vitiligo lesions might still lead to failure of repigmentation. Vitamin D deficiency What is known? 1,25-dihydroxyvitamin D3 or vitamin D is a fat-soluble vitamin, which is obtained by humans through diet and is synthesized in the skin from 7-dehydrocholesterol under the influence of UV light. It regulates calcium and bone metabolism, controls cell proliferation and differentiation and exerts immunoregulatory activities.[98] Vitamin D has a nuclear receptor called vitamin D receptor (VDR). VDRs are present in the cells involved in calcium and bone metabolism, and also in the keratinocytes, melanocytes, fibroblasts and immune system cells of the skin.[98] Vitamin D exerts a significant effect on the melanocytes and keratinocytes via various mechanisms. In vitro studies have shown that vitamin D3 increases melanogenesis and tyrosinase content of cultured human melanocytes and protects the melanocytes from UVB-induced apoptosis, thus, contributing to repigmentation in vitiligo macules.[98,99] Evidence supporting the role of vitamin D in inducing repigmentation in vitiligo skin comes from various studies in which vitamin D analogues, including calcipotriol and tacalcitol, have been shown to enhance repigmentation in patients with vitiligo.[100-102] In addition, vitamin D has been shown to exert immunomodulatory effects by suppressing the levels of proinflammatory cytokines such as IL-6, IL-8, tumour necrosis factor (TNF)-α and TNF-γ.[103] Recent updates In a recent investigation by Ustun et al., insufficient (<30 ng/ml) or very low (<15 ng/ml) levels of vitamin D were observed in majority of patients, although the difference was not significant when 41 control patients were compared to 25 patients with vitiligo.[104] Another Pigment International | Volume 4 | Issue 2 | July-December 2017 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update study investigated 40 patients with vitiligo and 40 age- and gender-matched controls wherein significantly lower serum vitamin D levels were seen in the patients in relation to the controls.[105] In a recent systematic review and meta-analyses by Upala et al., it was concluded that a significantly lower concentration of serum 25-hydroxyvitamin D was seen in patients with vitiligo compared with healthy controls.[106] The following reasons have been theorized behind decreased vitamin D levels in vitiligo patients: (i) consumption of vitamin D in the autoimmune process and (ii) decreased sun exposure by patients in an attempt to prevent sunburn. The former was supported by a study by Saleh et al., who found that patients with vitiligo and autoimmune diseases have lower serum 25(OH)D levels than patients with vitiligo without autoimmune diseases, though, the difference was not statistically significant.[105] On the contrary, recent studies by Karagün et al.,[107] Karagüzel et al.,[108] and Khurrum et al.,[109] could not find any statistically significant difference in vitamin D levels between patients and healthy controls. Nonetheless, Karagüzel et al. concluded that after six months of treatment, lesion size decreased in patients who received combination treatment with topical tacrolimus 0.1% and vitamin D daily (P < 0.001); while the lesion size increased in patients who received only topical therapy (P < 0.01), thereby, substantiating the role of vitamin D supplementation in patients with vitiligo.[108] Hyperhomocystinemia What is known? Vitamin B12 and folic acid are important cofactors required by the enzyme homocysteine (Hcy) methyltransferase for the regeneration of methionine from Hcy in the activated methyl cycle.[110] Consequently, a nutritional deficiency in either of these two vitamins results in an increase in Hcy levels and a decrease in methionine levels in the circulation.[111,112] Reduced levels of vitamin B12 and folic acid have been reported in patients with vitiligo.[113-115] Moreover, it has been noted that homocystinuria is associated with fair skin and hair, a phenomenon often described as ‘pigmentary dilution’.[116] Low CATactivity is detected in patients with vitiligo, which is known to affect Hcy metabolism.[117] In addition, it has been suggested that an increase in local Hcy levels interferes with normal melanogenesis and plays a role in the pathogenesis of vitiligo by inhibiting the action of histidase and tyrosinase enzymes in the skin.[118] In a pilot study by Shaker and El-Tahlawi, involving 26 patients with vitiligo, it was found that the mean serum Hcy level in the patient group was significantly higher than in the control group (P < 0.001).[119] The mean Hcy level in patients with progressive disease was significantly higher than those in the control group (P < 0.001). In patients with stable disease, the mean Hcy level was higher, but not significantly, (P > 0.05), whereas in patients with regressive disease, the mean Hcy level was almost the same as that of the controls (P > 0.05).[119] Several theories back up the possible effects of elevated Hcy on melanocytes in vitiliginous skin. (i) The production of toxic ROS by Hcy oxidation adds to the oxidative stress in vitiligo that may contribute to the destruction of the melanocytes in vitiligo skin.[120,121] The fact that folic acid has an antioxidant effect in vitiligo backs up this hypothesis.[122] (ii) Hcy inhibits tyrosinase enzyme probably by interacting with copper at the active site of the enzyme.[123] (iii) Other harmful effects of homocysteinemia may be due to the reaction of Hcy with proteins forming disulphides and the conversion of Hcy to highly reactive thiolactone, which could react with the proteins forming NH–CO– adducts, thus, affecting the body’s proteins and enzymes.[124] However, some researchers did not find a significant difference in levels between patients with vitiligo and controls.[125,126] Recent updates In the recent years, there was a surge of studies that supported the role of elevated levels of Hcy in the etiopathogenesis of vitligo.[127-130] However, the major drawback of all the studies discussed so far was that they were performed on a small number of participants. Finally, Alghamdi et al.[130] and Chen et al.[131] published large studies, which included 306 and 2000 participants, respectively. Alghamadi et al. included 153 patients with vitiligo and 153 age- and sex-matched healthy controls and recorded that Hcy and vitamin B12 levels were not significantly different in patients with vitiligo from those in healthy controls.[130] Chen et al. conducted a study involving 1000 patients with vitiligo and 1000 age- and sex-matched controls and found that patients with vitiligo had higher levels of serum Hcy as well as lower activity concentrations of methylenetetrahydrofolate reductase (MTHFR) gene than the controls.[131] Thus, the findings of these two large studies further added to the conflict. In a recent study, Anbar et al., found significantly increased Hcy level in patients’ lesional-induced bulla, although no differences were seen in the serum levels between the cases and the controls.[132] They suggested the possibility that Hcy is produced locally in the lesions, and as such, Pigment International | Volume 4 | Issue 2 | July-December 2017 71 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update needs a larger lesional surface area to have a detectable level in the serum. Thus, they concluded that larger the surface area affected higher the serum Hcy levels. This reinforced the conclusions drawn by Silverberg and Silverberg, who reported elevated levels of serum Hcy in cases with extensive vitiligo and recommended it as a severity marker on the initial examination of patients with vitiligo.[133] In a recent study conducted in India, serum Hcy levels were found to be higher than the western reference standards in both cases and controls.[134] This could partly be explained by a predominantly vegetarian Indian population included in the study, whose diet is deficient in vitamin B12 and partly by genetic polymorphisms in the MTHFR gene.The authors did not notice any significant difference in the Hcy levels between cases and controls and suggested that serum Hcy may not be a reliable marker in the Indian population probably because of differences in dietary habits.[134] ROLE OF TUMOUR NECROSIS FACTOR ALPHA Tumour necrosis factor-alpha (TNF-α) is one of the major cytokines implicated in the pathogenesis of vitiligo. TNF-α has been shown to inhibit melanocyte Figure 1: Proposed patho-mechanisms behind the convergence theory. Convergence theory proposes that the various triggers, perhaps, work in combination to bring about onset of vitiligo. (I) Genetic theory: In a genetically predisposed person, various environmental triggers such as UV radiation, stress and ROS bring about the onset of vitiligo. (II) Neurohumoral hypothesis: Stress brings about an increased secretion of catecholamines and neuropeptides leading to increased production of free radicals, which bring about damage to melanocytes and generation of neoantigens, thereby, triggering immune response. (III) Autocytotoxic hypotheses: Exposure to UV radiation leads to spontaneous production of ROS and increased HMGB1 (high-mobility group box 1) protein level, which brings about activation of caspases, and subsequent loss of melanocytes. (IV) Autoimmune hypothesis: Various triggers bring about synthesis of neoantigens, which initiate an autoimmune phenomenon. (V) Melanocytorrhagy: ROS, structural alterations in melanocytes and alterations in tenascin lead to loss of adhesion of melanocytes to the basement membrane which results in transepidermal elimination of melanocytes on exposure to mild trauma 72 Pigment International | Volume 4 | Issue 2 | July-December 2017 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update Table 1: A summary of the major theories implicated in the pathogenesis of vitiligo and its Recent updates Theory Genetic theory Autoimmune hypothesis Oxidative stress hypothesis Autocytotoxic hypothesis Neurohumoral hypothesis What is known? Several candidate genes, MHC, ACE, CAT, CTLA-4, COMT, ESR, MBL2, PTPN22, HLA, NALP1, XBP1, FOXP1 and IL-2RA, have been associated with generalized vitiligo *SV: Various new pathogenic genes have been identified separately for SV and NSV. Melanocyte-specific CD8+ T-cells and follicular T helper (Tfh) cells bring about cytotoxic and autoimmune responses against the melanocytes *The role of IFN γ, IL-17, Th-17 cells, IL-33 and Treg cells is being singly recognized in vitiligo. An alteration of the redox status of skin and blood stream of patients with vitiligo is well known Environmental exposures and melanin synthesis pathways lead to autocytotoxic damage to melanocytes Psychological stressors and nervous pathways have an impact on and bring about the release of neuropeptides, which eventually generate melanotoxic by-products * *ROS and UVB bring about the secretion of HMGB1, a non-histone DNA-binding protein, from the keratinocytes which leads to increased production of caspases and subsequent apoptosis of melanocytes A significant increase in the expression of CRH and CRHR-1 in the lesional and non-lesional skin of patients with vitiligo has been reported as a form of systemic compensation to restore normal pigmentation in vitiligo lesions which, however, fails because of defective melanogenesis pathway in vitiligo lesions * *Newer anti-melanocyte antibodies have been found in high titres in patients with NSV What is new? The role of microRNAs (miRNAs) and Toll-like receptors (TLRs) has been put forward Recent studies have found that the epidermal H2O2 level is not increased but rather decreased in patients with NSV *A decreased activity of Nrf2 ARE and FOXO3a protein leading to impaired antioxidant mechanism has been seen in patients with vitiligo differentiation from stem cells, hamper melanocyte function and destroy melanocytes through induction of various apoptotic pathways.[135] However, the use of anti-TNF-α agents has been considered to have mixed results. There is increasing data on the occurrence of vitiligo as a side effect of anti-TNF-α therapy used for a variety of autoimmune diseases such as psoriasis or chronic inflammatory rheumatic diseases.[136-138] On the other hand, TNF-α inhibition has been found to halt disease progression in patients with progressive vitiligo by quashing cell-mediated immunity.[139] These two strikingly different effects of anti TNF-α therapy can be explained by different effects of various anti TNF-α agents on T reg production and activation and on Th1/Th2 cytokine balance. For example, in ankylosing spondylitis infliximab reduces and etanercept enhances IFN-γ production.[139] In addition, the co-occurrence of vitiligo with various inflammatory diseases (including psoriasis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis) is well described, therefore, the development or worsening of skin depigmentation may be coincidental and related to the underlying disease. Thus, it has been suggested that etanercept should be considered the preferred anti-TNF-α agent in patients at risk of developing vitiligo to mitigate the risk of this adverse event during therapy for other conditions.[139] THE CONVERGENCE THEORY The convergence theory states that all the aforementioned theories, namely genetic, neurohumoral, autocytoxic, autoimmunity, melanocytorrhagy, altered cellular environment and impaired melanocyte migration, each contribute to the pathogenesis of vitiligo and none are mutually exclusive.[140,141] This theory has been summarized in Figure 1. Table 1 summarizes the various theories implicated in the pathogenesis of vitiligo and Recent updates in each of the proposed theories. CONCLUSION The cause of vitiligo still remains unknown, although, it is clear that several different pathophysiological processes may be involved. The best-supported hypothesis so far is the autoimmune hypothesis followed by the oxidative stress theory. Newer theories, such as melanocytorrhagy, decreased melanocyte survival and the role of HMGB-1 DNA-binding protein, homocysteine and vitamin D deficiency have recently been put forward. Because all of these theories seem plausible, it is likely that vitiligo may indeed include an array of disorders with different pathophysiological background yet a common phenotype. Pigment International | Volume 4 | Issue 2 | July-December 2017 73 [Downloaded free from http://www.pigmentinternational.com on Tuesday, June 25, 2019, IP: 109.88.140.131] Arora and Kumaran: Pathogenesis of vitiligo: An update Financial support and sponsorship Nil. 18. 19. Conflicts of interest There are no conflicts of interest. 20. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 74 Glassman SJ. Vitiligo, reactive oxygen species and T-cells. Clin Sci (Lond) 2011;120:99-120. Zailaie MZ. Epidermal hydrogen peroxide is not increased in lesional and non-lesional skin of vitiligo. 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