Year : 2021 | Volume
: 5 | Issue : 1 | Page : 36--42
Serum biomarkers of vitiligo
Mohamed Ibrahim ElGhareeb
Department of Dermatology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Mohamed Ibrahim ElGhareeb
Department of Dermatology, Faculty of Medicine, Zagazig University, Zagazig
The pathogenesis of vitiligo is complex, although the driving factors seem to become gradually clarified. This may help to identify possible targets for both detection of activity as well as discovering new therapeutic agents. In the coming years, new clinical trials are expected based on this scientific progress. Logically, a biomarker that allows an early and accurate determination of treatment response will also be of a considerable value. In contrast to other inflammatory skin disorders such as psoriasis or atopic dermatitis, vitiligo lacks obvious inflammatory signs, which can be easily evaluated by clinical examination. Several clinical activity signs have been described in vitiligo (such as hypochromic areas, blurred borders and confetti-like depigmentation, and Koebners' phenomenon), although these signs are only present in a subset of active vitiligo patients. Moreover, it is unclear whether these signs can be used to evaluate disease activity over time. The hallmark of vitiligo is its unpredictable clinical course, including periods of disease stability and disease flares. This complicates the daily management of vitiligo. Biomarker analysis could be useful to follow patients over time and even predict the chance of future disease progression, allowing to tailor the treatment to the individual biomarker profile.
|How to cite this article:|
ElGhareeb MI. Serum biomarkers of vitiligo.Clin Dermatol Rev 2021;5:36-42
|How to cite this URL:|
ElGhareeb MI. Serum biomarkers of vitiligo. Clin Dermatol Rev [serial online] 2021 [cited 2022 Nov 30 ];5:36-42
Available from: https://www.cdriadvlkn.org/text.asp?2021/5/1/36/309779
Biomarkers analysis can be useful to follow patients over time and even predict the chance of future disease progression. The following biomarkers are proposed to be biomarkers of vitiligo activity:
CXC motif ligand
CXC motif ligand (CXCL) 10 is a chemokine that belongs to the CXC subfamily. CXCL10 does its function through binding to chemokine (CXC motif) receptor 3 (CXCR3). CXCL10 and its receptor, CXCR3, appears to participate in the pathogenesis of many autoimmune diseases.
It is induced by interferon (IFN)-γ in many cell types, such as neutrophils, lymphocytes, fibroblasts, endothelial cells, thyrocytes, and other epithelial cells.
By binding to its specific receptor (CXCR) 3, CXCL10 regulates immune responses by recruitment and activation of T-cells, monocytes, and natural killer cells. CXCR3 is expressed immune cells also by endothelial cells, mesangial cells, thyrocytes, and other epithelial cells. Recently, it has been found that the tissue expressions of CXCR3 and CXCL10 are increased in many autoimmune diseases and play major role in leukocyte homing to the inflammation site and contribute to the process of tissue damage.
Determination of high level of CXCL10 in the peripheral liquids is a marker of host immune response, especially the Th1-orientated immune response. In inflamed tissues, the recruited Th1 lymphocytes are responsible for IFN-γ and tumor necrosis factor (TNF)-α production, which in turn stimulate CXCL10 secretion from the above mentioned cells, therefore, creating an amplification feedback loop and enhance the autoimmune process.
CXCL10 were investigated based on the discovery of an IFN-γ signature in vitiligo.
Wang et al. investigated several members of the CXCR3 pathway. They found that CXCL10 were linked with progressive cases, also CXCL10 values were obviously different between stable and active vitiligo patients.
Two additional studies with a limited number of patients did not found a significant association between CXCL10 and the disease activity although one study observed a trend.,
Highly sensitive C-reactive protein
C-reactive protein (CRP) is a sensitive marker for systemic inflammation. Interleukin (IL)-1, IL-6, and TNF-α are mediators for the modulation of the hepatic synthesis of acute phase reactants as CRP.
Hypersensitive CRP (hsCRP) test is a quantitative laboratory test that analyzes very low amounts of CRP in the serum. This test is commonly used as a diagnostic and prognostic marker for cardiac diseases and is a comprehensive index for evaluating coronary complications. CRP is an acute phase protein secreted in the blood stream by the liver in response to inflammatory cytokines such as IL-6 and several other systemic inflammation biomarkers.,
Standard CRP (normal levels of 0–0.5 mg/l) has been used for years in patients with acute inflammation or for evaluating evident chronic inflammation. A level of <1 mg/l is considered low-risk, 1–3 mg/l medium-risk, and more than 3 mg/l as high-risk inflammation. For levels more than 10 mg/l, the source of inflammation or infection should be sought and the test should be repeated after recovery.
HsCRP has also been used as an acceptable index for milder systemic inflammation in several disorders such as diabetes as well as cardiac and chronic obstructive pulmonary diseases.
Ghaderi and Nezafati found that the serum level of hsCRP did not differ between the case and the control groups.
Another study also found no significant difference between the two groups and showed that the local inflammation induced by vitiligo has insignificant effect on the CRP level. Moreover, they recommend another study involving a higher number of participants with higher percentages of body involvement and longer disease duration to shed more light on this important subject.
It is possible that an increase of local homocysteine (Hcy) interferes with normal melanogenesis and may plays a role in the pathogenesis of vitiligo. Vitamin B12 and folic acid, levels which are decreased in vitiligo patients, are important cofactors in the metabolism of Hcy. Nutritional deficiency in these two vitamins will result in increased Hcy level in the circulation, a finding that expected to occur in vitiligo.
It also inhibit tyrosinase enzyme by binding with copper (Cu) at its active site, resulting in reversible hypopigmentation.
Two studies showed that Hcy concentrations were increased in the vitiligo patients according to the disease activity.,
However, other relatively well-sized studies showed that there is no association between Hcy levels and vitiligo activity.,,
S100B is a member of the family of S100 proteins that include a multigene group of 21 low-molecular weight proteins.
S100B expression has been reported in many tissues, including melanocytes, astrocytes, oligodendrocytes, Schwann cells, neural progenitor cells, kidney epithelial cells, skeletal myofibers, Langerhans cells, adipocytes, and a subpopulation of lymphocytes.
A recent study showed that S100B expressed in melanocytes but not in keratinocytes or fibroblasts, also showed that it was released passively by damaged tissues.
Speeckaert et al. observed higher circulating levels of S100B in patients with active vitiligo and increased in patients with recent disease activity (<6 months) compared to all other vitiligo patients, also found a strong correlation between S100B serum levels and body surface area affected in patients with active depigmentation, but no correlation in patients with stable vitiligo.
Lower S100B concentrations (nanomolar levels) have been found to be beneficial, while higher concentrations (micromolar levels) are harmful. Rapidly increasing extracellular levels of S100B result in neuronal dysfunction or cell death, through an inflammatory response that stimulates microglia and astrocytes to recruit and produce pro-inflammatory cytokines, increased calcium levels, and nitric oxide, which cause harmful effects in the tissue.
Increased S100B level in serum has been found to be useful in monitoring the prognosis and follow-up of patients with malignant melanoma?. Cell damage, subsequent death by apoptosis or necrosis, and constant drainage from tumor sites are the major sources of S100B protein in the blood of such patients.
A protective effect of S100A2 was observed in melanoma cells, with S100A2 upregulation being associated with increased expression of the tumor suppressorp53. S100B has protective effects on melanocytes at the lower concentrations but has pro-inflammatory and harmful effects at the higher concentrations.
Brain-derived neutrophic growth factor
Brain-derived neurotrophic factor (BDNF) is one of the most important neurotrophins that regulates synaptic plasticity. It is also crucial for learning and memory processes.
It has been established that BDNF signaling in the human brain modulates behavior. In addition to its role in learning and memory, BDNF has been associated with mood-related behaviors. BDNF is widely studied in neuropsychiatric disorders such as schizophrenia, major depressive disorder, and bipolar disorder.
The role of neurotrophins and their receptors has been recently identified in the control of skin hemostasis and hair growth.
Neurotrophins mediate proliferation and survival of epidermal keratinocytes and also influence the proliferation and survival of melanocytes.
One study suggests that reduced serum levels of BDNF may be an etiological factor in the development of vitiligo, also may be an indicator of future psychiatric disorders in patients with vitiligo. It may be a biomarker for psychosomatic disorders that may be present in patients with vitiligo.
IFN-γ is a pleiotropic cytokine that is a key regulator of the immune system.
In addition to host defense, IFN-γ induce autoantibodies, activate autologous cytotoxic T-cells, and induce target cell apoptosis.,
Serum IFN-γ was increased in vitiligo patients compared to controls and in active compared to stable vitiligo One study confirmed these findings, while another study did not find any difference.,
SOX-10 is a melanocyte transcription factor which is expressed in embryonic melanoblasts.
It is involved in the differentiation of tissues that derived from the neural crest, and it is expressed in the central and peripheral nervous system, sympathetic and parasympathetic ganglia, and enteric ganglia in the gastrointestinal tract during human embryogenesis. It also expressed in the submandibular glands, the heart, the lung, and the pancreas. Adults expression of SOX10 has been detected in the brain, small intestine, colon, prostate, and heart.
SOX10 has been found to bind to the promoter of microphtalmia-associated transcription factor, a gene important for the development of melanocytes and other cells derived from neural crest.
It was identified as an autoantigen in vitiligo associated with autoimmune polyendocrine syndrome Type 1 (APS I), possibly suggesting a general role in the pathogenesis of vitiligo, although the frequency of SOX10 antibodies was only 3.2% in the patients with isolated vitiligo.
The study showed that SOX10 is expressed in human adult skin melanocytes and identified it as autoantigen in (APS I). Immunoreactivity against these proteins is associated with vitiligo in APS I. Strong reactivity against SOX10 is also detected in a subgroup of patients with idiopathic vitiligo.
IL-23 is a member of the IL-12 family that activates the function of Th17 cells to promote inflammatory responses. It has been found that IL-23 is essential for the development of autoimmune diseases, as psoriasis, rheumatoid arthritis, inflammatory bowel disease, and autoimmune diabetes. This cytokine induces the production of Th17 cells, so it was thought that IL-23 mediates autoimmunity by secretion of the IL-17 family.
In patients with vitiligo, increased serum IL-17 levels were observed and suggest that IL-17 play a role in the immune response in early-onset disease.
It is expressed by inflammatory macrophages, that are activated to produce IL-1, TNF-α, and IL-23 itself. IL-23 seems to have a central role in autoimmunity.
It was demonstrated that IL-23 plays an important role in the central regulation of the cellular mechanisms involved in inflammation. It may induce an autocrine loop within the innate immune system, lead to production of numerous mediators of inflammation.
Vaccaro et al. showed that serum IL-23 levels are significantly higher in vitiligo patient as compared with controls, and there was a significant positive correlation of serum IL-23 levels with disease duration, extent, and activity.
Low Vitamin D levels have been associated with autoimmune diseases, including systemic lupus, diabetes mellitus, multiple sclerosis, and rheumatoid arthritis.
It may affect both innate and adaptive immune responses through receptors in T and B lymphocytes, macrophages, and dendritic cells. The exact mechanism by which Vitamin D affects autoimmunity is unknown, but there is a clear regulation of immune cells by Vitamin D in vitro.
It also increases tyrosinase activity and melanogenesis through a nuclear hormone receptor the Vitamin D receptor in melanocytes.
Few reports have investigated the association between vitiligo and the reduced Vitamin D levels, but these studies provide conflicting results.,
Ustun et al. investigated 25 vitiligo patients and 41 controls, insufficient (<30 ng/ml) or very low (<15 ng/ml) levels of Vitamin D, were observed in the majority of patients, but the difference was not significant compared to the control group. It was stated that a large number of studies had reported low levels of serum Vitamin D in autoimmune diseases, but it remains unclear if this is a cause or a result of the autoimmune diseases.
Another study investigated forty vitiligo patients and forty controls. Significantly lower serum Vitamin D levels were seen in the patients compared to controls.
Another study showed also decreased serum Vitamin D levels in patients with vitiligo compared to controls, but this difference was not significant.
Vitamin D and its analogs are used to treat skin disorders such as psoriasis and vitiligo. Patients with vitiligo have been treated with topical calcipotriene.
It was observed that Vitamin D and ultraviolet (UV) B irradiation promoted the proliferation of melanocytes.
Many studies have been reported the treatment of vitiligo with Vitamin D analogs alone or in combination with UV light or corticosteroids to enhance repigmentation.
Vitamin B12 and folic acid
It is believed that patients with vitiligo are more likely to have pernicious anemia and Vitamin B12 deficiency. Vitamin B12 and folic acid are major determinants of Hcy levels and a nutritional deficiency in either of them results in hyperhomocysteinemia.
A lot of studies showed that, the serum level of Hcy was significantly increased in vitiligo patients than in the control and serum Vitamin B12 level was significantly lower in vitiligo patients than in the controls.,,
Many study showed that there was no statistically significant difference between vitiligo patients and controls in the serum Hcy, Vitamin B12, and folic acid levels.,
Zinc and copper
Zinc (Zn) and Cu are two of the trace elements that found in very small amounts in the body.
They are involved in many homeostatic mechanisms of the body, such as inflammation, specific immunity, and oxidative stress.
Zn is one of the important trace elements related to health and disease. Zn in combination with other micronutrients such as Cu, cobalt, nickel, iron, manganese, and Ca++ plays an important role in the process of melanogenesis.
They are antioxidants involved in the destruction of free radicals and potential anti-apoptotic factors for protecting cell proteins from oxidation. Furthermore, Cu and Zn play roles in stimulating cell-mediated immunity responses, synthesizing and releasing of melanocyte stimulating hormone, which are also important in melanogenesis.
A lot of studies showed that serum Zn levels were significantly lower in vitiligo patient than control.,,,,
In the presence of Zn deficiency, absorption of Cu is enhanced, so reduced serum Zn levels was accompanied by elevated serum Cu levels. Helmy et al. showed that Cu levels were significantly higher in active vitiligo patients compared to the controls.
Many studies reported no statistically significant Cu level change between the vitiligo patients and the control group.,
Granulocyte-macrophage colony-stimulating factor and its antibodies
Recent studies showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a central role in the pathogenesis of several autoimmune and inflammatory diseases, including rheumatoid arthritis and multiple sclerosis. It has been reported that its overexpression in the stomach can lead to autoimmune gastritis. Furthermore, increased levels of GM-CSF autoantibodies have been found in patients with Crohn's disease.
The role of GM-CSF in autoimmune and inflammatory diseases makes it of interest for assessment in vitiligo. The data for this role involve worsening disease in animals by targeting the GM-CSF gene or by blocking the GM-CSF antibody.
It is also used as a factor that could affect the prognosis after transplantation of cultured autologous melanocytes (TCAM) and act as a biomarker of vitiligo patients' prognosis after TCAM treatment, as circulating serum levels of GM-CSF were significantly higher in vitiligo patients with excellent repigmentation group after TCAM compared to the poor or fair repigmentation group. The results of this study suggest that elevated serum levels of GM-CSF may serve as the serum biomarkers to predict the prognosis of TCAM.
Macrophage migration inhibitory factor
Macrophage inltration has also been found in vitiligo lesions, with increased numbers present in the perilesional skin. It is proposed that macrophages are involved in clearing melanocytes that have been induced to apoptose by cytotoxic T lymphocytes.
Macrophage migration inhibitory factor (MIF) was originally identied as a lymphokine that concentrates macrophages at inammatory loci. It is a potent activator of macrophages in vivo and is considered to play an important role in cell-mediated immunity.
A study showing that MIF probably has a role in the pathogenesis of vitiligo done by Serarslan et al. which assessed the serum of thirty patients with vitiligo and thirty healthy controls. They demonstrated that mean serum MIF level is higher than that of controls, indicating the involvement of MIF in the pathogenesis of vitiligo, also there was a positive correlation between disease duration and MIF levels in patients with vitiligo. Serum MIF levels of patients with localized vitiligo were lower than those of patients with acral, acrofacial and generalized vitiligo.
Some soluble forms of tumor necrosis factor receptor
The TNF receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind TNFs via an extracellular cysteine-rich domain.
In their active form, the majority of TNF receptors form trimeric complexes in the plasma membrane. Most TNF receptors contain transmembrane domains (TMDs), although some can be cleaved into soluble forms (e.g., TNFR1) and some lack a TMD entirely (e.g., decoy receptor 3). In addition, most TNF receptors require specific adaptor protein such as TNF receptor-associated death domain, TNFR–associated factor, receptor-interacting protein, and Fas-associated death domain protein for downstream signaling. TNF receptors are primarily involved in apoptosis and inflammation, but they can also take part in other signal transduction pathways, such as proliferation, survival, and differentiation. TNF receptors are expressed in a wide variety of tissues, especially in leukocytes.
Soluble cluster of differentiation 27
Cluster of differentiation (CD) 27 is a transmembrane protein and member of the TNFRSF, expressed on T, B, and natural killer cells. By binding to its ligand (CD70), CD27 ensures lymphocyte survival, increased T-cell proliferation, and memory cell formation.
Its expression supports helper T-cell type 1 (TH1) development. Soluble cluster of differentiation 27 (sCD27) can be released into the blood circulation from the cell surface of activated lymphocytes by differential splicing or by shedding of extracellular domain of the membrane-bound receptor protein.
The serums CD27 level has been used as a biomarker to monitor immune activation and disease burden in various inflammatory disorders; however, it is currently not clear whether sCD27 has a functional role in these conditions or is a byproduct of T-cell activation.
Studies in both human and mouse models indicate that CD27 signaling can promote IFN-γ–dependent immune responses, which is particularly relevant for vitiligo.
The active contribution of sCD markers in the inflammatory processes has recently been confirmed. These contributions include the immunologic-stimulating effects of sCD27 by inducing T-cell activation. In addition, sCD27 increases immunoglobulin G production and provides an activation signal for antigen-primed B lymphocytes.
Soluble cluster of differentiation 25
sCD25 has been implicated in the development of autoimmunity. Through inhibiting the downstream signaling of IL-2R, sCD25 favors TH17 development. By acting as a decoy receptor for IL-2, T-cell responses are turned toward a TH17 phenotype. In this regard, increased circulating TH17 cells and increased serum levels of IL-17 have been associated with active vitiligo.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Speeckaert R, Speeckaert M, De Schepper S, van Geel N. Biomarkers of disease activity in vitiligo: A systematic review. Autoimmun Rev 2017;16:937-45.|
|2||Antonelli A, Ferrari SM, Giuggioli D, Ferrannini E, Ferri C, Fallahi P, et al. Chemokine (C-X-C motif) ligand (CXCL) 10 in autoimmune diseases. Autoimmun Rev 2014;13:272-80.|
|3||Groom JR, Luster AD. CXCR3 ligands: Redundant, collaborative and antagonistic functions. Immunol Cell Biol 2011;89:207-15.|
|4||Rashighi M, Agarwal P, Richmond JM, Harris TH, Dresser K, Su MW, et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med 2014;6:223ra23.|
|5||Wang XX, Wang QQ, Wu JQ, Jiang M, Chen L, Zhang CF, et al. Increased expression of CXCR3 and its ligands in patients with vitiligo and CXCL10 as a potential clinical marker for vitiligo. Br J Dermatol 2016;174:1318-26.|
|6||Maouia A, Sormani L, Youssef M, Helal AN, Kassab A, Passeron T, et al. Differential expression of CXCL9, CXCL10, and IFN-γ in vitiligo and alopecia areata patients. Pigment Cell Melanoma Res 2017;30:259-61.|
|7||Strassner JP, Rashighi M, Ahmed Refat M, Richmond JM, Harris JE. Suction blistering the lesional skin of vitiligo patients reveals useful biomarkers of disease activity. J Am Acad Dermatol 2017;76:847-55.e5.|
|8||Ganter U, Arcone R, Toniatti C, Morrone G, Ciliberto G. Dual control of C-reactive protein gene expression by interleukin-1 and interleukin-6. EMBO J 1989;8:3773-9.|
|9||Ridker PM, Cushman M, Stampfer MJ. HS CRP in the primary prevention setting. N Engl J Med 2000;342:836-43.|
|10||Miesbach W, Gökpinar B, Gilzinger A, Claus D, Scharrer I. Predictive role of hs-C-reactive protein in patients with antiphospholipid syndrome. Immunobiology 2005;210:755-60.|
|11||Ridker PM, Danielson E, Fonseca FA. Measuring hsCRPAn important part of a comprehensive risk profile or a clinically redundant practice. PLoS Med 2008;7:e1000196.|
|12||Ramirez D, Patel P, Casillas A, Cotelingam J, Boggs P, Bahna SL, et al. Assessment of high-sensitivity C-reactive protein as a marker of airway inflammation in asthma. Ann Allergy Asthma Immunol 2010;104:485-9.|
|13||Ghaderi R, Nezafati P. A new biomarker in patients with vitiligo: A case-control study. MOJ Immunol 2016;3:00106.|
|14||Namazi MR, Nozari F, Ghoreyshi H. Serum levels of hypersensitive-C-reactive protein in vitiligo. Indian Dermatol Online J 2018;9:53-4.|
|15||Shaker OG, El-Tahlawi SM. Is there a relationship between homocysteine and vitiligo? A pilot study. Br J Dermatol 2008;159:720-4.|
|16||Karadag AS, Tutal E, Ertugrul DT, Akin KO, Bilgili SG. Serum holotranscobalamine, Vitamin B12, folic acid and homocysteine levels in patients with vitiligo. Clin Exp Dermatol 2012;37:62-4.|
|17||Singh S, Singh U, Pandey SS. Increased level of serum homocysteine in vitiligo. J Clin Lab Anal 2011;25:110-2.|
|18||Gupta S, D'souza P, Dhali TK, Arora S. Serum homocysteine and total antioxidant status in vitiligo: A case control study in Indian population. Indian J Dermatol 2016;61:131-6.|
|19||Yasar A, Gunduz K, Onur E, Calkan M. Serum homocysteine, Vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo. Dis Markers 2012;33:85-9.|
|20||Zaki AM, Abdo HM, Ibrahim IM, Ibrahim AKI. Serum homocysteine and vitiligo. Gulf J Dermatol Venereol 2014;21:15-20.|
|21||Eckert RL, Broome AM, Ruse M, Robinson N, Ryan D, Lee K, et al. S100 proteins in the epidermis. J Invest Dermatol 2004;123:23-33.|
|22||Sorci G, Riuzzi F, Arcuri C, Tubaro C, Bianchi R, Giambanco I, et al. S100B protein in tissue development, repair and regeneration. World J Biol Chem 2013;4:1-2.|
|23||Cheong KA, Noh M, Kim CH, Lee AY. S100B as a potential biomarker for the detection of cytotoxicity of melanocytes. Exp Dermatol 2014;23:165-71.|
|24||Speeckaert R, Voet S, Hoste E, van Geel N. S100B is a potential disease activity marker in nonsegmental vitiligo. J Invest Dermatol 2017;137:1445-53.|
|25||Rothermundt M, Peters M, Prehn JH, Arolt V. S100B in brain damage and neurodegeneration. Microsc Res Tech 2003;60:614-32.|
|26||Hu J, Ferreira A, Van Eldik LJ. S100beta induces neuronal cell death through nitric oxide release from astrocytes. J Neurochem 1997;69:2294-301.|
|27||Ghanem G, Loir B, Morandini R, Sales F, Lienard D, Eggermont A, et al. On the release and half-life of S100B protein in the peripheral blood of melanoma patients. Int J Cancer 2001;94:586-90.|
|28||Lin J, Yang Q, Wilder PT, Carrier F, Weber DJ. The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma. J Biol Chem 2010;285:27487-98.|
|29||Birlea SA. S100B: Correlation with active vitiligo depigmentation. J Invest Dermatol 2017;137:1408-10.|
|30||Lu Y, Christian K, Lu B. BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 2008;89:312-23.|
|31||Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012;64:238-58.|
|32||Botchkarev VA, Botchkareva NV, Peters EM, Paus R. Epithelial growth control by neurotrophins: Leads and lessons from the hair follicle. Prog Brain Res 2004;146:493-513.|
|33||Stefanato CM, Yaar M, Bhawan J, Phillips TJ, Kosmadaki MG, Botchkarev V, et al. Modulations of nerve growth factor and Bcl-2 in ultraviolet-irradiated human epidermis. J Cutan Pathol 2003;30:351-7.|
|34||Yanik ME, Erfan G, Albayrak Y, Aydin M, Kulac M, Kuloglu M, et al. Reduced serum brain-derived neurotrophic factor in patients with first onset vitiligo. Neuropsychiatr Dis Treat 2014;10:2361-7.|
|35||Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: An overview of signals, mechanisms and functions. J Leukoc Biol 2004;75:163-89.|
|36||Moore F, Colli ML, Cnop M, Esteve MI, Cardozo AK, Cunha DA, et al. PTPN2, a candidate gene for type 1 diabetes, modulates interferon-gamma-induced pancreatic beta-cell apoptosis. Diabetes 2009;58:1283-91.|
|37||Pérez-Rodríguez R, Roncero C, Oliván AM, González MP, Oset-Gasque MJ. Signaling mechanisms of interferon gamma induced apoptosis in chromaffin cells: Involvement of nNOS, iNOS, and NFkappaB. J Neurochem 2009;108:1083-96.|
|38||Ala Y, Pasha MK, Rao RN, Komaravalli PL, Jahan P. Association of IFN-γ:IL-10 cytokine ratio with nonsegmental vitiligo pathogenesis. Autoimmune Dis 2015;2015:423490.|
|39||Bhardwaj S, Rani S, Srivastava N, Kumar R, Parsad D. Increased systemic and epidermal levels of IL-17A and IL-1β promotes progression of non-segmental vitiligo. Cytokine 2017;91:153-61.|
|40||Dwivedi M, Laddha NC, Shah K, Shah BJ, Begum R. Involvement of interferon-gamma genetic variants and intercellular adhesion molecule-1 in onset and progression of generalized vitiligo. J Interferon Cytokine Res 2013;33:646-59.|
|41||Southard-Smith EM, Kos L, Pavan WJ. Sox 10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet 1998;18:60-4.|
|42||Bondurand N, Kobetz A, Pingault V, Lemort N, Encha-Razavi F, Couly G, et al. Expression of the SOX10 gene during human development. FEBS Lett 1998;432:168-72.|
|43||Lee M, Goodall J, Verastegui C, Ballotti R, Goding CR. Direct regulation of the microphthalmia promoter by Sox10 links Waardenburg-Shah syndrome (WS4)-associated hypopigmentation and deafness to WS2. J Biol Chem 2000;275:37978-83.|
|44||Hedstrand H, Ekwall O, Olsson MJ, Landgren E, Kemp EH, Weetman AP, et al. The transcription factors SOX9 and SOX10 are vitiligo autoantigens in autoimmune polyendocrine syndrome type I. J Biol Chem 2001;276:35390-5.|
|45||Croxford AL, Mair F, Becher B. IL-23: One cytokine in control of autoimmunity. Eur J Immunol 2012;42:2263-73.|
|46||Duvallet E, Semerano L, Assier E, Falgarone G, Boissier MC. Interleukin-23: A key cytokine in inflammatory diseases. Ann Med 2011;43:503-11.|
|47||Tang C, Chen S, Qian H, Huang W. Interleukin-23: As a drug target for autoimmune inflammatory diseases. Immunology 2012;135:112-24.|
|48||Vaccaro M, Cannavò SP, Imbesi S, Cristani M, Barbuzza O, Tigano V, et al. Increased serum levels of interleukin-23 circulating in patients with non-segmental generalized vitiligo. Int J Dermatol 2015;54:672-4.|
|49||AlGhamdi K, Kumar A, Moussa N. The role of Vitamin D in melanogenesis with an emphasis on vitiligo. Indian J Dermatol Venereol Leprol 2013;79:750-8.|
|50||Adorini L, Penna G. Control of autoimmune diseases by the Vitamin D endocrine system. Nat Clin Pract Rheumatol 2008;4:404-12.|
|51||Ustun I, Seraslan G, Gokce C, Motor S, Can Y, Ugur Inan M, et al. Investigation of Vitamin D levels in patients with vitiligo vulgaris. Acta Dermatovenerol Croat 2014;22:110-3.|
|52||Saleh HM, Abdel Fattah NS, Hamza HT. Evaluation of serum 25-hydroxyvitamin D levels in vitiligo patients with and without autoimmune diseases. Photodermatol Photoimmunol Photomed 2013;29:34-40.|
|53||Karagün E, Ergin C, Baysak S, Erden G, Aktas H, Ekiz Ö, et al. The role of serum Vitamin D levels in vitiligo. Postepy Dermatol Alergol 2016;33:300-2.|
|54||Xu QX, Du J, He PY, Zhang JZ, Zhu TJ. Effects of 1alpha, 25-dihydroxyvitamin D(3) and UVB on cell proliferation and melanin synthesis of cultured human melanocyte. Beijing Da Xue Xue Bao Yi Xue Ban 2004;36:483-6.|
|55||Parsad D, Kanwar AJ. Topical Vitamin D analogues in the treatment of vitiligo. Pigment Cell Melanoma Res 2009;22:487-8.|
|56||Montes LF, Diaz ML, Lajous J, Garcia NJ. Folic acid and Vitamin B12 in vitiligo: A nutritional approach. Cutis 1992;50:39-42.|
|57||Kim MH, Kim E, Passen EL, Meyer J, Kang SS. Cortisol and estradiol: Nongenetic factors for hyperhomocyst(e)inemia. Metabolism 1997;46:247-9.|
|58||Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007;370:263-71.|
|59||Karsli Ceppioglu S, Yurdun T, Canbakan M. Assessment of matrix Gla protein, Klotho gene polymorphisms, and oxidative stress in chronic kidney disease. Ren Fail 2011;33:866-74.|
|60||Arora PN, Dhillon KS, Rajan SR, Sayal SK, Das AL. Serum zinc levels in cutaneous disorders. Med J Armed Forces India 2002;58:304-6.|
|61||Inamadar AC, Palit A. Acrodermatitis enteropathica with depigmented skin lesions simulating vitiligo. Pediatr Dermatol 2007;24:668-9.|
|62||Shameer P, Prasad PV, Kaviarasan PK. Serum zinc level in vitiligo: A case control study. Indian J Dermatol Venereol Leprol 2005;71:206-7.|
|63||Molokhia MM, Portnoy B. Neutron activation analysis of trace elements in skin. VII. Copper and zinc in vitiligo, moles and seborrhoeic warts. Br J Dermatol 1973;88:347-53.|
|64||Brüske K, Salfeld K. Zinc and its status in some dermatologic diseases – A statistical assessment. Z Hautkr 1987;62 Suppl 1:125-31.|
|65||Madhavi D, Divyamalini T, Sarada C. Oxidative stress in the pathogenesis of vitiligo. Int J Pharm Bio Sci 2014;5:820-8.|
|66||Wang YD, Liu XH, Lv XH. Analysis of serum trace elements of vitiligo patients in DaQing district. J Qiqihar Univ Med 2012;33:39-40.|
|67||Yanagisawa H. Clinical aspects of zinc deficiency. J Jpn Med Assoc 2002;127:261-8.|
|68||Tomita H. Taste Disorder and Diet. Tokyo: Kodansha Ltd.;2002. p. 3-140.|
|69||Helmy MI, Gayyar EL, Hawas S, Eissa AE. Role of oxidative stress in the pathogenesis of vitiligo. J Pan Arab Leag Dermatol 2004;15:97-105.|
|70||Wang XM. A correlative study on SOD and serum zinc copper iron in patients with vitiligo. World Element Med 2011;18:31-2.|
|71||Wu Y, He N, Li JS, Liang L. The zinc and copper levels in serum of 70 vitiligo patients from Guangxi province. Chin J Dermatol Venereol 2010;24:722-7.|
|72||Shiomi A, Usui T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm 2015;2015:568543.|
|73||Goldstein JI, Kominsky DJ, Jacobson N, Bowers B, Regalia K, Austin GL, et al. Defective leukocyte GM-CSF receptor (CD116) expression and function in inflammatory bowel disease. Gastroenterology 2011;141:208-16.|
|74||Wu XG, Hong WS, Xu A. GM-CSF: A possible prognostic serum biomarker of vitiligo patients' considered for transplantation treatment with cultured autologous melanocytes: A pilot study. J Eur Acad Dermatol Venereol 2016;30:1409-11.|
|75||Rezaei N, Gavalas NG, Weetman AP, Kemp EH. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol 2007;21:865-76.|
|76||Shimizu T. Role of macrophage migration inhibitory factor (MIF) in the skin. J Dermatol Sci 2005;37:65-73.|
|77||Serarslan G, Yönden Z, Sögüt S, Savas N, Celik E, Arpaci A, et al. Macrophage migration inhibitory factor in patients with vitiligo and relationship between duration and clinical type of disease. Clin Exp Dermatol 2010;35:487-90.|
|78||Hehlgans T, Pfeffer K. The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: Players, rules and the games. Immunology 2005;115:1-20.|
|79||Gravestein LA, Borst J. Tumor necrosis factor receptor family members in the immune system. Semin Immunol 1998;10:423-34.|
|80||Speeckaert R, Lambert J, van Geel N. Clinical significance of serum soluble CD molecules to assess disease activity in vitiligo. JAMA Dermatol 2016;152:1194-200.|
|81||Ciccarelli BT, Yang G, Hatjiharissi E, Ioakimidis L, Patterson CJ, Manning RJ, et al. Soluble CD27 is a faithful marker of disease burden and is unaffected by the rituximab-induced IgM flare, as well as by plasmapheresis, in patients with Waldenström's macroglobulinemia. Clin Lymphoma Myeloma 2009;9:56-8.|
|82||Huang J, Jochems C, Anderson AM, Talaie T, Jales A, Madan RA, et al. Soluble CD27-pool in humans may contribute to T cell activation and tumor immunity. J Immunol 2013;190:6250-8.|
|83||Dang LV, Nilsson A, Ingelman-Sundberg H, Cagigi A, Gelinck LB, Titanji K, et al. Soluble CD27 induces IgG production through activation of antigen-primed B cells. J Intern Med 2012;271:282-93.|
|84||Russell SE, Moore AC, Fallon PG, Walsh PT. Soluble IL-2Rα (sCD25) exacerbates autoimmunity and enhances the development of Th17 responses in mice. PLoS One 2012;7:e47748.|
|85||Zhou L, Shi YL, Li K, Hamzavi I, Gao TW, Huggins RH, et al. Increased circulating Th17 cells and elevated serum levels of TGF-beta and IL-21 are correlated with human non-segmental vitiligo development. Pigment Cell Melanoma Res 2015;28:324-9.|