Animal models of vitiligo: Matching the model to the question

Vitiligo is an autoimmune disease of the skin that is characterized by patchy depigmentation (i.e., white spots) and results from the loss of melanocytes, which are pigment-producing cells. The pathogenesis of human vitiligo consists of an interaction between intrinsic melanocyte defects, environmental factors, and autoimmune mechanisms that target these cells for destruction. Human clinical and translational studies have outlined pathways that are important in human disease; however, combining human correlative studies with mechanistic studies in representative preclinical animal models is a powerful approach to study disease pathogenesis and develop new treatments. Because of the complex pathogenesis of vitiligo, it is unlikely that any one single animal model will adequately reflect all factors implicated in the initiation, progression, and maintenance of the disease. Therefore, vitiligo is best modeled by multiple systems—each with its strengths and weaknesses—that allow insight into specific components of vitiligo pathogenesis. In this paper, we describe some of the available animal models that have been developed to study vitiligo.     

白癜风动物模型研究进展

白癜风的病因和发病机制尚未完全阐明,遗传、自身免疫、氧化应激和环境等多种因素参与了白癜风的发病, 建立适宜的白癜风动物模型可为研究其发病机制和开发新疗法奠定基础。相较自发性白癜风模型,诱导性模型能更好的模拟白癜风发病的病理过程及影响因素。本文着重综述了诱导性白癜风动物模型的最新进展。     

Relevance of autoimmune thyroiditis in children and adolescents with vitiligo

Background Vitiligo is the most common pigmentation‐related disorder worldwide. An autoimmune etiology is widely considered, and genetic factors may play an important role in its pathogenesis. The purpose of this study was to assess the incidence of thyroid dysfunctions and autoimmune thyroiditis in children with vitiligo and to identify related factors. Methods Fifty children with vitiligo and 50 control children were enrolled. Data on age, onset, duration, disease activity, presence of thyroid disorder, other autoimmune diseases, halo nevi, poliosis, and mucosal vitiligo were determined. Serum free triiodothyronine, free thyroxine, total T3, total T4, thyroid‐stimulating hormone, and antibodies to thyroperoxidase and thyroglobulin were measured. Thyroid gland efficiency was evaluated. Results The mean age at onset of vitiligo was 7.26 ± 4.43 years. The duration of vitiligo was 2.26 ± 2.95 years. Vulgaris‐type vitiligo was the most common form in our patients (56%), and 42% reported at least one family member with thyroid disorder, autoimmune disease, or both. Overt hypothyroidism or hyperthyroidism were not detected. We found a significant association between autoimmune thyroiditis and both sex and disease duration (P = 0.046 and P = 0.07, respectively), but no association between autoimmune thyroiditis and age, age at onset of vitiligo, halo nevi, poliosis, mucosal involvement, disease activity, or family history of vitiligo, autoimmunity, or thyroid disorders. Conclusions Children with vitiligo show an increased incidence of autoimmune thyroiditis. Children with vitiligo, especially girls and subjects with generalized/vulgaris‐type vitiligo, should be screened annually for thyroid function and antithyroid antibodies to assist in the early diagnosis and therapy of autoimmune thyroiditis.     

白癜风与自身免疫性甲状腺疾病

白癜风的病因及发病机制尚未完全阐明,目前多认为自身免疫在白癜风的发病中占重要地位.近年来发现,白癜风常伴发其他自身免疫性疾病,如自身免疫性甲状腺疾病、胰岛素依赖型糖尿病、恶性贫血、Addison病、系统性红斑狼疮、炎性肠病等,其中以自身免疫性甲状腺疾病最多见.从易感基因、甲状腺自身抗体、甲状腺激素水平、CD4+CD25+调节性T细胞、氧化应激等方面就白癜风伴发自身免疫性甲状腺疾病的研究进展进行概述,进一步探讨白癜风与自身免疫性疾病的相关性.     

Th17细胞在非节段型白癜风发病机制中的作用

自身免疫调节异常是非节段型白癜风发病的主要机制,Th17细胞作为新发现的CD4+T辅助性T细胞（Th细胞）亚群,可打破自身免疫耐受,导致自身免疫性黑素细胞破坏,在白癜风发病中起重要作用。本文就Th17细胞在白癜风发病机制中所起作用加以综述。     

白癜风相关致病因素的研究进展

白癜风是获得性色素脱失性皮肤病,其病因较复杂。致病的相关因素可能与遗传因素、自身免疫、应激因素、精神创伤、神经化学因子、黑素细胞自身破坏、角质形成细胞功能异常及微量元素缺乏等有关。为了进一步明确发病原因,力求病因学治疗,本文通过查找文献,收集数据,就白癜风发病的相关因素进行系统的综述,为今后相关研究及治疗奠定基础。     

The genetics of generalized vitiligo and associated autoimmune diseases

Generalized vitiligo is an acquired disorder in which patches of depigmented skin, overlying hair, and oral mucosa result from progressive autoimmune loss of melanocytes from the involved areas. Although vitiligo is perhaps the most common pigmentary disorder, insufficiently clear clinical definition of the disorder and lack of a good laboratory animal model have inhibited progress in understanding its pathobiology, its environmental triggers, and in developing specific and effective therapeutic approaches. Vitiligo results from a complex interaction of environmental, genetic, and immunologic factors, which ultimately contribute to melanocyte destruction, resulting in the characteristic depigmented lesions. In the past few years, studies of the genetic epidemiology of generalized vitiligo have led to the recognition that vitiligo is part of a broader, genetically-determined, autoimmune/autoinflammatory diathesis. Attempts to identify genes involved in vitiligo susceptibility have involved both allelic association studies of candidate genes and genome-wide linkage analyses to discover new genes, and these studies have begun to shed light on the mechanisms of vitiligo pathogenesis. It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel therapeutic and prophylactic targets for future approaches to the treatment and prevention of vitiligo and its associated autoimmune diseases.     

Role of interleukin-17 in the pathogenesis of vitiligo

Background. Skewing of the immune response towards T helper (Th)1 or Th17 and away from regulatory T cells (Tregs) and Th2 cells may be responsible for the development and progression of autoimmune disease. An autoimmune theory has been proposed in the pathogenesis of vitiligo. No previous reports have investigated alterations in IL‐17 produced by Th17 cells in lesional skin in vitiligo. Aim. To investigate the role of IL‐17 in the pathogenesis of vitiligo by assessing its levels in lesional skin and serum of patients with vitiligo compared with controls. Methods. In total, 30 patients with vitiligo and 20 controls matched for age and gender were enrolled in the study. Serum and tissue IL‐17 levels were measured by ELISA and compared between both groups for correlations with age, gender, family history, disease duration, activity of vitiligo and percentage of involved body surface area. Results. A significant difference between patients and healthy controls was found for both serum and tissue IL‐17 levels (P < 0.001 for both). Significant positive correlations were found between disease duration and IL‐17 level in both serum (r = 0.42, P = 0.02) and lesional skin (r = 0.45, P < 0.015); between extent of vitiligo and IL‐17 levels in both serum (r = 0.65, P < 0.001) and skin (r = 0.48, P < 0.05); and between the serum and the tissue IL‐17 levels in patients with vitiligo (r = 0.54, P = 0.002). Conclusions. Multiple factors have been implicated in the pathogenesis of vitiligo. The increased levels of IL‐17 we found in serum and lesional skin suggest an important role for this cytokine in the pathogenesis of vitiligo.     

A Multicenter Collaborative Study by the Korean Society of Vitiligo about Patients' Occupations and the Provoking Factors of Vitiligo

Background

It was previously thought that persons with genetic predispositions to vitiligo develop the condition after exposure to various precipitating environmental factors. However, in many cases, the aggravating factors of vitiligo have not been clearly identified.

Objective

To identify the aggravating factors of vitiligo in the working environment and daily life.

Methods

A total of 489 vitiligo patients were recruited from 10 institutions in South Korea; patients were provided with a questionnaire about environmental factors and behavior patterns in the workplace and in daily life, and their association with vitiligo.

Results

Ninety-five of the 470 enrolled patients (20.2%) answered that environmental risk factors in daily life and in the workplace affected the development of vitiligo. The most frequently attributed causes were trauma and burn (13.6%), followed by sunlight (12.8%), stress (12.8%), cleaning products/disinfectant/chemicals (4.9%), and hair dye (2.1%).

Conclusion

Vitiligo of the hand and foot was associated with frequent exposure to aggravating materials and overexposure to sunlight, along with frequent trauma of these areas, all of which could be considered important risk factors of vitiligo. The development of vitiligo could potentially be controlled through the early detection of aggravating factors.     

Vitiligo: interplay between oxidative stress and immune system

Vitiligo is a multifactorial polygenic disorder with a complex pathogenesis, linked with both genetic and non‐genetic factors. The precise modus operandi for vitiligo pathogenesis has remained elusive. Theories regarding loss of melanocytes are based on autoimmune, cytotoxic, oxidant–antioxidant and neural mechanisms. Reactive oxygen species (ROS) in excess have been documented in active vitiligo skin. Numerous proteins in addition to tyrosinase are affected. It is possible that oxidative stress is one among the main principal causes of vitiligo. However, there also exists ample evidence for altered immunological processes in vitiligo, particularly in chronic and progressive conditions. Both innate and adaptive arms of the immune system appear to be involved as a primary event or as a secondary promotive consequence. There is speculation on the interplay, if any, between ROS and the immune system in the pathogenesis of vitiligo. The article focuses on the scientific evidences linking oxidative stress and immune system to vitiligo pathogenesis giving credence to a convergent terminal pathway of oxidative stress–autoimmunity‐mediated melanocyte loss.     

Commentary from the Editorial Board to Vitiligo: interplay between oxidative stress and immune system (Laddha et al.)

Vitiligo pathogenesis is very puzzling, and novel mechanisms possibly involved in the development of this disorder are frequently explored. Recently, some authors proposed an interplay between oxidative stress and immune system at the basis of melanocyte loss. According to the experimental evidence, they suggest that exposition to environmental agents might lead to an association between vitiligo and other autoimmune diseases. Accordingly, it is proposed that increased reactive oxygen species due to environmental agents could induce a modification of both melanocytic structures and other tissue proteins, or might disregulate the immune system, influencing the appearance of vitiligo and autoimmune comorbidities.     

Autoimmunity as an aetiological factor in vitiligo

Vitiligo is a common dermatological disorder characterized by the presence on the skin of depigmented macules resulting from the destruction of cutaneous melanocytes. Autoimmunity is an important hypothesis with regard to vitiligo aetiology and the evidence for autoimmune responses being involved in the pathogenesis of this disorder will be discussed in the present review. All immune system compartments, including innate and adaptive immunity have been implicated in vitiligo development. Particularly relevant are autoantibodies and autoreactive T cells in vitiligo patients that have cytotoxic effects upon pigment cells. Furthermore, predisposition to vitiligo appears to be associated with certain alleles of the major histocompatibility complex class II antigens as well as with other autoimmune-susceptibility genes. Moreover, the association of vitiligo with autoimmune disorders, the animal models of the disease, and the positive response to immunosuppressive therapeutic agents emphasize the role of autoimmunity in the development of this disorder.     

白癜风并发自身免疫性甲状腺疾病的研究现状

白癜风常并发其他自身免疫性疾病,如自身免疫性甲状腺疾病(autoimmunne thyroid disease,AITD)、类风湿关节炎、1型糖尿病、恶性贫血、系统性红斑狼疮(systemic lupus erthematosus,SLE)、艾迪生病、斑秃等,其中以AITD最多见,包括Graves病、慢性淋巴细胞性甲状腺炎(桥本病)、亚急性甲状腺炎、甲状腺相关性眼病等,但有关白癜风并发AITD确切机制研究甚少。鉴于白癜风是一种多因素、多基因遗传性疾病,发病机制复杂,与遗传和各种非遗传因素相关,多数认为是由基因、环境和免疫系统的相互作用,导致共同的终末通路,即氧化应激-自身免疫介导的黑素细胞缺失,特别是非节段型白癜风(non-segmental vitiligo,NSV)。该文从白癜风的基因、自身免疫和氧化应激3个关联机制上综述、阐述其与AITD的关系。     

Increased interleukin-6 and granulocyte-macrophage colony stimulating factor levels in the sera of patients with non-segmental vitiligo

BACKGROUND: Although the cause of vitiligo is unknown, an autoimmune theory has been proposed, and there is now convincing evidence that cytokines have an important role in pathogenesis of autoimmunity. OBJECTIVE: To study the possible role of interleukin-1, beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenesis of vitiligo. METHODS: The authors measured the serum levels of the above-mentioned cytokines from 50 patients with the vitiligo compared with 20 healthy volunteers, employing the method of radioimmunoassay. RESULTS: The results showed that the serum levels of both IL-6 and GM-CSF of the patients with both focal type and generalized type of vitiligo, and the serum level of IL-1 beta of the generalized type,were significantly, higher than those of normal controls in the patients with segmental vitiligo, the serum levels of all the cytokines tested were not significantly different from those of the normal controls. The GM-CSF levels of both focal type and generalized type, and the IL-6 level of the generalized type in progressive stage were significantly higher than those in stable state. CONCLUSION: It is speculated that IL-6 and GM-CSF may be involved in the autoimmune mechanism of non-segmental vitiligo. However, more evidence is required before a definite conclusion can be drawn.     

Two Cases of Vitiligo Developed on the Persisting Dermal Melanocytosis: Is There a Difference between Epidermal Melanocytes and Dermal Melanocytes?

Vitiligo is one of the most common pigmentary skin disorders; it is characterized by circumscribed depigmented macules due to the destruction of melanocytes. Although the etiology of vitiligo has not been fully elucidated, multiple factors including autoimmune and oxidative stress have been implicated in the pathogenesis of vitiligo. In contrast, dermal melanocytosis is histologically characterized by the presence of dermal melanocytes. It has been described that there are ectopic dermal melanocytes, which have failed to reach their proper location. A literature search revealed very few reports of patients with vitiligo developing vitiligo within dermal melanocytosis. Here, we report two cases of patients with vitiligo that occurred at pre-existing sites of dermal pigmented lesions. The histopathology showed the loss of epidermal melanocytes in spite of the existence of melanocytes in the dermis. There was no significant infiltration of inflammatory cells in the dermis. These cases illustrate unknown environmental factors as well as heterogeneity.     

Role of Histamine as a Toxic Mediator in the Pathogenesis of Vitiligo

Background:

The precise cause of vitiligo is still unclear. Multiple theories have been proposed, including genetic, autoimmune, neural, and biochemical mechanisms. An immune mediated pathogenesis is indeed the most popular theory. The autoimmune hypothesis considers the role of toxic mediator that might cause an injury to the melanocytes with the release of an antigenic substance and subsequent autoimmunization.

Aims:

This study performed over a period of 10 years (February 1975 to June 1985) aims at exploring the role that histamine might play in the pathogenesis of vitiligo.

Materials and Methods:

Fifty patients with a particular type of vitiligo characterized by faint white patches occurring with significant pruritus and a history of atopy were selected and blood histamine levels were determined by Bio-Assay method.

Results:

Blood histamine values of patients with vitiligo of short duration and with pruritus were significantly increased in comparison with values of matched controls.

Conclusion:

Histamine appears to play a significant role in the pathogenesis of a particular type of vitiligo characterized by faint hypopigmented patches with significant itching.     

白癜风细胞免疫学发病机制研究进展

白癜风发病机制主要包括自身免疫、氧化应激、遗传易感、黑素细胞凋亡、角质形成细胞功能异常等。近年研究表明,自身免疫是其发病的关键环节,本文对白癜风细胞免疫发病机制的研究进展进行了综述。     

Vitiligo - Part 1

Vitiligo is a chronic stigmatizing disease, already known for millennia, which mainly affects melanocytes from epidermis basal layer, leading to the development of hypochromic and achromic patches. Its estimated prevalence is 0.5% worldwide. The involvement of genetic factors controlling susceptibility to vitiligo has been studied over the last decades, and results of previous studies present vitiligo as a complex, multifactorial and polygenic disease. In this context, a few genes, including DDR1, XBP1 and NLRP1 have been consistently and functionally associated with the disease. Notwithstanding, environmental factors that precipitate or maintain the disease are yet to be described. The pathogenesis of vitiligo has not been totally clarified until now and many theories have been proposed. Of these, the autoimmune hypothesis is now the most cited and studied among experts. Dysfunction in metabolic pathways, which could lead to production of toxic metabolites causing damage to melanocytes, has also been investigated. Melanocytes adhesion deficit in patients with vitiligo is mainly speculated by the appearance of Köebner phenomenon, recently, new genes and proteins involved in this deficit have been found.     

Association between the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants with vitiligo: study on a Mexican population

BackgroundVitiligo is characterized by an autoimmune response targeting melanocytes, thus resulting in skin depigmentation. There are several genetic components involved in the development of vitiligo, of which various gene polymorphisms are currently considered as risk factors. For example, the CTLA4 (T-lymphocyte antigen 4) +49A/G (rs231775) and CT60 (rs3087243) gene variants have been associated with a predisposition for autoimmune diseases in different populations; however, their involvement in the development of vitiligo remains controversial.ObjectiveWe evaluated the association between vitiligo and the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants in a Mexican population.MethodsA total of 116 vitiligo patients and 117 control subjects from northeast Mexico were included in the study and analyzed through PCR-RFLP to determine whether there is an association between vitiligo and CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants.ResultsNo statistical difference was observed for both gene polymorphisms between vitiligo patients and controls (p > 0.05). Otherwise, vitiligo activity, family history of vitiligo, personal history of autoimmune diseases, or sex did not show any difference (p > 0.05).ConclusionAs suggested by the analysis of a northeastern Mexican population, the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants do not constitute a risk factor in the development of vitiligo.