HSP70i accelerates depigmentation in a mouse model of autoimmune vitiligo

Vitiligo is a T-cell-mediated autoimmune disease of the skin. Progressive depigmentation accelerates in response to stress. Personal trauma, contact with bleaching phenols, overexposure to UV, and mechanical injury can lead to progressive loss of melanocytes. This study was focused on the role of stress protein heat shock protein (HSP)70 for translating stress into an autoimmune disease to melanocytes. Intracellular HSP70 can act as a cytoprotectant, preventing apoptosis in cells under stress. Isoform HSP70i can be secreted by live cells, and in prior in vitro studies, HSP70 has been shown to activate dendritic cells and elicit an immune response to chaperoned proteins and peptides. Here, the role of HSP70 in precipitating and perpetuating vitiligo was assessed in vivo in a mouse model of autoimmune vitiligo. In this model, depigmentation was introduced by gene gun vaccination with eukaryotic expression plasmids encoding melanocyte differentiation antigens. Inclusion of human and mouse-derived inducible HSP70 in the vaccination protocol significantly increased and accelerated depigmentation in this model, accompanied by the induction of prolonged humoral responses to HSP70. Cytotoxicity toward targets loaded with a K(b)-restricted tyrosinase-related protein 2-derived peptide correlated with depigmentation. The data presented strongly support a role for HSP70i in progressive depigmentation in vivo.     

Bases inmunológicas de la hipopigmentación vitiligoide asociada a melanoma

Vitiligo is a skin condition characterized by white, hypopigmented macules. Melanocyte loss is a feature of the disease, and it has been hypothesized that an autoimmune mechanism could be responsible for the depigmentation. Melanoma is a malignancy that develops in melanocytes; if not detected and treated early, it is often deadly. Leukoderma, a condition characterized by depigmentation of the skin, is sometimes associated with malignant melanoma. An immune response against melanocyte antigens leading to destruction of either melanoma cells or melanocytes has been observed in both vitiligo and melanoma. Studies in animal models and humans have shown that humoral and cell-mediated immune responses are involved in modulating cytotoxic activity against tumor cells and normal melanocytes. The study of factors associated with anti-tumor immunopathogenic mechanisms —autoimmunity for example— may provide us with tools for the diagnosis and treatment of diseases such as vitiligo and malignant melanoma.     

Enhanced bleaching treatment: opportunities for immune‐assisted melanocyte suicide in vitiligo

Depigmentation in vitiligo occurs by progressive loss of melanocytes from the basal layer of the skin, and can be psychologically devastating to patients. T cell‐mediated autoimmunity explains the progressive nature of this disease. Rather than being confronted with periods of rapid depigmentation and bouts of repigmentation, patients with long‐standing, treatment‐resistant vitiligo can undergo depigmentation treatment. The objective is to remove residual pigmentation to achieve a cosmetically acceptable result – that of skin with a uniform appearance. In the United States, only the use of mono‐benzyl ether of hydroquinone (MBEH) is approved for this purpose. However, satisfactory results can take time to appear, and there is a risk of repigmentation. MBEH induces necrotic melanocyte death followed by a cytotoxic T‐cell response to remaining, distant melanocytes. As cytotoxic T‐cell responses are instrumental to depigmentation, we propose that combining MBEH with immune adjuvant therapies will accelerate immune‐mediated melanocyte destruction to achieve faster, more definitive depigmentation than with MBEH alone. As Toll‐like Receptor (TLR) agonists – imiquimod, CpG, and Heat Shock Protein 70 (HSP 70) – all support powerful Th1 responses, we propose that using MBEH in combination with these agents can achieve superior depigmentation results for vitiligo patients.     

Generalized vitiligo after lymphocyte infusion for relapsed leukaemia

Vitiligo is an autoimmune disease caused by T-lymphocyte-mediated destruction of melanocytes. We describe two patients with generalized vitiligo caused iatrogenically after donor lymphocyte infusion (DLI) for leukaemia relapse over 3 years after bone marrow transplantation (BMT). Neither the sibling donor nor the recipient had vitiligo or other autoimmune diseases, and vitiligo did not occur after the first BMT. DLI was accompanied by skin graft-versus-host disease in both cases, which was controlled with immunosuppression. However, over several months, progressive generalized and persistent skin depigmentation occurred in both patients. Peripheral blood molecular studies showed the complete disappearance of host haematolymphopoiesis. The specific destruction of melanocytes in both patients was therefore probably mediated by new alloreactive lymphocytes infused from the donors.     

Delayed-amelanotic (DAM or Smyth) chicken: melanocyte dysfunction in vivo and in vitro

Chickens of the autoimmune delayed-amelanotic (DAM or Smyth) line develop postnatal feather amelanosis and severe visual defects, both of which are presumed to be due to a dysfunction of melanocytes and a subsequent autoimmune response that eliminates pigment cells. In this report we elucidate further the melanocytic defect. We present a morphologic analysis of the mildly affected erratic (eDAM) group of Smyth chicken whose partial depigmentation and lack of visual impairment resemble human vitiligo more so than do the complete amelanosis and blindness in the classical Smyth line. Histologically, the sequential events leading to amelanosis in the young Smyth chicken occur simultaneously in the feathers of adult eDAM Smyth chickens, and the infiltration of the feather pulp with mononuclear leukocytes correlates with the extent of local pigmentary abnormality. Cytochemical localizations of dopa-oxidase and acid-phosphatase activities in eDAM feather melanocytes suggest that melanogenesis and autophagocytosis of melanosomes occur in tandem and that the rates of both are higher in these cells than in melanocytes of normally pigmented control chickens. Assays for tyrosinase activity in feather follicles indicate a hypermelanization in eDAM feathers and in the pigmented feathers of young Smyth chicks prior to the onset of depigmentation. Finally, we report on the establishment of pure, proliferative cultures of neural crest-derived melanocytes from control and Smyth chicken embryos. The degenerative events in Smyth chicken melanocyte cultures mimic in part those of the cells in vivo and are therefore indicative of a genetic defect that is independent of the immune system.     

Retinoic acid synergistically enhances the melanocytotoxic and depigmenting effects of monobenzylether of hydroquinone in black guinea pig skin

Monobenzylether of hydroquinone (MBEH) has long been utilized for the depigmentation therapy of patients with extensive vitiligo. In this approach, the normally pigmented areas surrounding vitiligo lesions are depigmented to achieve a uniform skin tone. One of the important disadvantages of MBEH therapy, however, is the resistance of a considerable number of vitiligo patients against the depigmenting effect of this agent. We have previously proposed that the glutathione-dependent cytoprotection of melanocytes can be impaired through the inhibition of the enzyme glutathione S-transferase by retinoic acid (RA). The combination of RA with melanocytotoxic agents could thus lead to increased susceptibility of melanocytes to such compounds. In this study we have shown, for the first time, that the melanocytotoxic and depigmenting effects of MBEH are synergistically enhanced when it is combined with RA. The treatment of black guinea pig skin with RA (0.025%) alone induced no significant changes in the number of epidermal melanocytes and no skin depigmentation. On the other hand, MBEH (10%) produced mild to moderate skin depigmentation and reduced the average number of melanocytes from 76 (+/-5)/field (magnification: x 40) in control sites, to 42 (+/-6)/field in the depigmented skin. The RA (0.025%)-MBEH (10%) combination, however, produced a complete degree of depigmentation in the majority of treated sites after 10 days of application and reduced the average number of melanocytes to only 6 (+/-6)/field. RA-MBEH combination serves as a very potent skin depigmenting formula and now awaits future assessments of its potential use for the treatment of extensive vitiligo.     

中药治疗白癜风作用机制的研究进展

白癜风(vitiligo)是一种常见的后天性皮肤色素脱失性疾病。该病的病因和发病机制尚不清楚。目前大多数学者认为该病发生是具有遗传因素的个体在多种内外因素的作用下,出现免疫功能、神经精神及内分泌、代谢等多方面的功能紊乱,导致酪氨酸酶系统的抑制或黑素细胞的破坏,最终使皮肤色素脱失。目前发病原因主要有4个学说,即自身免疫学说、黑素细胞自毁学说、神经化学因子学说、遗传学说等。中药治疗白癜风在辨证论治的基础上取得了较好的疗效,但作用机制尚不明确。该文主要从自身免疫学说、黑素细胞自毁学说、神经化学因子学说综述中药治疗白癜风的客观依据。     

Laser treatment for further depigmentation in vitiligo

Background In patients with vitiligo, sometimes the greatest part of the skin has already lost its melanocytes. The remaining pigmented patches can be removed by using strong bleaching creams, but many adverse events have been reported with this treatment. Anew depigmentation therapy could be treatment with a Ruby laser. Methods Before treatment, the patients filled out a questionnaire about their vitiligo history. Eight patients with remaining pigmentation of the arms, hands, and face were treated once with a Ruby laser. Patients were monitored for developing repigmentation during the 9 months after treatment. Results In patients with a positive Koebner phenomenon, a permanent state of depigmentation was reached after laser therapy. None of the treated patients showed severe side-effects. Conclusions Ruby laser treatment can be an effective, fast, and safe method for removing cosmetically disturbing remnants of normal pigmentation in vitiligo patients with a positive Koebner phenomenon.     

Vitiligo and pernicious anemia presenting as congestive heart failure

The skin often provides diagnostic clues to systemic disorders. Vitiligo is an acquired disease characterized by depigmentation of the skin due to destruction of melanocytes. Vitiligo may be an autoimmune disease and is associated with other disorders that may also arise due to autoimmune mechanisms. We present the unusual case of vitiligo associated with pernicious anemia in a patient who presented to the hospital because of hyperdynamic congestive heart failure.     

Melanocyte detachment after skin friction in non lesional skin of patients with generalized vitiligo

BACKGROUND: In vitiligo, melanocytes are gradually lost in depigmented macules of the skin. The disappearance of melanocytes has, however, not been clearly observed and consequently the aetiology of the disease (autoimmune, neural, cytotoxic) is still elusive. The starting point of vitiligo macules is frequently determined by local conditions such as wounds and excoriations, but may also follow minor traumas such as pressure or repeated friction. This prominent feature is often neglected. OBJECTIVES: To clarify the biological consequences of repeated friction on the attachment and survival of melanocytes in non lesional vitiligo skin. METHODS: Light reproducible skin friction was performed for 4 min on the volar forearm of 18 patients with extensive vitiligo and five controls with normal healthy skin. Biopsies from the test area and control skin were taken at 1, 4, 24 and 48 h following friction. Serial sections were examined with standard light microscopy, transmission electron microscopy, histochemistry and immunohistochemistry (dihydroxyphenylalanine, HMB-45, E-cadherin and an early apoptosis marker, M30 cytoDEATH antibody). RESULTS: The observation of sections at 1 and 48 h after friction on vitiligo skin and at all time points in controls revealed no changes. In contrast, in vitiligo skin at 4 and 24 h after friction, several melanocytes had undergone detachment and were found in various suprabasal positions, including the stratum spinosum, granular layer, and within and outside the stratum corneum. CONCLUSIONS: Detachment and transepidermal elimination of melanocytes following minor mechanical trauma in non lesional vitiligo skin is probably the cause of depigmentation occurring in the isomorphic response (Koebner phenomenon). We propose that transepidermal elimination of melanocytes in vitiligo should be regarded as a possible mechanism of chronic loss of pigment cells, perhaps previously damaged by another process.     

白癜风与自身免疫性甲状腺疾病的研究进展

临床流行病学研究发现,白癜风常伴发一些自身免疫性疾病,特别是自身免疫性甲状腺疾病.关于白癜风伴发自身免疫性甲状腺疾病已有许多的病例报道.相对于健康人群,白癜风患者中甲状腺相关抗体水平升高,伴发自身免疫性甲状腺疾病的白癜风患者往往患病年限长,皮损范围较大.白癜风患者体内Th17/Treg失衡,黑素细胞表达的相关蛋白被看作自身抗原,这些抗原有部分也表达于甲状腺组织,这是白癜风伴发自身免疫性甲状腺疾病的免疫基础.白癜风的易感基因位点有些与自身免疫疾病相关,这些位点是白癜风伴发自身免疫性甲状腺疾病的遗传因素.目前发现,-428T FoxD3变异与白癜风发生有密切关系,与抗TPO抗体及抗甲状腺球蛋白抗体升高相关.     

Experimental approaches to assess melanocytes mosaicism in segmental vitiligo

Vitiligo is an autoimmune disease of the skin that results in localized or disseminated white macules. One common feature of several existing classification protocols is the distribution of the disease into two main subtypes, non-segmental vitiligo (NSV) and segmental vitiligo (SV). SV is characterized by depigmentation spreading within one or more skin segments while NSV is widespread. Several clinical-epidemiological observations suggest that SV has distinct autoimmune pathophysiology compared to NSV. Furthermore, the clinical distribution pattern of SV lesions closely resembles other melanocyte mosaicism diseases. These observations led us to hypothesize that SV is caused by a localized autoimmune reaction targeting epidermal mosaicism melanocytes. Here, we proposed examples of experimental approaches to assess mosaicism in SV patients.     

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.     

白癜风与黑素瘤关系的研究进展

白癜风是以皮肤黑素细胞破坏导致的获得性色素脱失性疾病;黑素瘤是皮肤、黏膜黑素细胞异常增生导致的一种恶性肿瘤。近年来研究发现黑素瘤患者的白癜风发生率远远高出正常人群,这一现象的发生可能是机体抗黑素瘤的细胞及体液免疫应答作用于正常黑素细胞的结果。     

A mouse model of vitiligo induced by monobenzone

The paucity of vitiligo animal models limits the understanding of vitiligo pathogenesis and the development of therapies for the skin disorder. In this study, we developed a new mouse model of vitiligo by topically applying the skin‐depigmenting agent monobenzone on mice. We demonstrated that monobenzone‐induced skin depigmentation on the non‐exposed sites and that the severity of lesions depended on drug dosage. The result of the histological examination of the depigmented skin indicated loss of epidermal melanocytes and perilesional accumulation of CD8⁺ T cells. Furthermore, the monobenzone‐induced depigmentation of the Rag1 gene knockout did not appear on the non‐exposed sites, supporting the involvement of infiltrating CD8⁺ T cells in melanocyte destruction. Resemblance in histological characteristics and pathogenesis between monobenzone‐induced depigmentation and active human vitiligo suggests good potential of our mouse model for use in vitiligo research.     

Childhood vitiligo

Vitiligo is a depigmentation disorder resulting from autoimmune destruction of cutaneous melanocytes. The psychosocial ramifications of this often disfiguring disease can be substantial. Half of the patients with vitiligo experience disease onset in childhood. Although largely similar to the disease in adults, pediatric vitiligo does have differences in epidemiology, associations, and treatment. We review vitiligo as it relates to the pediatric population, emphasizing key differences with adults and the latest treatment advances.     

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.     

The color of skin: white diseases of the skin,nails, and mucosa

White diseases are a heterogenous group characterized by hypopigmentation or depigmentation. Skin and eye color are determined by the number and size of melanosomes present. Melanin is produced by melanosomes in the melanocytes present within the epidermis of the skin, uvea, and retinal pigmented epithelium (RPE). Conditions altering the number of melanocytes or concentration of melanin result in a lack of pigmentation, appearing as “white diseases” ranging from the well-known albinism and vitiligo to more esoteric white hand syndrome and Degos disease.     

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.