Autoimmune aspects of depigmentation in vitiligo

Autoimmune depigmentation of the skin, vitiligo, afflicts a considerable number of people, yet no effective therapeutic modalities have been developed to treat it. In part, this can be attributed to the obscure etiology of the disease, which has begun to reveal itself only recently. It is known that pigment is lost as a function of reduced melanocyte numbers in the epidermis, and that depigmentation is accompanied by T cell influx to the skin in the vast majority of patients. Characterizing such infiltrating T cells as type 1 proinflammatory cytokine-secreting cells reactive with melanocyte-specific antigen is a major step toward effective therapy. Melanoma research has shown that differentiation antigens, also expressed by normal melanocytes, can be immunogenic when expressed in the melanosomal compartment of the cell. Similar reactivity to melanosomal antigens is apparent for T cells infiltrating vitiligo skin. It may eventually be possible to treat patients with decoy antigens that anergize such Tcells, or to prevent recruitment of the T cells to the skin altogether. In this respect, it is important that T cells are recruited to the skin as a function of dendritic cell activation and that dendritic cells are likely activated at sites of epidermal trauma as a consequence of stress proteins that spill over into the microenvironment. Stress proteins chaperoning antigens representative of the cells from which they were derived are then processed by dendritic cells and contribute to their activation. Activated dendritic cells not only migrate to draining lymph nodes to recruit T cells but may execute cytotoxic effector functions as well. The contribution of the effector functions to actual depigmentation of the skin remains to be investigated.     

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.     

Engineering a new mouse model for vitiligo

Although the precise mechanisms that trigger vitiligo remain elusive, autoimmune responses mediate its progression. The development of therapies has been impeded by a paucity of animal models, since mice lack interfollicular melanocytes, the primary targets in vitiligo. In this issue, Harris et al. describe a mouse model in which interfollicular melanocytes are retained by Kit ligand overexpression and an immune response is initiated by transplanting melanocyte-targeting CD8+ T cells.     

A mouse model for vitiligo

As the result of a long search for a depigmenting mouse that could serve as a model for the study of vitiligo, we have located a strain that arose from the C57BL/6J. Its provisional genetic designation is C57BL/6J Ler-vit/vit. This vitiligo mouse has congenital dorsal and ventral white spots (piebaldism) as well as progressive replacement of pigmented hairs by white hairs with each spontaneous molt or after plucking. The lack of pigment is due to the absence of melanocytes from the amelanotic hair follicles and epidermis. As in human beings and the Smyth chicken model, there is also diminution of ocular pigment. Reciprocal skin transplants between C57BL/6J and vitiligo mice, and transplants into nude mice, suggest a programmed pigment cell death in the vitiligo mice. Like human beings with vitiligo, maximally depigmented vitiligo mice have a decreased contact sensitivity response in comparison to age-matched C57BL/6J controls. The resistance to injected B16 melanomas is lowered. Vitiligo mice show no signs of premature aging. Already at this early stage in the study of this new animal model, there are findings that open a range of new approaches to the study and treatment of patients with vitiligo and melanomas.     

Molecular and cellular basis of depigmentation in vitiligo patients

Vitiligo is a chronic skin disease characterized by the appearance of zones of depigmentation. It is mostly described as an autoimmune disease in which the immune system destroys the melanocytes. Consistent with this origin, genetic studies have implicated genes encoding proteins mediating the immune response targeting melanocytes in the aetiology of this disease, together with proteins specific to these cells. However, the destruction of melanocytes by the immune system is neither global nor complete, because the patients do not display total depigmentation. The etiopathology of vitiligo is clearly complex and cannot be simply reduced to an autoimmune reaction directed against pigmented cells. Intrinsic changes have been observed in the melanocytes, keratinocytes and dermal cells of vitiligo patients. Identification of the molecular and cellular changes occurring in normally pigmented skin in vitiligo patients, and an understanding of these changes, is essential to improve the definition of trigger events for this disease, with a view to developing treatments with long‐term efficacy. This review focuses on the early events identified to date in the non‐lesional regions of the skin in vitiligo patients and discusses the process of repigmentation from melanocyte stem cells.     

Inflammatory changes in vitiligo: stage I and II depigmentation

Frequent failure of early studies to demonstrate inflammatory changes in vitiligo led many investigators to consider the disease as noninflammatory. However, others found an inflammatory element in vitiliginous lesions. In this study we tried to verify that assumption. Twenty-five patients (10 males and 15 females) with common vitiligo and 11 normal healthy individuals were included. Histopathologic studies were carried out using epon-embedded sections stained with modified toluidine blue stain. Comparisons of the results of histopathologic examination of the stained specimens of vitiliginous lesions (both stage I and II), marginal areas, and uninvolved normal skin of vitiligo patients with normal healthy control were performed. Focal spongiosis was observed in 48% of the specimens of vitiligo patients and largely limited to the marginal areas and stage I vitiligo lesions. Epidermal mononuclear cell infiltration was seen in 80% of both the marginal areas and stage I vitiligo specimens. The number of these cells was significantly higher than that in stage II lesions and uninvolved skin. Many of the epidermotropic lymphocytes were grouped together, forming clusters resembling Pautrier microabscesses. The extent of epidermal mononuclear cell invasion did not always parallel the density of the subjacent dermal infiltrate. Vitiligo is an inflammatory disease, and the epidermal lymphocytic infiltration is most likely the primary immunologic event.     

虹膜脱色素为首发的白癜风一例

患儿女,6个月龄,因左眼周白斑伴睫毛变白3个月余来我院就诊。患儿家属3个月前发现患儿左眼睑白斑,未予重视,后白斑渐扩大至左眼鼻侧眼周,伴睫毛变白。患儿出生时双眼虹膜颜色一致,出生后10 d患结膜炎,愈后开始出现虹膜颜色渐变淡。患儿的父母及其三代亲属无相关疾病史。体检：全身各系统检查同一般正常同龄儿……     

A central role for inducible heat‐shock protein 70 in autoimmune vitiligo

Inducible heat‐shock protein 70 (HSP70i) is a protein regulated by stress that protects cells from undergoing apoptosis. Such proteins are marvellously well conserved throughout evolution, which has placed them in the spotlight for helping to understand the intriguing relationship between infection and immunity. In the presence of stress proteins, dendritic cells (DCs) will sense this alarm signal and respond by recruiting immune cells of different plumage to fit the occasion. In times of stress, melanocytes will secrete antigen‐bound HSP70i to act as an alarm signal in activating DCs that comes equipped with an address of origin to drive the autoimmune response in vitiligo. Here we pose that if the autoimmune response is funnelled through HSP70i, then blocking the stress protein from activating DCs can lend new treatment opportunities for vitiligo.     

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.     

Alopecia areata and universalis in the Smyth chicken model for spontaneous autoimmune vitiligo

The Smyth line (SL) chicken model for spontaneous, postnatal expression of vitiligo may also show varying incidences and degrees of severity ranging from alopecia areata-like to universalis-like integumental changes. Although human vitiligo patients are known to have a four times greater chance of having alopecia areata than do people without vitiligo, in the SL model, feather loss is limited to birds that show some degree of amelanosis of feather and skin tissue. Both the vitiligo and the alopecia have an autoimmune component, as shown by histologic and immunologic studies, including the correctional influences of corticosterone and cyclosporine-A. The major histocompatibility haplotype (MHC) has a major effect on the incidence and expression of the vitiligo, as well as the alopecia that occurs within vitiliginous birds. Three different MHC haplotypes were identified in the original line that was selected for vitiligo, and from these, three sublines were developed, each homozygous for a different haplotype. Of the three sublines (SL101, SL102, and SL103) the vitiligo has a significantly earlier onset and severity in the SL101 than in the other two lines. The incidence of alopecia, however, is significantly lower in the SL101 subline than in the other two. Inheritance of the vitiligo is polygenic with an additional genetic component for the alopecia trait. It is hypothesized, but as yet unproven, that a feather development defect interacts with the SL melanization and immunologic defects to initiate the partial (areata) and complete (universalis) alopecias. The alopecia universalis is rarely seen until adulthood and is characterized by short (<0.5 cm), undeveloped feathers. If feather growth resumes in these birds, the feathers dry up, cease to grow, and often break off.     

IgA autoimmune disorders: development of a passive transfer mouse model

IgA is present in the skin in several dermatoses, including dermatitis herpetiformis, linear IgA bullous dermatosis, and Henoch-Schoenlein purpura. The neutrophilic infiltration in the area of the IgA deposition suggests that IgA is responsible for the associated inflammatory events. The mechanism for this process is unproven, but is likely to involve IgA-mediated neutrophil chemotaxis with inhibition of chemotaxis by dapsone. Elucidation of the mechanism of IgA-mediated inflammation will require an animal model. We have established a model for linear IgA bullous dermatosis as a prototype disease to be studied. IgA mouse monoclonal antibodies against a linear IgA bullous dermatosis antigen have been passively transferred to SCID mice with human skin grafts. This has produced neutrophil infiltration and basement membrane vesiculation in 4 of 12 mice tested. We conclude that an animal model for the pathogenesis of IgA dermatoses with IgA deposition and inflammation can be produced by passive transfer of mouse IgA antibodies against a linear IgA antigen.     

白癜风样小鼠皮肤脱色模型研究进展与思考

【摘要】 白癜风的病因及发病机制均未明确,动物模型是白癜风研究的重要工具。除传统的白癜风小鼠模型外,许多新模型逐渐建立,如表达表皮黑素细胞、黑素细胞反应性T细胞的小鼠模型、K14-SCF/h3TA2/HLA-A2三转基因（Vitesse鼠）小鼠模型、自身免疫诱导的小鼠模型、化学试剂诱导的小鼠模型等,这些模型与人白癜风高度相似,在可重复性和稳定性等方面都有不同程度提高,已成为研究白癜风发病机制、探索治疗靶点和评判疗效的良好模型。本文综述目前白癜风样小鼠脱色模型的研究进展,并分析存在的问题。