The haptenation theory of vitiligo and melanoma rejection: a close-up

The 'Haptenation theory' concerns the multicausal pathogenesis of vitiligo ending ultimately in the (partial) disappearance of melanocytes from the skin and/or hairs. The melanocyte specificity is attributed to the tyrosinase-catalysed production of haptogenic ortho-quinones that covalently bind to tyrosinase or other melanosomal proteins to generate neo-antigens. These latter, in turn, trigger an immunological cascade resulting in a melanocyte-specific delayed-type hypersensitivity reaction that eliminates melanocytes and produces the characteristic depigmentation. This causal chain of events is critically discussed with special reference to factors modifying the process and the possible influence of various biochemical changes, such as raised levels of catecholamines and epidermal hydrogen peroxide, which have been reported to be associated with the onset of vitiligo. This all adds up to the typical vitiligo reaction pattern or syndrome, which demands a treatment strategy involving most of the already known therapies. Similar pathogenetic mechanisms might be engaged in the enhancement of cellular immunity (vaccination) against melanoma.     

UVB 311 nm tolerance of vitiligo skin increases with skin photo type

It is assumed that skin is protected against sunburn by melanin. In patients with vitiligo, there are white patches in the normal pigmented skin. We noticed that there is a difference in burning capacity of these white patches between people with different skin types. With UVB 311 nm lamps, we irradiated both lesional and non-lesional skin with increasing doses in 33 patients with vitiligo, divided into 5 groups according to skin type (II-VI). Twenty-four hours later we assessed the minimal erythema dose and found a correlation between skin type and UV sensitivity in both lesional skin and normal skin. We suggest that there must be a protection mechanism, other than that offered by melanin pigmentation. The antioxidant status may play a role in this phenomenon.     

Vitiligo

Vitiligo is an acquired skin disorder caused by the disappearance of pigment cells from the epidermis that gives rise to well defined white patches which are often symmetrically distributed. The lack of melanin pigment makes the lesional skin more sensitive to sunburn. Vitiligo can be cosmetically disfiguring and it is a stigmatizing condition, leading to serious psychologic problems in daily life. It occurs worldwide in about 0.5% of the population and it occurs as frequently in males as it does in females. The cause is unknown, but might involve genetic factors, autoimmunity, neurologic factors, toxic metabolites, and lack of melanocyte growth factors. Since a causative (gene) treatment is not (yet) available, current modalities are directed towards stopping progression and to achieving repigmentation in order to repair the morphology and functional deficiencies of the depigmented skin areas. Many treatments have been used for some time; however; there are some new developments: narrowband ultraviolet (UV) B (311nm) therapy, the combination of corticosteroid cream + UVA therapy, and the transplantation of autologous pigment cells in various modalities. In widespread vitiligo, residual pigment can be removed by depigmentation agents. Sunscreens, camouflage products, and good guidance may help the patient cope better with the disease.     

Repigmentation in vitiligo vulgaris by autologous minigrafting: Results in nineteen patients

Background: Minigrafting is a successful therapy for localized vitiligo but has never been reported for vitiligo vulgaris.Objective. Our purpose was to evaluate the efficacy of minigrafting in vitiligo vulgaris.Methods: In 59 patients with stable vitiligo vulgaris, a minigraft test was done by implanting two minigrafts in the lesion to be grafted. Patients were selected for grafting when spread of pigment was observed within 3 months. The rate of repigmentation was evaluated by digital image analysis.Results: Twenty-three patients (36 lesions), of 24 with a positive minigraft test, were grafted. The results of 19 patients were analyzed, showing 80% to 99% repigmentation in 14 lesions, 50% to 80% repigmentation in 10 lesions, and zero to 50% repigmentation in 12 lesions. Time of observation varied from 3 to 12 months after grafting. Best results were observed after 9 to 12 months. In all patients with a positive Koebner phenomenon depigmentation of the minigrafts developed.Conclusion: Autologous minigrafting is an effective therapy for stable vitiligo vulgaris in a selected group of patients.     

The effect of H 1 and H 2 receptor antagonists on melanogenesis

Background: Histamine was found to stimulate melanogenesis in cultured human melanocytes specifically mediated by histamine H 2 receptors via protein kinase A activation. Based on this finding, the effect of topically applied H 2 antagonist on UVB-irradiated Guinea pigs' skin was examined and found to be suppressive on the post-irradiation melanogenesis. Aims: In this study, we tried to explore the role of topically applied H 1 and H 2 receptor antagonists, in inhibition of UVB-induced melanization. Methods: The effect of topically applied H 1 and H 2 receptor antagonists in inhibition of melanization was done clinically and histochemically using Fontana Masson and DOPA reactions compared with placebo. Results: The post-irradiation pigmentation was found to be brownish/black instead of the original light brown color. This color change occurred below the shaved orange-red fur suggesting a switch of melanogenesis from pheomelanin to eumelanin. The induced pigmentation was suppressed by topically applied H 2 antagonist while both H 1 antagonist and vehicle had no effect. The microscopic examination showed that the keratinocytes in the H 2 antagonist-treated areas contained few melanosomes while the nearby dendrites are full of them. Conclusion: H 2 antagonists' inhibition of UVB-induced pigmentation is not only due to suppression of melanization but also due to a specific action on melanosomes' transfer.     

Gene expression patterns in melanocytic cells: candidate markers for early stage and malignant transformation.

Different stages of differentiation of human melanocytic cells, such as normal melanocytes, naevus and melanoma cells, reflect distinct gene expression patterns. A PCR-based subtractive hybridization and display method was applied to identify genes that are differentially expressed in melanocytic cells in relation to early stage and malignant transformation. This resulted in the identification of a number of candidate cDNAs differentially expressed among melanocytes, naevus cells, and (non)-metastatic melanoma cells. Out of this collection of cDNAs, 16 clones were screened that comprised 12 novel genes, one previously identified expressed sequence tag related to vesicular trafficking (Ras-related protein Rab5b). The other three were also known genes that were either related to cell motility (beta-tubulin), pre-mRNA splicing (small nuclear protein U1A), or of unknown function (the human TI227-H gene). The differential expression patterns of Rab5b and two novel gene fragments (pCMa1, pCMn2) were further assessed in melanocytic cells. pCMa1 was expressed more in metastatic melanoma than in primary melanoma cells. In contrast, pCMn2 was expressed in both non-metastatic and metastatic melanoma cells, but was not detectable in either normal melanocytes or naevus cells. The Ras-related protein Rab5b showed lower levels of expression in highly metastatic than in other melanoma cells. These three cDNAs may therefore be involved in the early stage and malignant transformation of melanocytes.     

Dermal substitutes for full-thickness wounds in a one-stage grafting model

We tested different biodegradable matrix materials as dermal substitutes in a porcine wound model. Matrixes were covered with a split-skin mesh graft and protected with a microporous, semipermeable membrane, which prevents blister formation, wound infection and provides ultimate healing conditions. Evaluation parameters were as follows: epithelization, dermal reconstitution, wound contraction, and cosmetic and functional aspect. A microfibrillar matrix of nondenatured collagen gave the best result, with immediate fibroblast ingrowth and epidermal outgrowth. Slight inflammatory reaction and minimal wound contraction were observed. Application of a split-skin mesh graft, in combination with this collagen matrix, generated a thicker dermal layer than did a split-skin mesh graft directly applied on a wound bed. However, the histologic dermal architecture was less optimal than one obtained with a full-thickness punch graft method. Other matrixes caused inflammatory reactions, interfering with epithelization and dermal reconstitution. We conclude that a nondenatured collagen matrix, in combination with a split-skin mesh graft, can provide a substitute dermis in a full-thickness wound. This combination is preferable to a split-skin mesh graft directly applied on the wound bed. With our microporous semipermeable membrane, the combined use of a dermal substitute and a split-skin mesh graft can be applied in a single-stage operation.