Presence or Absence of Melanocytes in Vitiligo Lesions: An Immunohistochemical Investigation

Poole, I. Caroline Le; Wijngaard, R.M.J.G.J. van den; Westerhof, W.; Dutrieux, Richard P.; Das, Pranab K.

doi:10.1111/1523-1747.ep12476645

Cited by 191 publications

(134 citation statements)

References 31 publications

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“…It appears to be highly unlikely that melanocytes are responsible for the observed increase, as the highest tenascin content is observed in lesional skin, where melanocytes are absent. 1 Moreover, using melanocytes cultured from several donors, no tenascin production was observed by Western blotting, ELISA assays or immunohistology (results not shown). This is in accordance with observations reported by Herlyn et al concerning a lack of tenascin production by melanocytes.…”

Section: Discussionmentioning

confidence: 96%

“…1 It has been suggested that defective adhesion is involved in loss of melanocytes in this pigmentary disorder. 2 Moreover, the persistence of depigmented lesions is suggestive of defective melanocyte migration which may be reversed by photochemotherapy, 2 and therefore baseline expression of adhesion molecules may differ in vitiligo as compared with control skin.…”

mentioning

confidence: 99%

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Tenascin is overexpressed in vitiligo lesional skin and inhibits melanocyte adhesion

Poole

Wijngaard

Westerhof³

et al. 1997

British Journal of Dermatology

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SummaryThe aetiology of vitiligo remains obscure. In this study, the role of integrins in the observed inability of melanocytes to repopulate lesional skin was investigated. Antibodies directed to a 2 , a 3 , a 5 , a v , a 6 , b 1 and b 3 integrin subunits were used. Immunohistology revealed no marked differences in the overall levels of expression of integrins between control, non-lesional, perilesional or lesional skin. Moreover, no differences were noted in the level of expression of integrins or the adhesive capacity between cultured control cells derived from three separate donors and vitiligo-derived melanocytes from two donors. Rather, it was clearly observed that towards the lesion, vitiligo skin contains increasing amounts of tenascin in the basal membrane and papillary dermis in five patients employing T2H5 antihuman tenascin antibody. The anti-adhesive effect observed in vitro for this extracellular matrix molecule using normal melanocytes may contribute to loss of pigment cells in vitiligo or to ineffective repopulation of the lesions.In vitiligo, melanocytes are gradually lost in depigmenting lesions of the skin. 1 It has been suggested that defective adhesion is involved in loss of melanocytes in this pigmentary disorder. 2 Moreover, the persistence of depigmented lesions is suggestive of defective melanocyte migration which may be reversed by photochemotherapy, 2 and therefore baseline expression of adhesion molecules may differ in vitiligo as compared with control skin. Melanocyte adhesion, spreading and migration is mediated by integrins. 3 Employing antibodies to integrin subunits, the specific integrins involved in each process have been identified in vitro. 3,4 Importantly, all integrins thus far identified on melanocytes can also be found on neighbouring keratinocytes. Although immunohistology has been employed to identify integrins expressed on melanocytes in situ per se, 3 this may not be the method of choice to determine differences in the level of expression by melanocytes. Even by double immunostaining procedures, it is difficult to distinguish between integrin expression by melanocytes vs. neighbouring keratinocytes. Therefore, in vitro cultures derived from control as well as from vitiligo non-lesional skin were employed to investigate further potential differences in adhesive behaviour in vitiligo and control skin. In addition, the use of cultured cells provides the opportunity to perform functional adhesion assays. In this respect it is of great interest to note that cultured melanocytes from nonlesional vitiligo skin appear to retain disease-related characteristics. It has been demonstrated that vitiligo melanocytes have altered growth characteristics under limiting conditions. 5 Moreover, upon electron microscopic observation, dilated rough endoplasmic reticulum (RER) is apparent in diseased cells from human and mouse vitiligo subjects. 6,7 Therefore, the use of cultured cells to investigate differences in adhesive characteristics is justified.The level of expression of relevant i...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Tenascin is overexpressed in vitiligo lesional skin and inhibits melanocyte adhesion

Poole

Wijngaard

Westerhof³

et al. 1997

British Journal of Dermatology

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“…As poorly functioning melanocytes have been isolated from lesional vitiligo skin and cultured in vitro, [48][49][50][51] the deterioration of melanocyte function may be an early and crucial event in vitiligo. We found that miR-25 downregulated the expression of TYR, TYRP1 and TYRP2, as well as tyrosinase activity in melanocytes, thus impairing melanin synthesis.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress-induced overexpression of miR-25: the mechanism underlying the degeneration of melanocytes in vitiligo

et al. 2015

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Oxidative stress has a critical role in the pathogenesis of vitiligo. However, the specific molecular mechanism involved in oxidative stress-induced melanocyte death is not well characterized. Given the powerful role of microRNAs (miRNAs) in the regulation of cell survival as well as the fact that the generation of miRNAs can be affected by oxidative stress, we hypothesized that miRNAs may participate in vitiligo pathogenesis by modulating the expression of vital genes in melanocytes. In the present study, we initially found that miR-25 was increased in both serum and lesion samples from vitiligo patients, and its serum level was correlated with the activity of vitiligo. Moreover, restoration of miR-25 promoted the H 2 O 2 -induced melanocyte destruction and led to the dysfunction of melanocytes. Further experiments proved that MITF, a master regulator in melanocyte survival and function, accounted for the miR-25-caused damaging impact on melanocytes. Notably, other than the direct role on melanocytes, we observed that miR-25 inhibited the production and secretion of SCF and bFGF from keratinocytes, thus impairing their paracrine protective effect on the survival of melanocytes under oxidative stress. At last, we verified that oxidative stress could induce the overexpression of miR-25 in both melanocytes and keratinocytes possibly by demethylating the promoter region of miR-25. Taken together, our study demonstrates that oxidative stress-induced overexpression of miR-25 in vitiligo has a crucial role in promoting the degeneration of melanocytes by not only suppressing MITF in melanocytes but also impairing the paracrine protective effect of keratinocytes. Therefore, it is worthy to investigate the possibility of miR-25 as a potential drug target for anti-oxidative therapy in vitiligo. Vitiligo is a disfiguring dermatosis with an incidence rate of approximately 0.5-1.0% in the populations worldwide. 1 Characterized by patchy depigmentation of the skin, the disease can affect the patients' self-image, or even cause depression, thus substantially decreasing life quality among vitiligo patients. 2 Although several etiological theories, including genetic predisposition, 3-5 autoimmunity, 6,7 melanocytorrhagy 8,9 and toxic metabolites 10 have been proposed to participate in the pathogenesis of vitiligo, the exact mechanism of melanocyte degeneration in depigmented lesions still remains unclear.The generation of oxidative stress has long been demonstrated to have a crucial role in the onset and progression of vitiligo. 11,12 Owing to the pro-oxidant state generated during melanin synthesis, melanocytes are particularly vulnerable to oxidative stress. 13 In vitiligo, accumulation of toxic intermediates such as 6-and 7-BH4 and catecholamine, 14,15 concomitant with reduced levels and activity of catalase and several other antioxidant enzymes [16][17][18] have been demonstrated in patients' epidermis. Because of these intracellular metabolic disorder and compromised intrinsic antioxidant defenses, hydrogen peroxide (H 2 O ...

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“…Vitiligo is defined as a skin disorder characterized by progressive loss of pigmentation [1]. The age of onset is most frequently found in the 2nd decade of life, coinciding with major hormonal changes, yet a subset of patients acquires vitiligo much later in life [2].…”

Section: The History Of Autoimmune Vitiligomentioning

confidence: 99%

“…The distribution of lesions appears to vary accordingly [3]. It is thought that as much as 1% of the world population is afflicted by vitiligo [1]. Convincing epidemiologic studies to assess the distribution of vitiligo among ethnic groups are lacking and although there is currently no evidence for a bias towards a particular skin type, the appearance of milky-white skin lesions is particularly devastating against a background of darkly pigmented skin [4].…”

Section: The History Of Autoimmune Vitiligomentioning

confidence: 99%

Therapeutic implications of autoimmune vitiligo T cells

Oyarbide-Valencia¹,

Boorn²,

Denman³

et al. 2006

Autoimmunity Reviews

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Vitiligo is an autoimmune disease presenting with progressive loss of skin pigmentation. The disease strikes 1% of the world population, generally during teenage years. The progressive loss of melanocytes from depigmenting vitiligo skin is accompanied by cellular infiltrates containing both CD4+ and CD8+ T lymphocytes. Infiltrating cytotoxic T cells with high affinity T cell receptors have likely escaped clonal deletion in the thymus, allowing such T cells to enter the circulation. Through the expression of CLA, these T cells home to the skin where they express type 1-cytokine profiles and mediate melanocyte apoptosis via the granzyme/perforin pathway. T cells found juxtapositionally apposed to remaining melanocytes can be isolated from the skin. Vitiligo T cells have demonstrated reactivity to antigens previously recognized as target antigens for T cells infiltrating melanoma tumors. In a comparison to existing melanoma-derived T cells, vitiligo T cells displayed superior reactivity towards melanoma cells. It is thought that genes encoding the TCRs expressed by vitiligo skin infiltrating T cells can be cloned and expressed in melanoma T cells, thereby generating a pool of circulating T cells with high affinity for their targets that can redirect the immune response towards the tumor.

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Presence or Absence of Melanocytes in Vitiligo Lesions: An Immunohistochemical Investigation

Cited by 191 publications

References 31 publications

Tenascin is overexpressed in vitiligo lesional skin and inhibits melanocyte adhesion

Tenascin is overexpressed in vitiligo lesional skin and inhibits melanocyte adhesion

Oxidative stress-induced overexpression of miR-25: the mechanism underlying the degeneration of melanocytes in vitiligo

Therapeutic implications of autoimmune vitiligo T cells

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