Melanocyte‐Specific Immune Response in Melanoma and Vitiligo: Two Faces of the Same Coin?

Wańkowicz-Kalińska, Anna; Poole, Caroline Le; Wijngaard, Renè van den; Storkus, Walter J.; Das, Pranab K.

doi:10.1034/j.1600-0749.2003.00038.x

Cited by 58 publications

(38 citation statements)

References 66 publications

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“…Moreover, keratinocytes produce and release high amounts of proinflammatory cytokines including TNF-α, which promotes the expression of adhesion molecules on the melanocyte membrane (intercellular adhesion molecule 1), leading to further lymphocyte recruitment. By contrast, TNF-α directly interferes with some mitochondrial activities through the production of peroxides, leading to a mitochondrial-dependent cell death as well as activation of inflammatory genes through the nuclear translocation of nuclear factor κB (Moretti et al, 2002;Wankowicz-Kalinska et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study has shown that the anti-TNF-α agent etanercept can stop vitiligo progression and induce repigmentation in some cases (Kim et al, 2011). In vitro direct analyses of skin T cells from the margins of vitiliginous skin have shown that polarized type-1 T cells (CD4+ and CD8+), which secrete predominantly TNF-a and interferon-g, are associated with the destruction of melanocytes during active vitiligo (Huang et al, 2002;Wankowicz-Kalinska et al, 2003). In addition to causing apoptosis of melanocytes, TNF-α also inhibits melanocytogenesis through an inhibitory effect on tyrosinase and tyrosinase-related protein (Martínez-Esparza et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with vitiligo

Al-Harthi

Zouman²,

Arfin³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Vitiligo is an acquired depigmentary disorder of the skin, characterized by multiple susceptibility loci and genetic heterogeneity. The etiology of vitiligo is unknown but several hypotheses, including an autoimmune origin, have been proposed. Tumor necrosis factor (TNF)-α, a pleiotropic proinflammatory cytokine, has been shown to play a critical role in several autoimmune diseases including vitiligo. The aim of present study was to determine the association of TNF-α and -β gene polymorphisms with vitiligo in Saudi patients. TNF-α and -β genes were amplified in 123 Saudi patients and 200 matched controls using polymerase chain reaction to search for polymorphisms involved at positions -308, and intron 1 +252. The frequency of the TNF-α (-308) GA genotype was higher and the frequencies of the GG and AA genotypes were significantly lower in vitiligo patients compared to controls. These findings suggested that genotype GA-positive individuals at position -308 of TNF-α are susceptible to vitiligo, whereas the GG and AA genotypes might exert a protective effect. The frequency of allele A (TNF-α 2-allele) was significantly higher and that of allele G (TNF-α 1-allele) was lower in vitiligo patients compared to controls, indicating an association of allele A with susceptibility to TNF-α and -β polymorphisms in vitiligo vitiligo in Saudi patients. The results of our examination of TNF-β (intron 1 +252) polymorphisms showed a significant increase in the frequency of the GG genotype and allele G (TNF-b 1-allele) in vitiligo patients, suggesting a susceptibility of the GG genotype and allele G for vitiligo. By contrast, the high frequency of the GA genotype in controls might indicate a protective effect. The results of the present study strongly support a link between TNF-α (-308) and -β (intron 1 +252) polymorphisms and vitiligo in Saudi patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with vitiligo

Al-Harthi

Zouman²,

Arfin³

et al. 2013

Genet. Mol. Res.

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“…efficient destruction of transformed melanocytes, does occur very rarely. In this respect, reactivity to vitiligo melanocytes may be regarded as the effective variant of an immune response often ineffective in melanoma (reviewed in [11]). The mechanisms at the basis of these opposite effects are not known, but these data together with the resistance of melanoma to conventional chemotherapeutic and radiotherapeutic approaches make the melanoma/vitiligo dichotomy an important model for immunologic investigation.…”

Section: Introductionmentioning

confidence: 99%

Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo

et al. 2005

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Vitiligo is a skin disorder characterized by depigmented macules secondary to melanocyte loss. An unusual facet is its relation to melanoma: Cytotoxic T lymphocytes directed to melanocyte antigens are found in both conditions and imply a breakdown of tolerance, yet the resulting immune reaction is the opposite. The mechanisms at the basis of these opposite effects are not known. Here, we performed a direct comparison of whole melanocyte-specific T cell populations in the two diseases. We demonstrate that neither precursor frequencies of Melan-A/MART-1-specific T lymphocytes nor their status of activation differ significantly. However, by using a tetramer-based T cell receptor down-regulation assay, we documented a higher affinity of vitiligo T cells. We calculated that the peptide concentration required for 50% of maximal receptor downregulation differed by 6.5-fold between the two diseases. Moreover, only vitiligo T cells were capable of efficient receptor down-regulation and IFN-c production in response to HLA-matched melanoma cells, suggesting that this difference in receptor affinity is physiologically relevant. The differences in receptor affinity and tumor reactivity were confirmed by analyzing Melan-A/MART-1-specific clones established from the two diseases. Our results suggest that the quality, and not the quantity, of the melanocytespecific cytotoxic responses differs between the two pathologies.

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“…However, recent studies have shown that the level of thymic expression of melanocyte-specific Ags is highly variable between individuals (11). The patchy nature of vitiligo and variation in disease severity suggest that the autoreactive precursor frequency is not the only determinant of disease and that peripheral and local mechanisms are involved (5,8,12). The induction of melanocyte-specific peripheral CD8 ϩ T cell tolerance has been demonstrated in the neonate, when the epidermis is accessible to migrating T cells (13), but the situation in the adult is less clear.…”

mentioning

confidence: 99%

“…It is characterized by variable numbers of depigmented macules, which are often symmetrically placed and frequently affect exposed body areas and the skin around orifices (1,2). Although the precise etiology is unknown, an autoimmune component is strongly suggested by immune infiltrates and skinhoming autoreactive T cells (4 -6) that target melanocyte-specific Ags, such as melan-A/MART1, Gp100, tyrosinase, and tyrosinaserelated protein (TRP-1) 4 and TRP-2 (7,8). The role of central and peripheral tolerance directed toward melanocyte-specific Ags has been difficult to dissect due to the difficulty in tracking rare autoreactive T cells.…”

mentioning

confidence: 99%

CD4 T Cell-Dependent Autoimmunity against a Melanocyte Neoantigen Induces Spontaneous Vitiligo and Depends upon Fas-Fas Ligand Interactions

Lambe

Leung

Bouriez-Jones

et al. 2006

The Journal of Immunology

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Better understanding of tolerance and autoimmunity toward melanocyte-specific Ags is needed to develop effective treatment for vitiligo and malignant melanoma; yet, a systematic assessment of these mechanisms has been hampered by the difficulty in tracking autoreactive T cells. To address this issue, we have generated transgenic mice that express hen egg lysozyme as a melanocyte-specific neoantigen. By crossing these animals to a hen egg lysozyme-specific CD4 TCR transgenic line we have been able to track autoreactive CD4+ T cells from their development in the thymus to their involvement in spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris and Vogt-Koyanagi-Harada syndrome. Our findings show that CD4-dependent destruction of melanocytes is partially inhibited by blocking Fas-Fas ligand interactions and also highlights the importance of local control of autoimmunity, as vitiligo remains patchy and never proceeds to confluence even when Ag and autoreactive CD4+ T cells are abundant. Immune therapy to enhance or suppress melanocyte-specific T cells can be directed at a series of semiredundant pathways involving tolerance and cell death.

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Melanocyte‐Specific Immune Response in Melanoma and Vitiligo: Two Faces of the Same Coin?

Cited by 58 publications

References 66 publications

Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with vitiligo

Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with vitiligo

Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo

CD4 T Cell-Dependent Autoimmunity against a Melanocyte Neoantigen Induces Spontaneous Vitiligo and Depends upon Fas-Fas Ligand Interactions

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