Evaluation of serum trail level and DR4 gene variants as biomarkers for vitiligo patients

Edgünlü, Tuba Gökdoğan; Tekin, Nilgün Solak; Turkcu, Ummuhani Ozel; Karakas-Celik, Sevim; Urhan-Kucuk, Meral; Tekin, Leyla

doi:10.1111/jdv.13340

Cited by 4 publications

(4 citation statements)

References 10 publications

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“…Whereas some melanocytes might have died even before the CD8 + T cell arrives. HSP70‐exposed TNF related apoptosis‐inducing ligand (TRAIL) + DC are lytic towards TRAIL‐receptor‐expressing melanocytes 141,142 . Cells expressing TRAIL are also found to infiltrate the papillary dermis of patients with inflammatory vitiligo 143 .…”

Section: Innate Immune Activationmentioning

confidence: 99%

Mechanisms of melanocyte death in vitiligo

Chen

2020

Medicinal Research Reviews

149

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Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation. Genome‐wide associated studies have identified single‐nucleotide polymorphisms in a panel of susceptible loci as risk factors in melanocyte death. But vitiligo onset can't be solely attributed to a susceptive genetic background. Oxidative stress triggered by elevated levels of reactive oxygen species accounts for melanocytic molecular and organelle dysfunction, a minority of melanocyte demise, and melanocyte‐specific antigens exposure. Of note, the self‐responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo. The aberrantly heightened innate immunity, type‐1‐skewed T helper, and incompetent regulatory T cells tip the balance toward autoreaction and CD8+ cytotoxic T lymphocytes finally execute the killing of melanocytes, possibly alarmed by resident memory T cells. In addition to the well‐established apoptosis and necrosis, we discuss several death modalities like oxeiptosis, ferroptosis, and necroptosis that are probably employed in melanocyte destruction. This review focuses on the various mechanisms of melanocytic death in vitiligo pathogenesis to demonstrate a panorama of that. We hope to provide new insights into vitiligo pathogenesis and treatment strategies by the review.

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Section: Innate Immune Activationmentioning

confidence: 99%

Mechanisms of melanocyte death in vitiligo

Chen

2020

Medicinal Research Reviews

149

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“…In perilesional vitiligo skin, TNF-related apoptosisinducing ligand (TRAIL) þ dendritic cells (DC) are observed close to TRAIL receptor-expressing melanocytes (Kroll et al, 2005). Circulating TRAIL may also eliminate melanocytes (Edgunlu et al, 2016). Dying melanocytes then become a source of antigen for processing by DCs and presentation to T cells.…”

Section: Autoimmune Involvementmentioning

confidence: 99%

Replenishing Regulatory T Cells to Halt Depigmentation in Vitiligo

Poole

Mehrotra

2017

Journal of Investigative Dermatology Symposium Proceedings

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Vitiligo is a cutaneous autoimmune disease, especially devastating to patients with darker skin tones because of the contrast between unaffected and lesional skin. We studied immune cells infiltrating vitiligo skin and found very few regulatory T cells (Tregs). Vitiligo was not associated with a reduced frequency or function of circulating Tregs. To manipulate Treg function, we used mouse models expressing melanocyte-reactive TCRs, following changes in pelage color. We also isolated splenocytes to measure Treg function and evaluated cutaneous Treg abundance. Even small numbers of Tregs transferred into depigmenting mice could effectively interfere with depigmentation. The same holds true for treatment with rapamycin, readily translatable for use in human patients; such treatment may be well tolerated. Because vitiligo skin is relatively devoid of cells that produce the chemokine CCL22, whereas circulating Tregs express normal levels of its receptor CCR4, we overexpressed Ccl22 in the skin of vitiligo-prone mice to assess the resulting levels of depigmentation. Markedly reduced depigmentation was accompanied by Treg infiltration to the skin. With several options available to support a healthy balance between Tregs and effector T cells, the next challenge will be to render such treatment antigen specific and avoid general immunosuppression.

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“…[20] In addition, soluble TRAIL levels were reported to be significantly elevated in the serum of patients with vitiligo compared with control groups. [25] These reports suggest that TRAIL might be another death ligand that causes the autoimmune destruction of lesional melanocytes in vitiligo patients. Given the finding that FasL and TRAIL synergistically induce human melanocyte apoptosis ( Figure S7), FasL and TRAIL might be cooperatively involved in the autoimmune destruction of melanocytes in vitiligo patients.…”

Section: Discussionmentioning

confidence: 99%

Fas‐FasL interaction in cytotoxic T cell‐mediated vitiligo: The role of lesional expression of tumor necrosis factor‐α and interferon‐γ in Fas‐mediated melanocyte apoptosis

Jimbo

Nagai

Fujiwara

et al. 2019

Experimental Dermatology

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Vitiligo is an acquired skin depigmentation disorder resulting from the selective loss of epidermal melanocytes, and previous studies have suggested that a T lymphocyte‐mediated mechanism has a role in melanocyte loss. Although Fas‐Fas ligand (FasL) interactions are important for T lymphocytes to mediate cytotoxicity, there are only few reports examining the involvement of the Fas‐FasL pathway in vitiligo using in vivo mouse models. In addition, there have been no reports concerning Fas‐mediated apoptosis in human melanocytes in vitro. In this study, we found that the Fas‐mediated pathway is involved in cytotoxic T lymphocyte (CTL)‐dependent vitiligo in a mouse model and FasL‐induced apoptosis of human melanocytes. Tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ, the expression levels of which have been reported to be elevated in lesional skin of patients with vitiligo, synergistically upregulated Fas expression on human melanocytes but inhibited the Fas‐mediated apoptosis. Treatment with TNF‐α and IFN‐γ synergistically upregulated the expression of the anti‐apoptotic genes, c‐IAP2, c‐FLIP and MCL1. A siRNA knock‐down study showed that c‐FLIP and MCL1, but not c‐IAP2, were involved in inducing synergistic inhibitory effects on Fas‐mediated apoptosis. Furthermore, we found that FasL and TNF‐related apoptosis‐inducing ligand (TRAIL) synergistically induced apoptosis on human melanocytes. In conclusion, our results suggest that the Fas‐FasL pathway is involved in CTL‐dependent vitiligo and the elevated expression levels of TNF‐α and IFN‐γ in lesional skin may act synergistically on melanocytes to suppress Fas‐mediated apoptosis.

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Evaluation of serum trail level and DR4 gene variants as biomarkers for vitiligo patients

Cited by 4 publications

References 10 publications

Mechanisms of melanocyte death in vitiligo

Mechanisms of melanocyte death in vitiligo

Replenishing Regulatory T Cells to Halt Depigmentation in Vitiligo

Fas‐FasL interaction in cytotoxic T cell‐mediated vitiligo: The role of lesional expression of tumor necrosis factor‐α and interferon‐γ in Fas‐mediated melanocyte apoptosis

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