Vitiligo non-responding lesions to narrow band UVB have intriguing cellular and molecular abnormalities that may prevent epidermal repigmentation

IF 3.9 3区 医学 Q2 CELL BIOLOGY Pigment Cell & Melanoma Research Pub Date : 2024-02-11 DOI:10.1111/pcmr.13160
Nathaniel B. Goldstein, Andrea Steel, Landon Tomb, Zachary Berk, Junxiao Hu, Velmurugan Balaya, Laura Hoaglin, Kavya Ganuthula, Meet Patel, Erica Mbika, William A. Robinson, Dennis R. Roop, David A. Norris, Stanca A. Birlea
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Abstract

We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/β-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.

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对窄波段紫外线无反应的白癜风皮损有令人费解的细胞和分子异常,这可能会阻碍表皮再色素化。
我们发现,接受窄波段紫外线照射(NBUVB)治疗的人类白癜风患者在皮肤部位表现出局部的抗再色素沉着能力,这些皮肤部位具有不同的细胞和分子通路特征。通过免疫染色研究、发现阶段 RNA-Seq 分析和原位杂交确证,我们分析了从接受 NBUVB 治疗 6 个月后未再色素沉着(无反应)的白癜风皮损处采集的配对活检组织,并将其与来自同一患者的再色素沉着(有反应)皮损进行了比较。与有反应的皮损相比,无反应的皮损表皮呈黄褐色,黑素细胞(MC)总数、增殖和分化数量较低,衰老角质细胞(KC)和细胞毒性 CD8+ T 细胞数量增加。无反应皮损的异常反应是由 cAMP 通路和上游激活剂 PDE4B 以及 WNT/β-catenin 重着色通路失调驱动的。黄褐斑反应性病变表达高水平的 WNT10B 配体,这种分子可防止 NBUVB 诱导的表皮衰老,在培养的黑色素母细胞中可防止 α-MSH 的促黑色素生成作用。了解NBUVB诱导的白癜风再色素生成缺乏的途径,对于指导开发新的白癜风治疗策略大有希望。
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来源期刊
Pigment Cell & Melanoma Research
Pigment Cell & Melanoma Research 医学-皮肤病学
CiteScore
8.90
自引率
2.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Pigment Cell & Melanoma Researchpublishes manuscripts on all aspects of pigment cells including development, cell and molecular biology, genetics, diseases of pigment cells including melanoma. Papers that provide insights into the causes and progression of melanoma including the process of metastasis and invasion, proliferation, senescence, apoptosis or gene regulation are especially welcome, as are papers that use the melanocyte system to answer questions of general biological relevance. Papers that are purely descriptive or make only minor advances to our knowledge of pigment cells or melanoma in particular are not suitable for this journal. Keywords Pigment Cell & Melanoma Research, cell biology, melatonin, biochemistry, chemistry, comparative biology, dermatology, developmental biology, genetics, hormones, intracellular signalling, melanoma, molecular biology, ocular and extracutaneous melanin, pharmacology, photobiology, physics, pigmentary disorders
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