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The Clinical and Molecular Response of Pyoderma Gangrenosum to Interleukin 23 Blockade: Result from a proof-of-concept open-label clinical trial. 脓皮病对白细胞介素 23 阻断剂的临床和分子反应:概念验证开放标签临床试验的结果。
Pub Date : 2024-11-13 DOI: 10.1016/j.jid.2024.10.602
Akshay Flora, James Pham, Jane A Woods, Michael Radzeika, Hugh Dickson, Mathew Malone, John W Frew

Pyoderma Gangrenosum is a severe ulcerative disease with a great need for novel therapies. A major barrier to the development of novel therapies is a lack of understanding of disease pathogenesis. We present the results of a proof-of-concept open label clinical trial of IL-23p19 antagonism with Tildrakizumab ion Pyoderma Gangrenosum. Gene expression analysis identified pro-inflammatory genes associated with interferon responses and dendritic cell activity including IFI27, XBP1, SAA1 LGALS3 and STAT3 significantly downregulated in lesional tissue after 12 weeks of therapy. Immunohistochemistry confirmed reduction in IL-17A and IL-17 F positive cells as well as reduction in TNF-a, C5a and IL-1B positive cells in week 12 samples compared to baseline. Significant reduction in serum inflammation was observed via serum proteomics, with IL-8, IL-6, and CASP-8 levels reduced comparable to healthy controls at Week 12. Clinical outcomes demonstrated significant reduction in ulcer size, pain, itch and quality of life outcomes in line with the molecular findings. Differential expression of key inflammatory cytokines such as IL-8, CXCL5, PD-L1, SPP1 and MMP1 were observed in tissue and serum when stratified by clinical responders and non-responders. This data provides insights into the clinical relevance of alterations in molecular markers in pyoderma gangrenosum and the potential for the identification of clinically relevant biomarkers of disease activity.

脓皮病是一种严重的溃疡性疾病,亟需新型疗法。开发新型疗法的主要障碍是缺乏对疾病发病机制的了解。我们介绍了用 Tildrakizumab 离子脓疱疮拮抗 IL-23p19 的开放标签临床试验的概念验证结果。基因表达分析确定了与干扰素反应和树突状细胞活性相关的促炎基因,包括 IFI27、XBP1、SAA1 LGALS3 和 STAT3,这些基因在治疗 12 周后的皮损组织中显著下调。免疫组化证实,与基线相比,第12周样本中IL-17A和IL-17 F阳性细胞减少,TNF-a、C5a和IL-1B阳性细胞减少。通过血清蛋白质组学观察到,血清中的炎症明显减少,第12周时,IL-8、IL-6和CASP-8水平的降低幅度与健康对照组相当。临床结果表明,溃疡面积、疼痛、瘙痒和生活质量均显著降低,与分子研究结果一致。根据临床应答者和非应答者进行分层,在组织和血清中观察到关键炎性细胞因子的差异表达,如 IL-8、CXCL5、PD-L1、SPP1 和 MMP1。这些数据有助于深入了解脓皮病分子标记物变化的临床相关性,以及确定疾病活动的临床相关生物标记物的潜力。
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引用次数: 0
Apocrine gland damage and the release of specific keratins in early stage indicate the crucial involvement of apocrine glands in hidradenitis suppurativa. 分泌腺损伤和早期特异性角蛋白的释放表明,分泌腺在化脓性扁桃体炎中起着至关重要的作用。
Pub Date : 2024-11-13 DOI: 10.1016/j.jid.2024.09.021
Jiaqi Li, Sitong Li, Qiujing Zhang, Mengchen Liang, Xiang Chen, Yibo Feng, Zhanyan Pan, Tingting Hu, Qiong Wu, Guangjie Chen, Christos C Zouboulis, Xiaohui Mo, Qiang Ju

The apocrine glands (AGs) are not considered to be primarily involved in hidradenitis suppurativa (HS). This study investigated the potential role of AGs in HS pathogenesis using immunohistochemistry and single-cell sequencing of nonlesional skin (NLS) and early lesional skin (LS) from patients with HS (n = 12) and healthy controls (HC, n = 8). AG cell destruction was more frequent and AG size was significantly reduced in the NLS and LS. Barrier-related genes (e.g., claudin 1 and E-cadherin) were downregulated in the AGs of the NLS and LS. Damaged AGs in the LS primarily recruit and activate neutrophils via the CXCL-CXCR and SAA1-FPR2 pathways. Elevated levels of specific keratins (KRT18 and KRT19) released from damaged AGs were observed on the skin surface of patients and were associated with disease severity. KRT19 was also detected in the dermis of the NLS and LS and was surrounded by neutrophils and macrophages. Moreover, serum KRT19 levels in patients (n = 20) were significantly negatively correlated with the age at HS onset. Collectively, our findings provide previously unreported evidence that the AGs are damaged and release specific keratins in early HS lesions, indicating a crucial role of the AGs in HS pathogenesis.

人们并不认为脓疱性皮炎(HS)主要与分泌腺(AGs)有关。本研究采用免疫组化和单细胞测序方法,对 HS 患者(12 人)和健康对照组(8 人)的非皮损皮肤(NLS)和早期皮损皮肤(LS)进行了研究,探讨了 AG 在 HS 发病机制中的潜在作用。在NLS和LS中,AG细胞破坏更为频繁,AG体积明显缩小。屏障相关基因(如 claudin 1 和 E-cadherin)在 NLS 和 LS 的 AG 中下调。LS中受损的AG主要通过CXCL-CXCR和SAA1-FPR2途径招募和激活中性粒细胞。在患者皮肤表面观察到从受损 AGs 释放的特定角蛋白(KRT18 和 KRT19)水平升高,这与疾病的严重程度有关。在 NLS 和 LS 的真皮层中也检测到了 KRT19,其周围有中性粒细胞和巨噬细胞。此外,患者(n = 20)的血清 KRT19 水平与 HS 发病年龄呈显著负相关。总之,我们的研究结果提供了以前未曾报道过的证据,即在 HS 早期病变中 AGs 受到破坏并释放特异性角蛋白,这表明 AGs 在 HS 发病机制中起着至关重要的作用。
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引用次数: 0
FoxO3a Plays a Role in Wound Healing by Regulating Fibroblast Mitochondrial Dynamics. FoxO3a 通过调节成纤维细胞线粒体动力学在伤口愈合中发挥作用
Pub Date : 2024-11-13 DOI: 10.1016/j.jid.2024.10.600
Mariko Moriyama, Ryoichi Mori, Takao Hayakawa, Hiroyuki Moriyama

The skin plays a protective role against harmful environmental stress such as ultraviolet rays. Therefore, the skin is constantly exposed to potential injuries, and wound healing is a vital process for the survival of all higher organisms. Wound healing is dependent on aging and metabolic status at a whole-body level. Because the forkhead box O (FOXO) family plays a role in aging and metabolism, we investigated the molecular functions of FOXO3a in skin wound healing using FoxO3a-/- mice. We observed that FoxO3a-/- mice showed accelerated skin wound healing. During wound healing, more fibroblasts accumulated at the wound edges and migrated into the wound bed in FoxO3a-/- mice. Moreover, cell migration of dermal fibroblasts isolated from FoxO3a-/- mice was significantly induced. During the in vitro cell migration, we observed accelerated mitochondrial fragmentation and decreased oxygen consumption in the mitochondria of FoxO3a-/- fibroblasts. These changes were caused by the upregulation of mitochondrial Rho GTPase 1 (Miro1), which is an essential mediator of microtubule-based mitochondrial motility. Miro1 inhibition significantly attenuated cell migration, mitochondrial fragmentation, and mitochondrial recruitment to the leading edge of the cells. These data indicate that FoxO3a plays a crucial role in wound healing by regulating mitochondrial dynamics.

皮肤对紫外线等有害环境压力起着保护作用。因此,皮肤经常受到潜在的伤害,而伤口愈合是所有高等生物生存的重要过程。伤口愈合取决于全身的衰老和新陈代谢状况。由于叉头盒 O(FOXO)家族在衰老和新陈代谢中发挥作用,我们利用 FoxO3a-/- 小鼠研究了 FOXO3a 在皮肤伤口愈合中的分子功能。我们观察到,FoxO3a-/-小鼠的皮肤伤口愈合速度加快。在伤口愈合过程中,FoxO3a-/-小鼠有更多的成纤维细胞聚集在伤口边缘并迁移到伤口床。此外,从 FoxO3a-/- 小鼠体内分离的真皮成纤维细胞的细胞迁移也明显受到诱导。在体外细胞迁移过程中,我们观察到 FoxO3a-/- 小鼠成纤维细胞线粒体碎裂加速,耗氧量降低。这些变化是由线粒体 Rho GTPase 1(Miro1)的上调引起的,Miro1 是基于微管的线粒体运动的重要介质。抑制 Miro1 可明显减少细胞迁移、线粒体破碎和线粒体向细胞前缘的募集。这些数据表明,FoxO3a 通过调节线粒体动力学在伤口愈合中发挥着至关重要的作用。
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引用次数: 0
Increased mortality in diffuse systemic sclerosis patients with high circulating IFNα levels. 循环 IFNα 水平较高的弥漫性系统性硬化症患者死亡率增加。
Pub Date : 2024-11-12 DOI: 10.1016/j.jid.2024.09.020
François Maillet, Carine Schmidt, Vincent Bondet, Alexandre Bense, Darragh Duffy, Luc Mouthon, Mathieu Rodero, Benjamin Chaigne
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引用次数: 0
Cell Therapy and the Skin: Great Potential but in Need of Optimization. 细胞疗法与皮肤:潜力巨大但亟待优化。
Pub Date : 2024-11-12 DOI: 10.1016/j.jid.2024.09.011
Sam S Lee, Eddie Gibson Martinez Peña, Aiden A Willis, Chen Chia Wang, Nina Rossa Haddad, Luis A Garza

Cell therapy is rapidly growing owing to its therapeutic potential for diseases with currently poor outcomes. Cell therapy encompasses both nonengineered and engineered cells and possesses unique abilities such as sense-and-respond functions and long-term engraftment for persistent curative potential. Cell therapy capabilities have expanded to address a wide spectrum of diseases, and our review is focused on dermatological applications. The use of fibroblasts and keratinocytes as cell therapy has shown promise in skin disorders such as epidermolysis bullosa. Future efforts include testing the ability of fibroblasts to reprogram nonvolar to volar skin to reduce stump dermatoses in patients with limb loss using prosthetics.

细胞疗法因其对目前疗效不佳的疾病的治疗潜力而迅速发展。细胞疗法既包括非工程细胞,也包括工程细胞,具有独特的能力,如感知-反应功能和长期移植,具有持续治疗的潜力。细胞疗法的功能已扩展到治疗多种疾病,我们的综述将重点放在皮肤病的应用上。使用成纤维细胞和角质形成细胞作为细胞疗法已在表皮松解症等皮肤疾病中显示出前景。未来的工作包括测试成纤维细胞将非绒毛皮肤重编程为绒毛皮肤的能力,以减少使用假肢的肢体缺失患者的残肢皮肤病。
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引用次数: 0
Recent Advances in Juvenile Dermatomyositis: Moving toward Integration of Myositis-Specific Antibody Clinical Phenotypes, IFN-Driven Pathogenesis, and Targeted Therapies. 幼年皮肌炎的最新进展:迈向肌炎特异性抗体临床表型、IFN驱动发病机制和靶向治疗的整合。
Pub Date : 2024-11-11 DOI: 10.1016/j.jid.2024.09.017
Kristen L Chen, Yvonne E Chiu, Ruth Ann Vleugels, Dominic O Co, Hanna Kim, Sara E Sabbagh, Lisa M Arkin

Juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, is associated with significant morbidity despite therapeutic advances. Distinct clinical phenotypes have emerged, which can correlate with myositis-specific antibodies. Because translational data solidify the role of type I IFNs in JDM disease pathogenesis, integration of clinical and molecular phenotyping may impact the choice of targeted therapy. This paper reviews clinical and molecular phenotyping in JDM and translational insights into immune pathogenesis that have created emerging options for targeted therapy.

幼年皮肌炎(JDM)是最常见的儿科炎症性肌病,尽管治疗手段不断进步,但发病率仍然很高。目前已经出现了不同的临床表型,这些表型与肌炎特异性抗体相关。由于转化数据证实了 I 型 IFNs 在 JDM 疾病发病机制中的作用,因此整合临床和分子表型可能会影响靶向治疗的选择。本文回顾了 JDM 的临床和分子表型以及对免疫发病机制的转化研究,这些研究为靶向治疗提供了新的选择。
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引用次数: 0
Chronic Obstructive Pulmonary Disease Outcomes in Psoriasis Patients. 银屑病患者的慢性阻塞性肺病预后
Pub Date : 2024-11-08 DOI: 10.1016/j.jid.2024.10.596
Lily Guo, Sara N Bilimoria, Robin Kikuchi, Audrey Hao, Kaviyon Sadrolashrafi, Rebecca K Yamamoto, Hannah Tolson, Danielle Yee, April W Armstrong
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引用次数: 0
Topical Application of Nano-sized Graphene Oxide Cream Ameliorates Acute Skin Inflammation in Mice. 局部使用纳米级氧化石墨烯霜可改善小鼠急性皮肤炎症。
Pub Date : 2024-11-08 DOI: 10.1016/j.jid.2024.08.041
Hyun Jung Park, Sung Won Lee, Tae-Cheol Kim, Yun Hoo Park, Keun Soo Kim, Luc Van Kaer, Suklyun Hong, Seokmann Hong

We have previously shown that nano-sized graphene oxide (NGO) displays anti-inflammatory activities against natural killer T (NKT) cell-mediated sepsis. To address whether NGO could be applied to treat acute skin inflammation we developed a conventional skin Cetaphil® cream containing NGO (NGO cream) for topical application to skin lesions and investigated its therapeutic efficacy by employing the tape-stripping-induced acute skin inflammation model. Topical application of NGO cream to the wounded area significantly reduced skin lesions compared with the control cream. Moreover, NGO cream treatment prevented the tape-stripping-elicited infiltration of and IL1β production by skin neutrophils and dendritic cells (DCs). Furthermore, such anti-inflammatory effects of NGO cream were attributed to decreased infiltration of IL12-producing DCs and IFNγ-producing cells (e.g., CD4+ T, CD8+ T, γδ T, NK, and NKT cells) into the skin. In addition, topical NGO cream administration enhanced the expression of suppressive molecules such as FR4 on skin regulatory T cells. Through RNA sequencing analysis, we found that the preventive effect of NGO cream on acute skin inflammation may be correlated with the activation of keratinocytes located in the epidermis. Our results support NGO cream as a therapeutic option to control acute skin inflammation.

我们曾研究表明,纳米氧化石墨烯(NGO)对自然杀伤T细胞(NKT)介导的败血症具有抗炎活性。为了解决非政府组织是否可用于治疗急性皮肤炎症的问题,我们开发了一种含有非政府组织的传统皮肤 Cetaphil® 乳霜(非政府组织乳霜),用于局部涂抹于皮肤损伤处,并通过使用胶带绷带诱导的急性皮肤炎症模型研究了其疗效。与对照药膏相比,在受伤部位局部涂抹非政府组织药膏能明显减轻皮损。此外,NGO 药膏还能阻止胶带撕裂引起的皮肤中性粒细胞和树突状细胞(DCs)的浸润和 IL1β 的产生。此外,NGO 软膏的抗炎作用还归因于产生 IL12 的 DC 和产生 IFNγ 的细胞(如 CD4+ T、CD8+ T、γδ T、NK 和 NKT 细胞)对皮肤的浸润减少。此外,局部使用非政府组织药膏可增强皮肤调节性 T 细胞上 FR4 等抑制性分子的表达。通过 RNA 测序分析,我们发现非政府组织乳膏对急性皮肤炎症的预防作用可能与表皮角质细胞的活化有关。我们的研究结果支持将非政府组织乳膏作为控制急性皮肤炎症的一种治疗选择。
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引用次数: 0
Deconvoluted methylation profiles discriminate between closely related melanocytic nevi. 去卷积甲基化图谱可区分密切相关的黑素细胞痣。
Pub Date : 2024-11-08 DOI: 10.1016/j.jid.2024.10.595
Daniel Aldea, Nicolas Macagno, Elise Marechal, Mathias Moreno, Pauline Romanet, Morgane Pertuit, Jérémy Garcia, Nathalie Degardin, Stéphanie Mallet, Isabelle James, Guillaume Captier, Anne Barlier, Heather C Etchevers
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引用次数: 0
Disentangling Race from Skin Color in Modern Biology and Medicine. 在现代生物学和医学中将种族与肤色区分开来。
Pub Date : 2024-11-06 DOI: 10.1016/j.jid.2024.08.029
Valerie Horsley, Ophelia E Dadzie, Russell Hall, Nina G Jablonski

In this review, we examine the taxonomies used to classify people, which influenced the development of the modern disciplines of biology and medicine, including dermatology, throughout the world. Early European scientists and physicians were intertwined with the social environment that created classifications and hierarchies of skin-color-based races, which were reinforced by prevailing political systems that supported colonial economic structures and, in many cases, chattel slavery. Even after genomic analysis of diverse human DNA sequences have revealed that systems of skin color-based racial and ethnic classification lacked biological meaning and were socially constructed, these classifications persist and are reinforced by census classifications and frameworks for comparisons in biomedicine in many parts of the world. The bodies of knowledge and practices that were built on these classifications did not reflect the observable biological diversity of people but the dominant cultural institutions and economic systems of their times. We provide actions for our modern institutions to reduce the underpinnings and ramifications of racial and ethnic classifications ultimately to improve biomedical research and medical care for all patients.

在这篇综述中,我们将研究用于对人进行分类的分类法,这些分类法影响了包括皮肤病学在内的现代生物学和医学学科在全世界的发展。早期的欧洲科学家和医生与社会环境交织在一起,社会环境创造了以肤色为基础的人种分类和等级制度,而支持殖民地经济结构的主流政治制度又强化了这些分类和等级制度,在许多情况下,这些制度还包括动产奴隶制。即使在对不同人类 DNA 序列进行基因组分析后发现,基于肤色的种族和人种分类系统缺乏生物学意义,是由社会构建的,但这些分类仍然存在,并在世界许多地方的人口普查分类和生物医学比较框架中得到强化。建立在这些分类基础上的知识体系和实践并不反映可观察到的人的生物多样性,而是反映了当时占主导地位的文化机构和经济体系。我们为我们的现代机构提供了减少种族和民族分类的基础和影响的行动,最终改善所有患者的生物医学研究和医疗服务。
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引用次数: 0
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The Journal of investigative dermatology
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