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Curing Psoriasis. 治疗牛皮癣。
Pub Date : 2024-12-01 Epub Date: 2024-10-22 DOI: 10.1016/j.jid.2024.09.012
Su M Lwin, Shir Azrielant, Juan He, Christopher E M Griffiths

As medicine advances, cures are being found for diseases that were previously considered incurable, as is the case for some types of cancer. Traditionally, the term cure is reserved for resolution of disease, both at a clinical and a molecular level, which continues after cessation of treatment. Biologic therapies have revolutionized the definition of remission in severe psoriasis, with some patients achieving long-lasting disease suppression, but the disease nearly always relapses on withdrawal of the drug. Our improved understanding of the pathomechanisms of psoriasis, coupled with anecdotal reports of long-term clearance of the disease after cell-based therapies, leads us to the hypothesis that psoriasis is curable. We propose that cure of psoriasis can be achieved by restoring immune homeostasis through a combinatorial, personalized medicine approach encompassing early intervention to include biologics, advanced therapeutics, and lifestyle modification.

随着医学的发展,以前被认为是不治之症的疾病也找到了治愈方法,某些类型的癌症就是如此。传统上,"治愈 "一词是指疾病在临床和分子水平上得到缓解,并在停止治疗后继续存在。生物疗法彻底改变了重症银屑病缓解的定义,一些患者的病情得到了长期抑制,但停药后几乎总是复发。我们对银屑病的病理机制有了更深入的了解,再加上细胞疗法后疾病长期痊愈的轶事报道,使我们提出了银屑病是可以治愈的这一假设。我们建议,通过包括生物制剂、先进疗法和生活方式调整在内的早期干预、个性化组合医学方法来恢复免疫平衡,从而治愈银屑病。
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引用次数: 0
Residual Lesional Gene Expression in Psoriasis Patients with Complete Skin Clearance Treated with Guselkumab or Adalimumab in VOYAGE 1 and 2. VOYAGE 1 和 2》中接受古谢库单抗或阿达木单抗治疗的皮肤完全清除的银屑病患者的残留病变基因表达。
Pub Date : 2024-12-01 Epub Date: 2024-06-25 DOI: 10.1016/j.jid.2024.05.020
Andrew Blauvelt, Kenneth B Gordon, Richard G Langley, Patrick J Branigan, Yanqing Chen, Megan Miller, Chenglong Han, Steven Fakharzadeh, Ernesto J Muñoz-Elías, April W Armstrong
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引用次数: 0
Skin-resident γδ T cells mediate potent and selective antitumor cytotoxicity through directed chemotactic migration and mobilization of cytotoxic granules. 皮肤驻留的γδ T 细胞通过定向趋化迁移和细胞毒性颗粒的动员,介导强效和选择性的抗肿瘤细胞毒性。
Pub Date : 2024-11-19 DOI: 10.1016/j.jid.2024.10.607
Jiacai Yang, Zhihui Liu, Xiaohong Hu, Xiaorong Zhang, Yong Huang, Yunxia Chen, Cheng Chen, Ruoyu Shang, Yuanyang Tang, Wengang Hu, Jue Wang, Han-Ming Shen, Jun Hu, Weifeng He

Dendritic epidermal T cells (DETCs) are a unique subset of γδ T cells that reside predominantly in mouse epidermis, yet their antitumor functions remain enigmatic. Here we report that DETCs mediate potent and exquisitely selective cytotoxicity against diverse tumor types while sparing healthy cells. In vitro, DETCs induced apoptosis in melanoma, hepatoma, colon carcinoma and lymphoma lines in a dose- and time-dependent manner that required direct cell-cell contact. In vivo, adoptive DETC transfer significantly suppressed melanoma growth and metastasis while prolonging survival. Mechanistically, DETCs upregulated perforin/granzyme B expression upon tumor recognition, and inhibition of this pathway ablated cytotoxicity. DETCs selectively homed to and formed intimate contacts with tumor cells in vivo through directed chemotaxis and aggregation. Tumor engagement triggered pro-inflammatory DETC activation while dampening immunosuppressive factors in the microenvironment. Notably, mTOR signaling coupled tumor recognition to DETC trafficking, cytotoxicity and inflammatory programs, as rapamycin treatment impaired effector functions and therapeutic efficacy. Collectively, these findings establish DETCs as multidimensional antitumor effectors and provide insights for harnessing their unique biology for cancer immunotherapy.

树突状表皮 T 细胞(Dendritic epidermal T cells,DETCs)是γδ T 细胞的一个独特亚群,主要存在于小鼠表皮中,但其抗肿瘤功能仍是个谜。在这里,我们报告了 DETCs 对不同类型的肿瘤具有强效和极高的选择性细胞毒性,同时还能保护健康细胞。在体外,DETCs 以剂量和时间依赖性的方式诱导黑色素瘤、肝癌、结肠癌和淋巴瘤细胞株凋亡,这需要细胞与细胞之间的直接接触。在体内,DETCs的采纳转移能显著抑制黑色素瘤的生长和转移,同时延长存活时间。从机理上讲,DETCs在识别肿瘤后会上调穿孔素/粒酶B的表达,而抑制这一途径会削弱细胞毒性。在体内,DETCs通过定向趋化和聚集,选择性地归巢并与肿瘤细胞形成亲密接触。肿瘤接触会引发促炎性 DETC 激活,同时抑制微环境中的免疫抑制因子。值得注意的是,mTOR 信号将肿瘤识别与 DETC 的贩运、细胞毒性和炎症程序结合起来,因为雷帕霉素治疗会损害效应器功能和疗效。这些发现共同确立了 DETC 作为多维抗肿瘤效应因子的地位,并为利用其独特的生物学特性进行癌症免疫疗法提供了启示。
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引用次数: 0
Role of ADAM10/17-mediated Cleavage of LAG3 in the Impairment of Immunosuppression in Psoriasis. ADAM10/17 介导的 LAG3 分裂在银屑病免疫抑制损伤中的作用
Pub Date : 2024-11-19 DOI: 10.1016/j.jid.2024.10.606
Zengyang Yu, Xinyi Tang, Zeyu Chen, Yifan Hu, Shuqin Zhang, Chunyuan Guo, Jun Gu, Yuling Shi, Yu Gong

Despite extensive research on immune activation regulatory mechanisms, studies on immune suppression in psoriasis are limited. LAG3, a newly identified immune checkpoint, plays a crucial role in modulating immune responses and maintaining T regulatory (Treg) cell function. However, its involvement in psoriasis is unclear. We show that psoriasis is associated with reduced LAG3 expression in CD4 T cells and Treg cells. Further analysis revealed that the decline in LAG3 levels was linked to ADAM10/17-mediated proteolytic cleavage, which was upregulated in psoriasis. Clinical utilization of the IL-17A antagonist secukinumab, along with the in-vivo and in-vitro IL-17A-induced models, supported the potential of IL-17A to induce ADAM10/17 expression and trigger LAG3 cleavage. Through the Jurkat cell model, IL-17A was found to regulate ADAM10/17 expression by activating FOXM1. Additionally, treatment with the ADAM10/17 inhibitor GW280264X showed ameliorative effects on psoriasis-like mouse models and lipopolysaccharide-induced inflammation. Collectively, the findings of this study uncover the immune regulatory role of the ADAM10/17-LAG3 axis in psoriasis and highlight the therapeutic potential of targeting ADAM10/17 for psoriasis treatment.

尽管对免疫激活调节机制进行了广泛的研究,但有关银屑病免疫抑制的研究却十分有限。LAG3是一种新发现的免疫检查点,在调节免疫反应和维持T调节(Treg)细胞功能方面起着至关重要的作用。然而,它在银屑病中的参与还不清楚。我们的研究表明,银屑病与 CD4 T 细胞和 Treg 细胞中 LAG3 表达的减少有关。进一步的分析表明,LAG3 水平的下降与 ADAM10/17 介导的蛋白水解有关,而银屑病患者的 ADAM10/17 蛋白水解上调。IL-17A拮抗剂secukinumab在临床上的应用,以及体内和体外IL-17A诱导模型,支持了IL-17A诱导ADAM10/17表达和引发LAG3裂解的潜力。通过 Jurkat 细胞模型,发现 IL-17A 可通过激活 FOXM1 来调节 ADAM10/17 的表达。此外,ADAM10/17抑制剂GW280264X对银屑病样小鼠模型和脂多糖诱导的炎症有改善作用。总之,这项研究的结果揭示了ADAM10/17-LAG3轴在银屑病中的免疫调节作用,并强调了靶向ADAM10/17治疗银屑病的治疗潜力。
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引用次数: 0
Inhibition of pyruvate oxidation diminishes melanoma progression. 抑制丙酮酸氧化可减少黑色素瘤的发展。
Pub Date : 2024-11-18 DOI: 10.1016/j.jid.2024.10.605
B Seyran, I Avila, C Galvan, G Robles, C Murphy, H Christofk, W E Lowry
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引用次数: 0
Blood-borne bone marrow-derived epithelial cells searching for a niche: The Epithelial Transit Hypothesis. 血源性骨髓上皮细胞寻找生态位:上皮转运假说。
Pub Date : 2024-11-18 DOI: 10.1016/j.jid.2024.10.603
Stephanie M Holtorf, Rebecca J Morris
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引用次数: 0
Enhancer of TRPS1 rs12549956 influence hair thickness in Chinese populations. TRPS1 rs12549956 的增强子对中国人群头发厚度的影响。
Pub Date : 2024-11-13 DOI: 10.1016/j.jid.2024.10.601
Qili Qian, Sijie Wu, Junyu Luo, Yaqun Guan, Yajun Yang, Li Jin, Wenxin Zheng, Sijia Wang
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引用次数: 0
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
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The Journal of investigative dermatology
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