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Disorders of keratinization and other genodermatoses
Published in Rashmi Sarkar, Anupam Das, Sumit Sethi, Concise Dermatology, 2021
These are rare autosomal dominant disorders that show plantar keratoderma at pressure points, with occasional blistering and subungual hyperkeratosis. Hair and teeth anomalies may be present. The mutation lies in genes encoding for Keratin 6 (a & b), 16, and 17.
Transgenic Mice with Cytokine Mutations Affecting the Skin
Published in John P. Sundberg, Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
Manfred Blessing, Erby Wilkinson, Brigid L. M. Hogan
These patterns of expression make keratins valuable in two respects. First, as biochemical markers, they indicate different routes of differentiation in epidermal and follicular cells. Second, their gene promoters can be used to direct the expression of transgenes to specific subsets of epidermal cells. Only a few promoters of the many cytokeratin genes have been used in transgenic mice thus far. Among them are the promoters of the basally expressed keratin 14 gene,25 the suprabasally expressed keratin 1 and 10 genes,26,27 a hair keratin gene promoter,28 the keratin 5 gene promoter which directs transgene expression in basal keratinocytes and outer root sheath cells14 (and unpublished observations) and the keratin 6 gene promoter specific for outer root sheath cells.14,29 Weak and deregulated transgene expression is seen if relatively short promoter fragments are used,27,29,30 but larger promoter fragments strongly and faithfully express linked transgenes.6,11–15,26,28
Genodermatoses affecting the nail
Published in Eckart Haneke, Histopathology of the NailOnychopathology, 2017
Pachyonychia congenita type 1 is defined by mutations in the genes for keratin 6a/16, and type 2 displays keratin 6b/17 mutations. Although keratin 6a/16 mutations cause type 1 PC, the clinical phenotype appears to be more severe in subjects with a keratin 6a mutation as compared to those with a keratin 16 mutation.43 Double homozygous negative mutation of keratin 17 leads to a particularly severe phenotype of pachyonychia congenita with alopecia.44,45
LncRNA NORAD engages in psoriasis by binding to miR-26a to regulate keratinocyte proliferation
Published in Autoimmunity, 2021
Shuiqi Li, Xiaohua Zhu, Na Zhang, Ruixiang Cao, Lei Zhao, Xin Li, Jiang’an Zhang, Jianbin Yu
NORAD, a highly conserved non-coding RNA that mainly exists in the cytoplasm and regulates genome stability [27]. As a competitive endogenous RNA (ceRNA), NORAD regulates the expression of downstream factors by binding microRNAs (miRNAs) [28]. Chen et al. [14] reported that NORAD was highly expressed in melanoma patients and promoted the invasion and migration of malignant melanoma by binding to miR-205. As did in our preliminary experiment, firstly, the level of NORAD was detected and it was found highly expressed in pathological cell models, accompanied by the increased expression of keratinocyte proliferation-related proteins Keratin 6 (K6), Keratin 16 (K16), and Keratin 17 (K17). However, the keratinocyte proliferation was reduced when NORAD was lowly expressed, which confirmed that NORAD did regulate the keratinocyte proliferation in HaCaT cells stimulated by IL-22/LPS.
Keratinocyte differentiation antigen-specific T cells in immune checkpoint inhibitor-treated NSCLC patients are associated with improved survival
Published in OncoImmunology, 2021
Fiamma Berner, Rebekka Niederer, Jolien J. Luimstra, Oltin Tiberiu Pop, Ann-Kristin Jochum, Mette-Triin Purde, Omar Hasan Ali, David Bomze, Jens Bauer, Lena Katharina Freudenmann, Ana Marcu, Eva-Maria Wolfschmitt, Sebastian Haen, Thorben Gross, Marissa Lisa Dubbelaar, Marie-Therese Abdou, Petra Baumgaertner, Christina Appenzeller, Caroline Cicin-Sain, Tobias Lenz, Daniel E. Speiser, Burkhard Ludewig, Christoph Driessen, Markus Jörger, Martin Früh, Wolfram Jochum, Antonio Cozzio, Hans-Georg Rammensee, Juliane Walz, Jacques Neefjes, Lukas Flatz
We next determined whether peptides of the nine keratinocyte differentiation antigens are naturally presented via HLA molecules on human lung tumor cells. We therefore performed mass spectrometry-based immunopeptidome analyses of 16 primary human NSCLC tumor samples. Indeed, we identified HLA class I naturally presented peptides from seven of the keratinocyte differentiation antigens (desmocollin 3, ezrin, HSP27, keratin 6, keratin 14, keratin 17 and peroxiredoxin 2) on patient lung tumors (Figure 3a, Supplementary Table S5). In addition, we found naturally presented HLA class II ligands from all nine antigens on lung tumors (Supplementary Fig. S6, Supplementary Table S6). Naturally presented HLA ligands from keratin 6, keratin 14 and keratin 17 could not be assigned to a single keratin protein sequence due to their high sequence similarity and were therefore grouped together as keratins. Mapping of the tumor ligandome by mass spectrometry confirms that the identified peptides initiating CD8+ T cells responses in the earlier assays are truly presented peptides on the tumor HLA.
A new class of biologic agents facing the therapeutic paradigm in psoriasis: anti-IL-23 agents.
Published in Expert Opinion on Biological Therapy, 2018
Annalisa Tonini, Bruno Gualtieri, Salvatore Panduri, Marco Romanelli, Andrea Chiricozzi
A phase I, first-in-human, randomized, double-blind, and placebo-controlled study [67,68] showed high tolerability and dose-dependent efficacy of guselkumab. The trial design included two parts, one focusing on pharmacokinetics, immunogenicity, and safety of IV administration of single doses of 0.03, 0.1, 0.3, 1, 3, or 10 mg/kg or SC administration of single doses of 10, 30, 100, and 300 mg guselkumab in healthy subjects [67]. Part 2 [68] assessed the effects of single SC doses of guselkumab at 10, 30, 100, and 300 mg versus placebo in 24 patients with moderate-to-severe psoriasis throughout a 24-week period. At week 12, PASI 75 response was achieved by 50%, 60%, 60%, and 100% of patients treated with guselkumab at 10, 30, 100, and 300 mg, respectively, whereas no placebo-treated patient achieved a PASI 75 response. Most patients retained the achieved response through week 24, except for those in the 100 mg group, which gradually lost their response during follow-up. A significant reduction in IL-17A and CCL22 serum levels were observed at week 12 in guselkumab-treated patients, whereas serum levels of IFN-γ, TNF-α, IL-6, IL-1β, IL-8, IL-12p40, and IL-23p19 showed no significant changes at the same timepoint. Expression of both Th17-related and proliferative marker genes in skin lesions, particularly keratin 6A, keratin 16, S100 proteins (S100A15, S100A7, S100A8, S100A9), lipocalin 2, and CXCL1, was significantly decreased at week 12. Moreover, at week 12, T cells, CD11c+ dendritic cells, and epidermal thickness were significantly reduced in each group treated with guselkumab, except for dendritic cells in the 10 mg group. However, CD11c+ dendritic cells were significantly reduced, even in placebo-treated patients [68]. Guselkumab was very well tolerated and showed limited immunogenicity [67]. The most commonly reported AEs were infections, particularly upper respiratory tract infections, as well as headache, nausea, and fatigue [67,68]. Antibodies to guselkumab were positive in 3.3% of healthy subjects treated with IV-guselkumab, with slightly higher clearance and shorter half-life of the drug. No subject in the SC-guselkumab arms was positive for antidrug antibody detection [67].