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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keratin 5 gene promoter which directs transgene expression in basal keratinocytes and outer root sheath cells14 (and unpublished observations) and the keratin 6 gene promoter specific for outer root sheath cells.14,29 Weak and deregulated transgene expression is seen if relatively short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
Retinoids in Antiaging Therapy
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Zehra Aşiran Serdar, Ezgi Aktaş Karabay
Retinaldehyde is an intermediate metabolite formed in the transformation of retinol to retinoic acid in human keratinocytes (68). Its biologic activity results from its enzymatic transformation into retinoic acid via the activity of epidermal keratinocytes, and it is qualitatively similar to that of retinoic acid. Treatment with topical retinaldehyde was demonstrated to induce CRABP II mRNA and protein, increase epidermal thickness, increase keratin-14 expression, and enhance keratinocyte proliferation (69). Retinaldehyde 0.05% and 0.05% retinoic acid treatments are equally effective in reducing wrinkles and skin roughness, whereas retinaldehyde causes minimal irritation, leading patients to be compliant with the therapy (70,71). In another study, retinaldehyde creams at 0.1% and 0.05% doses were well tolerated and effectively improved photoaged skin (72). Daily application of topical 0.05% retinaldehyde after laser therapy was found to be associated with better results, suggesting that retinaldehyde can be used as an adjuvant therapy in antiaging procedures (73).
Epidermolysis bullosa
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Inherited EB results from mutations in any of several structural proteins present within the keratinocyte or the skin BMZ. Severity of skin and extracutaneous diseases is a reflection of the type of mutation that is present, as well as the ultrastructural location of the targeted protein. In EBS, blister cleavage occurs in basal or spinous layers of the epidermis, and keratinocytes have abnormal density and organization of keratin filaments. In JEB, blisters form in lamina lucida, where hemidesmosome structure and density are frequently diminished. In DEB, a blister cavity is formed beneath the lamina densa, and anchoring fibrils appear abnormal, reduced, or altogether absent. In Kindler syndrome, multiple cleavage planes may be seen with the same sample of skin [4–6]. The localized, generalized, and Dowling-Meara variants of EBS are caused by missense mutations in keratin-5 and keratin-14 genes (KRT5, KRT14). JEB-generalized is associated with premature termination codons in both alleles of any one of the three genes, LAMA3, LAMB3, and LAMC2, encoding the three constituent polypeptide chains of the laminin-332 gene. In JEB localized, there is a premature termination codon in one allele and another less disruptive mutation in the paired allele. DEB is caused by mutations in the collagen VII gene [3].
Targeting mitochondria in dermatological therapy: beyond oxidative damage and skin aging
Published in Expert Opinion on Therapeutic Targets, 2022
Tongyu C Wikramanayake, Jérémy Chéret, Alec Sevilla, Mark Birch-Machin, Ralf Paus
Interestingly, epidermal keratinocytes and their stem/progenitor cells appear to be independent of fully functional mitochondria, at least in neonatal mice [188]. Epidermal development, proliferation and skin barrier function all remain relatively intact in neonatal mice with the ETC functionally ablated in all skin epithelia (conditional knockout of mitochondrial transcription factor A, Tfam, using a keratin 14 promoter-driven Cre) [188]. This corresponds well to the abrogation of oxidative respiration through complex IV inhibition with potassium cyanide that does not completely halt human epidermal keratinocyte proliferation or induce their massive cell death ex vivo [200]. However, abnormalities are detected in keratinocyte terminal differentiation in Tfam knockout (-/-) mice, suggesting that mitochondrial ROS production is required for normal epidermal differentiation and skin barrier function [188,191]. These data in mouse models suggest that mitochondrial respiratory chain activity and related ROS production may interfere with the quality and speed of keratinocyte terminal differentiation and epidermal barrier formation in human skin as well, and not only epidermal aging and keratinocyte senescence [249–253]. Along these lines, threshold ROS levels appear to be required for human keratinocyte terminal differentiation in raft cultures [191].
Proteomic analysis shows that the main constituent of subepidermal localised cutaneous amyloidosis is not galectin-7
Published in Amyloid, 2021
Jessica R. Chapman, Anna Liu, San S. Yi, Enmily Hernandez, Maria Stella Ritorto, Achim A. Jungbluth, Melissa Pulitzer, Ahmet Dogan
The peptide profile identified by mass spectrometric analysis of the microdissected dermal amyloid deposits from the five patients with localised cutaneous lichen or macular amyloidosis were consistent with keratinic amyloidosis [9,22]. Specifically, keratin 5 was abundant and keratin 14 was also present in the microdissected amyloid deposits. Additionally, the common amyloidosis protein markers identified in all subtypes, apolipoprotein E and serum amyloid P, were detected in the amyloid deposits. Galectin-7 was not detected in any of the Congo red positive dermal regions. Galectin-7 was only detected in the overlying Congo red negative epidermis microdissected from the same biopsies (Table 2). Serum amyloid P and apolipoprotein E were not seen in the Congo red negative epidermis. Actin was present in both the amyloid deposits and the overlying unaffected epidermis at comparable levels.
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.