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  • 1
    Keywords: EXPRESSION ; CELL ; evaluation ; Germany ; MICROSCOPY ; DISEASE ; DISTINCT ; PROTEIN ; COMPONENTS ; DIFFERENTIATION ; MARKER ; IMPACT ; SKIN ; ALPHA ; MEMBRANE ; MUTATION ; REPAIR ; COMPONENT ; ABERRATIONS ; EXTRACELLULAR-MATRIX ; MUTATIONS ; BETA ; ADHESION ; CELL-ADHESION ; HUMAN KERATINOCYTES ; INTEGRIN ; epidermis ; ultrastructure ; MATRIX ; assembly ; basement membrane ; BASEMENT-MEMBRANE ; extracellular matrix ; ARRAY ; DEFECTS ; INTEGRINS ; analysis ; methods ; JAPANESE ; DEFECT ; immunoelectron microscopy ; EXTRACELLULAR-MATRIX PROTEIN-1 ; lipoid proteinosis ; microvasculature ; aberration ; DERMO-EPIDERMAL JUNCTION ; ECM1 ; HEMIDESMOSOMES ; LAMININ ISOFORMS ; LICHEN-SCLEROSUS ; skin and oral mucosa ; VII COLLAGEN
    Abstract: Background: Excessive basement membrane (BM) deposition in skin and mucosa is characteristic for lipoid proteinosis (LP; hyalinosis cutis et mucosae), an inherited disease caused by extracellular matrix protein 1 (ECM1) mutations. According to ultrastructure there are striking differences between junctional. and microvascular BM. Objective: Distinct analysis of the junctional zone in epidermis and oral mucosa, contrasting concentric BM arrays in the microvasculature; evaluation of impact on epithelial. histogenesis and differentiation, and specifically on adhesion structures to BM (hemidesmosomes). Methods: LP-epithelia were analyzed for alterations in differentiation, BM composition and texture, and hemidesmosomal components by indirect immunofluorescence (IIF), electron microscopy (EM), and immunoelectron microscopy (ImEM). Results: Most striking was the irregular deposition of collagen IV and VII, BM-laminin, and laminin-5 at the junctional. zone, accompanied by lamellate or punctuated structures below BM (IIF), whereas integrin alpha 6 beta 4 and bullous pemphigoid antigen-1 and -2 (BPAG-1/-2) were regularly aligned. Also integrins alpha 2 beta 1 and alpha 3 beta 1 remained restricted to the epidermal basal layer, while the tissue-specific differentiation markers keratin K1/10 (mucosa, additionally K4/13) appeared delayed indicating mild hyperplasia, further confirmed by focal K6/16 expression. Ultrastructure (EM) disclosed abundance of extended basal cell protrusions and junctional aberrations like exfoliating excessive BM material. Hemidesmosomes were complete, but ImEM indicated weakened interactions between their components (BRAG-1, -2, and HD1). Confirming IIF, collagen IV and VII, and laminin-5 appeared extensively scattered, the latter two probably remaining associated. Conclusions: Subtle defects in anchorage assembly, spanning the entire BM zone, apparently compromise epithelial-matrix adhesion, which may provoke (mechanical stress-induced) erroneous BM repair. (c) 2006 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17175139
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  • 2
    Keywords: EXPRESSION ; hormone ; SHAFT DIFFERENTIATION ; CYCLIC ALOPECIA ; MSX2
    Type of Publication: Journal article published
    PubMed ID: 21763112
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  • 3
    Keywords: EXPRESSION ; BLOOD ; Germany ; PROTEIN ; DIFFERENTIATION ; MARKER ; EXTRACELLULAR-MATRIX ; MUTATIONS ; HUMAN KERATINOCYTES ; MORPHOLOGY ; INTEGRIN ; INVOLVEMENT ; TUMOR ANGIOGENESIS ; ultrastructure ; MATRIX ; VESICLES ; extracellular matrix ; laminin ; HISTOLOGY ; function ; LOSSES ; JAPANESE ; POLARITY ; immunoelectron microscopy ; HUMAN-SKIN ; microvascular density ; basement membrane components ; EXTRACELLULAR-MATRIX PROTEIN-1 ; GENE ECM1 ; lipoid proteinosis ; microvasculature ; PERLECAN
    Abstract: Background: In lipoid proteinosis (LP) vascular anomalies represent severe functional defects caused by excessive deposition of basement membrane (BM)-like matrix, particularly around small subepithelial blood vessels. Objective: Correlation of microvascular anomalies in morphology and ultrastructure with extracellular matrix composition and cell interactions for elucidating vascular involvement in LP-pathophysiology. Methods: Biopsies from non-related LP-patients were analyzed by indirect immunofluorescence (IIF), electron microscopy (EM), and immune-EM (ImEM). Results: In LP-skin and mucosa the thickened vessel walls stained strongly for the BM-components type IV collagen, laminin, perlecan, and nidogen (IIF). Integrin (alpha 6 beta 4 was regularly collocated with endothelial surface markers such as PECAM (CD31). Ultrastructure (EM) revealed highly ordered matrix deposits around microvessels, with frequently collapsed lumina, functionally compensated by increased vascular density (histology, IIF). Pericytes were trapped between these concentric BM-layers at varying distances towards the periphery (EM), contrasting their regularly close endothelial apposition. Periodic type IV collagen patterns (ImEM) corroborated the multiple BM-leaflet structure and the lack of a common 'fused' endothelial-pericyte BM, seen normally. Presumptive secretory vesicles, abundant in both cell types, implied an equal contribution to BM-synthesis, but also indicated partial loss of endothelial polarity. Conclusions: In LP thickened vessel walls, composed of multiple BM, profoundly alter microvascular properties, also by interference with endothelial-pericyte interactions. The increased microvascular density reflects compensatory restoration for disabled function. Most remarkable was the exaggerated secretory activity (also at luminal surfaces) underlining the regulatory key role of extracellular matrix protein 1 (ECM1; mutated in LP) in export or turnover of all major BM-components. (c) 2006 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16497486
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  • 4
    Keywords: HPV8 Transgenic mice Skin papilloma development
    Abstract: Background: The human papillomavirus type 8 (HPV8) is associated with the development of nonmelanoma skin cancer. Transgenic mice expressing the complete early gene region of HPV8 (E6/E7/E1/ E2/E4 = CER) or E6 separately under the control of the keratin14 promoter spontaneously developed papillomas characterized by varying degrees of epidermal dysplasia. Papilloma growth could be synchronized by a single UVA/B irradiation of the skin, which led to the development of papillomas within three weeks. Objective: The objective of this study was to identify alterations in cellular gene expression correlated with HPV8 oncogene expression in transgenic mice. Methods: Weapplied global gene expression profiling by microarray analysis and confirmed deregulation of cellular genes by qRT-PCR and immunohistochemical analysis. Results: By comparison of non-lesional HPV8-CER skin with skin of the parental mouse strain FVB/n, two cellular genes, namely StefinA and Sprr2, coding for precursor proteins of the cornified envelope, were predicted to be strongly upregulated in transgenic skin, which could be confirmed in subsequent qRT-PCR experiments. StefinAand Sprr2mRNA expression was enhanced until day 7 afterUVtreatment with higher levels in HPV8 positive skin.While the expression of both genes returned to a normal level in the course of epidermis regeneration in wt mice, the expression persisted elevated in hyperplastic transgenic skin. Staining of an UV induced papilloma of FVB/n wt mouse revealed also strong expression of StefinA and Sprr2 indicating that upregulation in later stages of papilloma formation is independent of HPV8. Conclusion: In non-lesional HPV8-CER transgenic skin StefinA and Sprr2 were found to be indirect/direct transcriptional targets of HPV8.
    Type of Publication: Journal article published
    PubMed ID: 21458245
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  • 5
    Keywords: tumor ; carcinoma ; ASSOCIATION ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; BREAST-CANCER ; p53 ; DNA-DAMAGE ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; PIGMENTATION ; basal cell carcinoma of the skin ; MULTIFACTOR-DIMENSIONALITY REDUCTION ; P53 CODON-72 POLYMORPHISM ; POMC ; SUNTAN RESPONSE
    Abstract: Background: Basal cell carcinoma (BCC) of the skin is the most common neoplasm among the Caucasian population of the western world. Ultraviolet (UV) radiation-induced p53 activation promotes cutaneous pigmentation by increasing transcriptional activity of pro-opiomelanocortin (POMC) in the skin. Induction of POMC/alpha-melanocyte-stimulating hormone (alpha-MSH) activates the melanocortin 1 receptor (MC1R), resulting in skin pigmentation. The tumor suppressor p53 is a key player in stress responses that preserve genomic stability, responding to a variety of insults including DNA damage, hypoxia, metabolic stress and oncogene activation. Malfunction of the p53 pathway is an almost universal hallmark of human tumors. Polymorphisms in the gene encoding p53 (TP53) alter its transcriptional activity, which in turn may influence the UV radiation-induced tanning response. Objective: The aim of the present work is to test association between POMC and TP53 genetic variability, the possible interplay with host factors and the risk of basal cell carcinoma of skin. Methods: We covered the variability of the two genes we used 17 tagging polymorphisms in 529 BCC cases and 532 healthy controls. We have also tested the possible interactions between the genetic variants and three known risk factors for BCC: skin complexion, sun effect and skin response to sun exposure. Results: We did not observe any statistically significant association between SNPs in these two genes and BCC risk overall, nor interactions of SNPs with known BCC risk factors. However we found that, in the group of subjects with lower sun exposure, carriers of one copy of the C allele of the TP53 SNP rs12951053 had a decreased risk of BCC (OR = 0.28, 95% CI 0.12-0.62, P = 0.002). Conclusions: We have observed that the interplay of an environmental risk factor and one polymorphism in TP53 gene could modulate the risk of BCC. (C) 2011 Japanese Society for Investigative Dermatology.
    Type of Publication: Journal article published
    PubMed ID: 21536413
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  • 6
  • 7
    Keywords: carcinoma ; INFECTION ; antibodies ; VACCINES ; VIRUS-LIKE PARTICLES ; IMMUNOGENICITY ; CYTOTOXIC T-LYMPHOCYTES ; SKIN CANCERS ; capsomeres
    Abstract: Background: Infection with different species of cutaneous human papillomaviruses (cHPV) of genus alpha (c alpha HPVs) and associated skin disease are highly prevalent in solid organ transplant recipients (OTR), documenting the importance of the immunological control of HPV infection. Objectives: To investigate the natural course of c alpha HPV-specific cellular and humoral immune responses during systemic long-term immunosuppression. Methods: Integrating bead-based multiplex serology and flow cytometry we analyzed natural caHPV-specific antibodies and T-H cell responses against the major capsid protein L1 of HPV types 2, 27, 57 (species 4) and 3,10 and 77 (species 2) in sera and blood of OTR before and after initiation of iatrogenic immunosuppression and in comparison to immunocompetent individuals (IC). Results: Among OTR we observed an overall 42% decrease in humoral L1 -specific immune responses during the course of iatrogenic immunosuppression, comparing median values 30d before and 30d after initiation of immunosuppressive therapy (p 〈0.05). This difference disappeared after long-term (〉1 year) immunosuppression. The predominant cellular L1-specific immune response was of type T(H)1 (CD4(+)CD40L(+)IL-2(+)IFN-gamma(+)). Consistent with the detected L1-specific antibody titers, L1-specific T(H)1 responses were unchanged in long-term immunosuppressed OTR compared to IC. Notably, c alpha HPV-L1-specific IL-2(+)/CD40L(+)CD4(+) or IFN-gamma(+)/CD40L(+)CD4(+) T-H cell responses against any of the c alpha HPV-L1 types were significantly higher in OTR with clinically apparent common warts. Conclusion: The systemic humoral immune response against c alpha HPV may reflect the individual degree of iatrogenic immunosuppression indicating a higher susceptibility for c alpha HPV infection among OTR during the early phase after organ transplantation. Humoral c alpha HPV-specific immune responses may show a reconstitution to pre-transplantation levels despite continuous potent immunosuppression.
    Type of Publication: Journal article published
    PubMed ID: 25439730
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  • 8
    Abstract: BACKGROUND: K1 and K2 are the main type II keratins in the suprabasal epidermis where each of them heterodimerizes with the type I keratin K10 to form intermediate filaments. In regions of the ears, tail, and soles of the mouse, only K2 is co-expressed with K10, suggesting that these keratins suffice to form a mechanically resilient cytoskeleton. OBJECTIVE: To determine the effects of the suppression of both main keratins, K2 and K10, in the suprabasal plantar epidermis of the mouse. METHODS: Krt2(-/-) Krt10(-/-) mice were generated by crossing Krt2(-/-) and Krt10(-/-) mice. Epidermal morphology of soles of hind-paws was examined macroscopically and histologically. Immunofluorescence analysis and quantitative PCR analysis were performed to analyze the expression of keratins in sole skin of wildtype and Krt2(-/-) Krt10(-/-) mice. Highly abundant proteins of the sole stratum corneum were determined by electrophoretic and chromatographic separation and subsequent mass spectrometry. RESULTS: K2 and K10 are the most prominent suprabasal keratins in normal mouse soles with the exception of the footpads where K1, K9 and K10 predominate. Mice lacking both K2 and K10 were viable and developed epidermal acanthosis and hyperkeratosis in inter-footpad epidermis of the soles. The expression of keratins K1, K9 and K16 was massively increased at the RNA and protein levels in the soles of Krt2(-/-) Krt10(-/-) mice. CONCLUSIONS: This study demonstrates that the loss of the main cytoskeletal components of plantar epidermis, i.e. K2 and K10, can be only partly compensated by the upregulation of other keratins. The thickening of the epidermis in the soles of Krt2(-/-) Krt10(-/-) mice may serve as a model for pathomechanistic aspects of palmoplantar keratoderma.
    Type of Publication: Journal article published
    PubMed ID: 26603179
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  • 9
    Abstract: Systemic sclerosis (SSc) is one of the most complex systemic autoimmune diseases with multi-organ involvement and heterogeneous clinical manifestations. The exact etiology of SSc is still unknown. However, identified target structures are components of endothelial cells, the innate/adaptive immune systems and fibroblasts, resulting in the hallmarks of the disease in form of inflammation/autoimmunity, vasculopathy and fibrosis of the skin and internal organs. There has been a large body of evidence that the adaptive immune system with autoreactive T and B cells producing autoantibodies plays a central role in the pathogenesis of SSc but the role of earlier pathogenic processes involving the innate immune system, is far from being understood. There is strong evidence that a dysregulation of innate lymphoid cells and myeloid cells critically contributes to early pathogenic events in SSc. As disruption of vascular homeostasis and a fibroproliferative vasculopathy are hallmarks of early SSc, intravascular processes including platelet activation and interaction with neutrophils and monocytes, may even be upstream of innate immune deviation. Therefore, further studies of the dysregulated innate immune system may provide insights into novel and potentially curative treatments of SSc. In this review, we highlight the most relevant findings regarding the involvement of innate immune cells during the early stage of cutaneous fibrosis in SSc, with emphasis on the role of neutrophils, myeloid cells and innate lymphoid/NK cells in the pathogenesis of SSc and their potential as therapeutic targets for this difficult-to-treat autoimmune disease.
    Type of Publication: Journal article published
    PubMed ID: 28655471
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  • 10
    Abstract: BACKROUND: The fumaric acid ester (FAE) dimethylfumarate (DMF) is a small molecule immunomodulator successfully used for the treatment of psoriasis and multiple sclerosis (MS). DMF is thought to inhibit pathogenic immune responses with Th17/Th1T cells, and IL-23/IL-12 producing dendritic cells (DCs). 6-sulfo LacNAc expressing dendritic cells (slanDCs) are a human pro-inflammatory cell type found frequently among the infiltrating leukocytes in skin lesions of psoriasis and brain lesions of MS. OBJECTIVE: To explore the influence of DMF on functional properties and cell signaling pathways of slanDCs. METHODS: In the context of slanDCs we studied the role of DMF in modulating cell migration, phenotypic maturation, cytokine production, cell signaling and T cell stimulation. RESULTS: Initially, we observed the reduction of slanDCs numbers in psoriasis skin lesions of FAE treated patients. Studying whether DMF controls the migratory capacity of slanDCs to chemotactic factors expressed in psoriasis we observed an inhibition of the CX3CL1 and C5a depedent cell migration. DMF also attenuated the rapid spontaneous phenotypic maturation of slanDCs, as judged by a reduced CD80, CD86, CD83 and HLA-DR expression. In addition, we observed a DMF-dependent decrease of IL-23, IL-12, TNF-alpha and IL-10 secretion, and noticed a reduced capacity to stimulate Th17/Th1 responses. DMF targeted in slanDCs different intracellular cell signaling pathways including NFkappaB, STAT1 and HO-1. CONCLUSIONS: With this study we identify a frequent pro-inflammatory cell type found in psoriasis and MS as a relevant target for the therapeutic immunomodulatory effects of DMF.
    Type of Publication: Journal article published
    PubMed ID: 28732748
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