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  • 1.
    Agnarsdóttir, Margrét
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sooman, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Bolander, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Strömberg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rexhepaj, Elton
    UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gallagher, William
    UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Uhlen, Mathias
    Department of Proteomics, School of Biotechnology, AlbaNova University Center, KTH-Royal Institute of Technology, Stockholm, Sweden.
    Hedstrand, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    SOX10 expression in superficial spreading and nodular malignant melanomas2010In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 20, no 6, p. 468-478Article in journal (Refereed)
    Abstract [en]

    SOX10 is a transcription factor expressed in nerve cells and melanocytes. The aim of this study was to investigate the protein expression pattern of SOX10 in malignant melanoma tumors and to analyze whether the results correlated with clinical parameters and the proliferation marker Ki-67. Furthermore, proliferation and migration were analyzed in three different cell lines employing SOX10 small interfering RNA-mediated silencing. Expression patterns were determined in 106 primary tumors and 39 metastases in addition to 16 normal skin samples and six benign nevi employing immunohistochemistry and tissue microarrays. The immunohistochemical staining was evaluated manually and with an automated algorithm. SOX10 was strongly expressed in the benign tissues, but for the malignant tumors superficial spreading melanomas stained stronger than nodular malignant melanomas (P=0.008). The staining intensity was also inversely correlated with T-stage (Spearman's ρ=-0.261, P=0.008). Overall survival and time to recurrence were significantly correlated with SOX10 intensity, but not in multivariate analysis including T-stage. With the automated algorithm there was an inverse correlation between the SOX10 staining intensity and the proliferation marker, Ki-67 (ρ=-0.173, P=0.02) and a significant difference in the intensity signal between the benign tissues, the primary tumors and the metastases where the metastases stained the weakest (P≤0.001). SOX10 downregulation resulted in variable effects on proliferation and migration rates in the melanoma cell lines. In conclusion, the SOX10 intensity level differed depending on the tissue studied and SOX10 might have a role in survival. No conclusion regarding the role of SOX10 for in-vitro proliferation and migration could be drawn.

  • 2.
    Alimohammadi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Knight, Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Scalp necrosis as a late sign of giant-cell arteritis2013In: Case reports in immunology, ISSN 2090-6609, Vol. 2013, article id 231565Article in journal (Refereed)
    Abstract [en]

    Retinal infarction and scalp necrosis are described as unusual but devastating complications of giant-cell arteritis. We report a patient with this rare complication and emphasize the importance of timely diagnosis and treatment of giant-cell arteritis.

  • 3.
    Alimohammadi, Mohammed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Neurophysiological Measures of Efficacy and Safety for Botulinum Toxin Injection in Facial and Bulbar Muscles: Special Considerations2017In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 9, no 11, article id 352Article, review/survey (Refereed)
    Abstract [en]

    Botulinum toxin (BoNT) injections into facial and bulbar muscles are widely and increasingly used as medical treatments for cervical and facial dystonia, facial hemispasm, correction of facial palsy, hyperhidrosis, as well as cosmetic treatment of glabellar lines associated with grief and anger. Although BoNT treatment is generally considered safe, the diffusion of the toxin to surrounding muscles may result in complications, including difficulties swallowing, in a dose-dependent manner. The sensitivity of clinical examination for detecting adverse events after BoNT treatment is limited. Few reports have highlighted the potential effects on other muscles in the facial area due to the spreading of the toxin. The possibilities of spreading and thus unknown pharmacological BoNT effects in non-targeted muscles emphasise the importance of correct administration of BoNT in terms of dose selection, injection points, and appropriate effect surveillance. In this review article, we will focus on novel objective measures of efficacy and safety regarding BoNT treatment of facial muscles and the reasons why this is important.

  • 4. Aushev, M.
    et al.
    Mussolino, C.
    Cathomen, T.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Reichelt, J.
    Molecular surgery for epidermolysis bullosa simplex2014In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 170, no 4, p. E35-E35Article in journal (Other academic)
  • 5.
    Berg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Lindberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Possible gender differences in the quality of life and choice of therapy in acne2011In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 25, no 8, p. 969-972Article in journal (Refereed)
    Abstract [en]

    Background Acne is a very common skin disease that has major impact on the patients' quality of life. Although the disease has been extensively studied we still need more knowledge of factors influencing the decisions for choice of therapy. Objective To evaluate the relationships between clinical severity, patients' self-reported quality of life, treatment choice and the outcome of therapy in a structured out-patient acne clinic. Methods In total 211 consecutive patients (143 females, 68 males) at a structured acne clinic were included. At the first visit a clinical assessment was conducted, therapy was initiated and the patients answered a quality-of-life questionnaire (Dermatology Life Quality Index, DLQI). A follow up was performed after six months, when patients once again answered the DLQI questionnaire and the clinical outcome was assessed by the physician. Results The quality of life was improved after treatment at a group level. At the first visit, the quality of life showed a gender difference (females scoring worse) but did not correlate to the clinical grading nor to the choice of therapy. At six months the DLQI correlated with clinical outcome. Patients with isotretinoin therapy showed a significantly greater improvement in quality of life. There was a tendency to gender difference in the choice of therapy, as in females 32% of the patients were treated with isotretinoin although they were clinically graded as moderate. The corresponding figure for males was 23%. A correlation was found between the initial clinical grading and gender, age and the choice of therapy. Conclusion DLQI can be used to evaluate treatment effects in acne. However, the self-reported quality of life will depend on several factors including age, gender, psychosocial factors and clinical severity.

  • 6.
    Berne, Berit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Tammela, Monica
    Färm, Gunilla
    Inerot, Annica
    Lindberg, Magnus
    Can the reporting of adverse skin reactions to cosmetics be improved?: A prospective clinical study using a structured protocol2008In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 58, no 4, p. 223-227Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The use of cosmetics is rising, and adverse reactions to these products are increasing. In Sweden, the Medical Products Agency (MPA) keeps a voluntary reporting system for such adverse reactions. However, the reporting is sparse, consisting almost only of cases with test-proven allergic contact dermatitis, thus under-reporting the more common irritant reactions. OBJECTIVE: The aim of the study was to try to improve the reporting system. PATIENTS AND METHODS: Dermatologists at 3 dermatology departments used a structured protocol during the clinical investigation of 151 consecutive patients reporting skin reactions to cosmetics. The protocol included symptoms, signs, affected body site, suspected products, and final diagnosis after patch testing. Based on clinical data and patch test results, a causality assessment for each product was made according to a protocol used at the MPA. Results: Allergic contact dermatitis was found in 28% of the patients, and irritant reactions were equally common at 27%. CONCLUSIONS: Using this structured protocol, the cases of irritant dermatitis were also reported, and it is recommended that such a protocol is used as a standard to improve the reporting of adverse reactions to skin care products.

  • 7. Biazar, C.
    et al.
    Sigges, J.
    Patsinakidis, N.
    Ruland, V.
    Amler, S.
    Bonsmann, G.
    Kuhn, A.
    Haust, M.
    Nyberg, Filippa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Bata, Z.
    Mihályi, L.
    Olteanu, R.
    Pujol, R. M.
    Sánchez-Schmidt, J. M.
    Medenica, L.
    Skiljevic, D.
    Reich, A.
    Szepietowski, J. C.
    Dalle Vedove, C.
    Girolomoni, G.
    Hawro, T.
    Zalewska-Janowska, A.
    Glaeser, R.
    Huegel, R.
    Jedlicková, H.
    Bygum, A.
    Laurinaviciene, R.
    Benoit, S.
    Broecker, E.
    Bahmer, F. A.
    Aberer, E.
    Wutte, N.
    Lipozencic, J.
    Marinovic, B.
    Sárdy, M.
    Bekou, V.
    Ruzicka, T.
    Frances, C.
    Soutou, B.
    Lee, H.
    Worm, M.
    Gruschke, A.
    Hunzelmann, N.
    Steinbrink, K.
    Romiti, R.
    Sticherling, M.
    Erfurt-Berge, C.
    Avgerinou, G.
    Papafragkaki, D.
    Antiga, E.
    Caproni, M.
    Mayer, B.
    Volc-Platzer, B.
    Kreuter, A.
    Tigges, C.
    Heil, Peter Maximilian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Stingl, G.
    Cutaneous lupus erythematosus: First multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE)2013In: Autoimmunity Reviews, ISSN 1568-9972, E-ISSN 1873-0183, Vol. 12, no 3, p. 444-454Article, review/survey (Refereed)
    Abstract [en]

    In this prospective, cross-sectional, multicenter study, we assessed clinical and laboratory characteristics from patients with cutaneous lupus erythematosus (CLE) using the Core Set Questionnaire of the European Society of Cutaneous Lupus Erythematosus (EUSCLE). 1002 (768 females, 234 males) patients with different subtypes of CLE, such as acute CLE (ACLE, 304 patients), subacute CLE (SCLE, 236 patients), chronic CLE (CCLE, 397 patients), and intermittent CLE (ICLE, 65 patients), from 13 European countries were collected and statistically analyzed by an SPSS database. The main outcome measures included gender, age at onset of disease, LE-specific and LE-nonspecific skin lesions, photosensitivity, laboratory features, and the criteria of the American College of Rheumatology (ACR) for the classification of systemic lupus erythematosus. The mean age at onset of disease was 43.0±15.7 years and differed significantly between the CLE subtypes. In 347 (34.6%) of the 1002 patients, two or more CLE subtypes were diagnosed during the course of the disease and 453 (45.2%) presented with LE-nonspecific manifestations. Drug-induced CLE and SjögrenD́s Syndrome had the highest prevalence in SCLE patients (13.1% and 14.0%, respectively). Photosensitivity was significantly more frequent in patients with ACLE, SCLE, and ICLE compared with those with CCLE. The detection of antinuclear antibodies such as anti-Ro/SSA and anti-La/SSB antibodies revealed further significant differences between the CLE subtypes. In summary, the EUSCLE Core Set Questionnaire and its database facilitate the analysis of clinical and laboratory features in a high number of patients with CLE and will contribute to standardized assessment and monitoring of the disease in Europe.

  • 8.
    Blokzijl, Andries
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chen, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafsdottir, Sigrun M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vuu, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Hedstrand, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Elevated Levels of SOX10 in Serum from Vitiligo and Melanoma Patients, Analyzed by Proximity Ligation Assay2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0154214Article in journal (Refereed)
    Abstract [en]

    Background

    The diagnosis of malignant melanoma currently relies on clinical inspection of the skin surface and on the histopathological status of the excised tumor. The serum marker S100B is used for prognostic estimates at later stages of the disease, but analyses are marred by false positives and inadequate sensitivity in predicting relapsing disorder.

    Objectives

    To investigate SOX10 as a potential biomarker for melanoma and vitiligo.

    Methods

    In this study we have applied proximity ligation assay (PLA) to detect the transcription factor SOX10 as a possible serum marker for melanoma. We studied a cohort of 110 melanoma patients. We further investigated a second cohort of 85 patients with vitiligo, which is a disease that also affects melanocytes.

    Results

    The specificity of the SOX10 assay in serum was high, with only 1% of healthy blood donors being positive. In contrast, elevated serum SOX10 was found with high frequency among vitiligo and melanoma patients. In patients with metastases, lack of SOX10 detection was associated with treatment benefit. In two responding patients, a change from SOX10 positivity to undetectable levels was seen before the response was evident clinically.

    Conclusions

    We show for the first time that SOX10 represents a promising new serum melanoma marker for detection of early stage disease, complementing the established S100B marker. Our findings imply that SOX10 can be used to monitor responses to treatment and to assess if the treatment is of benefit at stages earlier than what is possible radiologically.

  • 9. Bornholdt, Dorothea
    et al.
    Atkinson, T. Prescott
    Bouadjar, Bakar
    Catteau, Benoit
    Cox, Helen
    De Silva, Deepthi
    Fischer, Judith
    Gunasekera, Chalukya N.
    Hadj-Rabia, Smail
    Happle, Rudolf
    Holder-Espinasse, Muriel
    Kaminski, Elke
    Koenig, Arne
    Megarbane, Andre
    Megarbane, Hala
    Neidel, Ulrike
    Oeffner, Frank
    Oji, Vinzenz
    Theos, Amy
    Traupe, Heiko
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    van Bon, Bregje W.
    Virtanen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Grzeschik, Karl-Heinz
    Genotype-Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS22013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 4, p. 587-594Article in journal (Refereed)
    Abstract [en]

    Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotypephenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.

  • 10.
    Bosdotter Enroth, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Rystedt, Alma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Covaciu, Lucian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hymnelius, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Rystedt, Einar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Nyberg, Rebecka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Naver, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Swartling, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Bilateral forearm intravenous regional anesthesia with prilocaine for botulinum toxin treatment of palmar hyperhidrosis2010In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 63, no 3, p. 466-474Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Treatment of palmar hyperhidrosis with botulinum toxin (BTX) requires effective anesthesia, but previous methods have not provided enough pain relief or have resulted in a prolonged impaired hand function. OBJECTIVE: This is a study of bilateral forearm intravenous regional anesthesia using prilocaine for BTX treatment of palmar hyperhidrosis. METHODS: In all, 166 patients (100 female and 66 male) were treated bilaterally with intracutaneous BTX type A injections using intravenous regional anesthesia with prilocaine (5 mg/mL). In a subgroup of patients, forearm nerves were studied with neurophysiologic methods and blood concentrations of prilocaine were measured. Pain evaluation with a visual analog scale was accompanied with a questionnaire about the treatment. RESULTS: In all, 95% of the patients answering the questionnaire (response rate 89%) were satisfied with the anesthetic effect. No serious adverse events occurred. There was a fast recovery of motor function (in median 6 minutes) and sensory function (in median 20 minutes). No subclinical signs of sensory nerve damage were found. LIMITATIONS: Recall and reporting bias are potential sources of limitations in this study. CONCLUSION: Bilateral forearm intravenous regional anesthesia provides an effective and well-tolerated anesthesia during BTX treatment of palmar hyperhidrosis.

  • 11. Broesby-Olsen, Sigurd
    et al.
    Dybedal, Ingunn
    Gülen, Theo
    Kielsgaard Kristensen, Thomas
    Boe Møller, Michael
    Ackermann, Leena
    Sääf, Maria
    Karlsson, Maria A
    Agertoft, Lone
    Brixen, Kim
    Hermann, Pernille
    Stylianou, Eva
    Mortz, Charlotte G
    Torfing, Trine
    Havelund, Troels
    Sander, Birgitta
    Bergström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Bendix, Marie
    Garvey, Lene H
    Weis Bjerrum, Ole
    Valent, Peter
    Bindslev-Jensen, Carsten
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Vestergaard, Hanne
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Multidisciplinary Management of Mastocytosis: Nordic Expert Group Consensus2016In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 96, no 5Article in journal (Refereed)
    Abstract [en]

    Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.

  • 12.
    Brozzetti, Annalisa
    et al.
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morelli, Silvia
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Minarelli, Viviana
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, S-17176 Stockholm, Sweden..
    Giordano, Roberta
    Univ Turin, Dept Med Sci, Div Endocrinol Diabetol & Metab, I-10126 Turin, Italy..
    De Bellis, Annamaria
    Univ Naples 2, Endocrinol Unit, Dept Cardiothorac & Resp Sci, I-80132 Naples, Italy..
    Perniola, Roberto
    V Fazzi Reg Hosp, Dept Pediat Neonatal Intens Care, I-73100 Lecce, Italy..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Falorni, Alberto
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy.
    Autoantibody Response Against NALP5/MATER in Primary Ovarian Insufficiency and in Autoimmune Addison's Disease2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 5, p. 1941-1948Article in journal (Refereed)
    Abstract [en]

    Context: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. Objectives: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. Methods: Autoantibodies against NALP5/MATER and inhibin chains-alpha and -beta A were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. Results: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-alpha/beta A autoantibodies. Conclusions: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.

  • 13.
    Buraczewska, Izabela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Lindberg, Magnus
    Lodén, Marie
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Long-term treatment with moisturizers affects the mRNA levels of genes involved in keratinocyte differentiation and desquamation2009In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 301, no 2, p. 175-181Article in journal (Refereed)
    Abstract [en]

    In a recent study, we showed that long-term treatment with two different moisturizers affected TEWL in opposite directions. Therefore, we decided to examine the effect of these moisturizers on the cellular and molecular level. In a randomized controlled study on 20 volunteers, epidermal mRNA expression of genes essential for keratinocyte differentiation and desquamation after a 7-week treatment with two moisturizers was analyzed. Treatment with one test moisturizer increased gene expression of involucrin, transglutaminase 1, kallikrein 5, and kallikrein 7, while the other moisturizer affected only expression of cyclin-dependent kinase inhibitor 1A. Thus, moisturizers are able to modify the skin barrier function and change the mRNA expression of certain epidermal genes. Since the type of influence depends on the composition of the moisturizer, these should be tailored in accordance with the requirement of the barrier of each individual patient, which merits further investigations.

  • 14.
    Buraczewska, Izabela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Lindberg, Magnus
    Lodén, Marie
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Moisturizers change the mRNA expression of enzymes synthesizing skin barrier lipids2009In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 301, no 8, p. 587-594Article in journal (Refereed)
    Abstract [en]

    In a previous study, 7-week treatment of normal human skin with two test moisturizers, Complex cream and Hydrocarbon cream, was shown to affect mRNA expression of certain genes involved in keratinocyte differentiation. Moreover, the treatment altered transepidermal water loss (TEWL) in opposite directions. In the present study, the mRNA expression of genes important for formation of barrier lipids, i.e., cholesterol, free fatty acids and ceramides, was examined. Treatment with Hydrocarbon cream, which increased TEWL, also elevated the gene expression of GBA, SPTLC2, SMPD1, ALOX12B, ALOXE3, and HMGCS1. In addition, the expression of PPARG was decreased. On the other hand, Complex cream, which decreased TEWL, induced only the expression of PPARG, although not confirmed at the protein level. Furthermore, in the untreated skin, a correlation between the mRNA expression of PPARG and ACACB, and TEWL was found, suggesting that these genes are important for the skin barrier homeostasis. The observed changes further demonstrate that long-term treatment with certain moisturizers may induce dysfunctional skin barrier, and as a consequence several signaling pathways are altered.

  • 15.
    Buraczewska, Izabela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Lindberg, Magnus
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Lodén, Marie
    Changes in skin barrier function following long-term treatment with moisturizers, a randomized controlled trial2007In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 156, no 3, p. 492-498Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Moisturizers are commonly used by patients with dry skin conditions as well as people with healthy skin. Previous studies on short-term treatment have shown that moisturizers can weaken or strengthen skin barrier function and also influence skin barrier recovery. However, knowledge of the effects on skin barrier function of long-term treatment with moisturizers is still scarce. OBJECTIVES: To investigate the impact of long-term treatment with moisturizers on the barrier function of normal skin, as measured by transepidermal water loss (TEWL) and susceptibility to an irritant, and to relate those effects to the composition of the designed experimental moisturizers. METHODS: Volunteers (n = 78) were randomized into five groups. Each group treated one volar forearm for 7 weeks with one of the following preparations: (i) one of three simplified creams, containing only a few ingredients in order to minimize the complexity of the system; (ii) a lipid-free gel; (iii) one ordinary cream, containing 5% urea, which has previously been shown to decrease TEWL. The lipids in the simplified creams were either hydrocarbons or vegetable triglyceride oil, and one of them also contained 5% urea. After 7 weeks, treated and control forearms were exposed for 24 h to sodium lauryl sulfate (SLS) using a patch test. TEWL, blood flow and skin capacitance of both SLS-exposed and undamaged skin were evaluated 24 h after removal of patches. Additionally, a 24-h irritancy patch test of all test preparations was performed on 11 volunteers in order to check their possible acute irritancy potential. RESULTS: Changes were found in the barrier function of normal skin after 7 weeks of treatment with the test preparations. The simplified creams and the lipid-free gel increased TEWL and skin response to SLS, while the ordinary cream had the opposite effect. One of the simplified creams also decreased skin capacitance. All test preparations were shown to be nonirritant, both by short-term irritancy patch test and by measurement of blood flow after long-term treatment. CONCLUSIONS: Moisturizers influence the skin barrier function of normal skin, as measured by TEWL and susceptibility to SLS. Moreover, the effect on skin barrier function is determined by the composition of the moisturizer. The ingredients which influence the skin barrier function need to be identified, and the mechanism clarified at the molecular level.

  • 16. Bygum, Anette
    et al.
    Virtanen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Brandrup, Flemming
    Ganemo, Agneta
    Sommerlund, Mette
    Strauss, Gitte
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Generalized and Naevoid Epidermolytic Ichthyosis in Denmark: Clinical and Mutational Findings2013In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 93, no 3, p. 309-313Article in journal (Refereed)
    Abstract [en]

    A Danish Swedish collaboration was established to identify and classify a Danish cohort of patients with epidermolytic ichthyosis, also known as epidermolytic hyperkeratosis. Patients were recruited from 5 dermatology departments in Denmark, and data were obtained using a structured questionnaire and a systematic examination together with photographs, histopathological descriptions and blood samples for mutational analysis. Sixteen patients from 12 families with generalized or naevoid epidermolytic ichthyosis and ichthyosis bullosa of Siemens were identified. Five families had mutations in K1 and 6 families had mutations in K10. Nine patients had been treated with systemic retinoids (etretinate, acitretin, isotretinoin or alitretinoin), but only 3 patients had acceptable treatment responses and chose to continue therapy. In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%). We identified 4 novel disease-causing mutations.

  • 17.
    Bäckvall, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Similar UV responses are seen in a skin organ culture as in human skin in vivo2002In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 11, no 4, p. 349-356Article in journal (Refereed)
    Abstract [en]

    Ultraviolet radiation (UVR) plays an important role in the development of non-melanoma skin cancer. Most tumors develop in chronically sun-exposed skin, most often in cosmetically sensitive locations, where in vivo experiments may be difficult to perform. In this study, we describe a skin organ culture model with preserved normal morphology and intact response to UVR. Skin explants from chronically sun-exposed and non-sun-exposed skin were irradiated with artificial UVA+UVB with and without topical sunscreen. UV-induced DNA damage, epidermal p53 response and repair kinetics were analyzed using immunohistochemistry. Four hours after UV-irradiation epidermal keratinocytes showed a strong immunoreactivity for thymine-dimers. Gradual repair during an incubation time resulted in few residual thymine-dimers after 48 h. Repair appeared to be more efficient in chronically sun-exposed skin compared with non-sun-exposed skin. There was also an accumulation of p53 protein in epidermal keratinocytes, peaking at 4-24 h after irradiation. Large interindividual differences with respect to formation and repair of thymine-dimers as well as induction and duration of the p53 response were observed. Skin explants treated with topical sunscreen prior to UV-irradiation showed a clear reduction of thymine-dimers and p53 expression. The epidermal UV-responses and repair kinetics in organ-cultured skin were similar to what was found in vivo. Our data suggest that organ-cultured skin provides a valuable tool for studies of UV-induced epidermal responses in chronically sun-exposed skin.

  • 18.
    Chamcheu, Jean Christopher
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Disease-causing Keratin Mutations and Cytoskeletal Dysfunction in Human Skin: In vitro Models and new Pharmacologic Strategies for Treating Epidermolytic Genodermatoses2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Epidermolysis bullosa simplex (EBS) and epidermolytic ichthyosis (EI) are rare skin fragility diseases characterized by intra-epidermal blistering due to autosomal dominant-negative mutations in basal (KRT5 or KRT14) and suprabasal (KRT1 or KRT10) keratin genes,  respectively. Despite vast knowledge in the disease pathogenesis, the pathomechanisms are not fully understood, and no effective remedies exist. The purpose of this work was to search for keratin gene mutations in EBS patients, to develop in vitro models for studying EBS and EI, and to investigate novel pharmacological approaches for both diseases.

    We identified both novel and recurrent KRT5 mutations in all studied EBS patients but one which did not show any pathogenic keratin mutations. Using cultured primary keratinocytes from EBS patients, we reproduced a correlation between clinical severity and cytoskeletal instability in vitro. Immortalized keratinocyte cell lines were established from three EBS and three EI patients with different phenotypes using HPV16-E6E7. Only cell lines derived from severely affected patients exhibited spontaneous keratin aggregates under normal culture conditions. However, heat stress significantly induced keratin aggregates in all patient cell lines. This effect was more dramatic in cells from patients with a severe phenotype. In organotypic cultures, the immortalized cells were able to differentiate and form a multilayered epidermis reminiscent of those observed in vivo. Addition of two molecular chaperones, trimethylamine N-oxide dihydrate (TMAO) and sodium 4-phenylbutyrate (4-PBA), reduced the keratin aggregates in both stressed and unstressed EBS and EI keratinocytes, respectively. The mechanism of action of TMAO and 4-PBA was shown to involve the endogenous chaperone system (Heat shock proteins e.g. Hsp70). Besides, MAPK signaling pathways also seemed to be incriminated in the pathogenesis of EBS. Furthermore, depending on which type of keratin is mutated, 4-PBA up-regulated Hsp70 and KRT4 (possibly compensating for mutated KRT1/5), and down-regulated KRT1 and KRT10, which could further assist in protecting EBS and EI cells against stress.

    In conclusion, novel and recurrent pathogenic keratin mutations have been identified in EBS. Immortalized EBS and EI cell lines that functionally reflect the disease phenotype were established. Two pharmacologic agents, TMAO and 4-PBA, were shown to be promising candidates as novel treatment of heritable keratinopathies in this in vitro model.

    List of papers
    1. Epidermolysis bullosa simplex due to KRT5 mutations: mutation-related differences in cellular fragility and the protective effects of trimethylamine N-oxide in cultured primary keratinocytes
    Open this publication in new window or tab >>Epidermolysis bullosa simplex due to KRT5 mutations: mutation-related differences in cellular fragility and the protective effects of trimethylamine N-oxide in cultured primary keratinocytes
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    2010 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 162, no 5, p. 980-989Article in journal (Refereed) Published
    Abstract [en]

    Summary Background Epidermolysis bullosa simplex (EBS) is a mechanobullous skin fragility disease characterized by cytolysis of basal keratinocytes and intraepidermal blistering often caused by mutations in keratin genes (KRT5 or KRT14). No remedies exist for these disorders presenting a need for development of novel therapies. Objectives To identify new genotype-phenotype relationships in vivo and in cultured primary EBS keratinocytes in vitro, and to study the cytoskeletal stabilizing effects of trimethylamine N-oxide (TMAO) in heat-stressed EBS cells. Methods Genomic DNA and cDNA samples from three Swedish patients with EBS were analysed for keratin mutations. Primary EBS keratinocyte cultures were established, heat stressed with and without added TMAO, followed by evaluation of cellular fragility. Results In addition to the previously reported KRT5 mutation (V186L) in one patient, two patients were found to have a novel I183M and recurrent E475G replacements in KRT5. Cultured EBS keratinocytes did not exhibit keratin aggregates or cell loss, except in the patient with the p.I183M mutation who showed 3% aggregates and 2% cell loss. Upon transient heat stress the number of aggregate-containing cells increased to 21%, 27% and 13%, respectively, in the p.I183M, p.E475G and p.V186L mutant cells. Interestingly, pretreatment with TMAO prior to heat stress, dose dependently reduced the number of aggregate-containing cells and cell loss. Conclusion These results revealed a genotype-phenotype correlation in EBS keratinocytes upon heat stress and suggest protein stabilization as a new therapeutic strategy.

    Place, publisher, year, edition, pages
    Wiley InterScience, 2010
    Keywords
    chemical chaperones, heat stress, keratin filament aggregates, keratin mutation, keratinocytes, protein stability
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-114415 (URN)10.1111/j.1365-2133.2009.09615.x (DOI)000276853600006 ()20128788 (PubMedID)
    Available from: 2010-05-03 Created: 2010-02-15 Last updated: 2017-12-12Bibliographically approved
    2. Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition
    Open this publication in new window or tab >>Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition
    Show others...
    2009 (English)In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 53, no 3, p. 198-206Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Epidermolysis bullosa simplex (EBS) is an autosomal inherited mechano-bullous disease, characterized by intraepidermal blistering and skin fragility caused by mutations in the keratin (KRT) 5 or 14 genes. Despite a vast knowledge about the intermediate filament pathology in this disease, the progress in therapy has been slow. Animal models and well-characterized continuous cell culture models of EBS are needed prior to clinical testing.

    OBJECTIVES: Our aim was to generate immortalized cell lines as an in vitro model for the study of EBS and test a chemical chaperone, trimethylamine N-oxide (TMAO), as a putative novel therapy.

    METHODS: We generated four immortalized cell lines, two each from an EBS patient with a KRT5-mutation (V186L) and a healthy control, using human papillomavirus 16 (HPV16) E6E7 as transducer. Cell lines were established in serum-free and serum-containing medium and assessed for growth characteristics, keratin expression profiles, ability to differentiate in organotypic cultures, and response to heat stress with and without the presence of TMAO.

    RESULTS: All cell lines have been expanded >160 population doublings and their cellular characteristics are similar. However, the formation of cytoplasmic keratin filament aggregates in response to heat-shock treatment differed between EBS and normal cell lines. Notably, serum-free established EBS-cell line was most vulnerable to heat shock but both cell lines exhibited significant reduction in the number of keratin aggregates containing cells by TMAO.

    CONCLUSION: The immortalized cell lines represent a suitable model for studying novel therapies for EBS. TMAO is a promising new agent for future development as a novel EBS therapy.

    Place, publisher, year, edition, pages
    Elsevier, 2009
    Keywords
    Chemical chaperone, Cytoprotection, EBS-cell lines, Genetic skin disorder, Human papilloma virus 16 E6/E7, Heat stress, Keratin, Organotypic epidermis, TMAO
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-88245 (URN)10.1016/j.jdermsci.2008.11.003 (DOI)000263766300005 ()19157792 (PubMedID)
    Available from: 2010-05-03 Created: 2009-01-27 Last updated: 2017-12-14Bibliographically approved
    3. Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation::  Involvement of heat shock proteins and MAP kinases
    Open this publication in new window or tab >>Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation::  Involvement of heat shock proteins and MAP kinases
    Show others...
    (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747Article in journal (Refereed) Submitted
    Abstract [en]

    Epidermolysis bullosa simplex (EBS) is an inherited epithelial tissue fragility disorder due to mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In some protein folding disorders such as cystic fibrosis and Alzheimer’s disease, chaperones and the ubiquitin-proteasome system modify disease severity, suggesting a novel therapeutic approach even for EBS. In this study, the effects of two chemical chaperones (trimethylamine-N oxide (TMAO) and 4-phenylbutyrate (4-PBA)) on heat stress-induced keratin aggregation responses were examined in newly and previously established immortalized control and EBS patient-derived keratinocyte cell lines. Heat-induced keratin-positive aggregates were observed in all EBS cells, which were most prominent in severe keratin-defective cell lines and less so in normal cells. The proportion of cells containing aggregates were dramatically reduced by TMAO and 4-PBA pretreatment. Furthermore, heat stress greatly induced MAP kinase activation (p38 and JNK) and increased Hsp70/Hsc70 expression, and TMAO was able to transiently modulate these effects. The results suggest that TMAO rescue may involve components of the endogenous chaperone and MAPK machineries, which may represent novel targets for the development of more effective treatments for EBS and other keratin-related genetic disorders.

    Keywords
    EBS, keratinocytes, keratin, MAPK, immunostaining, Hsp, TMAO, 4-PBA
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-123064 (URN)
    Available from: 2010-04-23 Created: 2010-04-23 Last updated: 2017-12-12Bibliographically approved
    4. Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype: A useful in vitro model for testing new treatments
    Open this publication in new window or tab >>Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype: A useful in vitro model for testing new treatments
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    2011 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 164, no 2, p. 263-272Article in journal (Refereed) Published
    Abstract [en]

    Background: Epidermolytic ichthyosis (EI) is a skin fragility disorder caused by mutations in genes encoding suprabasal keratins 1 and 10. While the aetiology of EI is known, model systems are needed for pathophysiological studies and development of novel therapies. Objectives To generate immortalized keratinocyte lines from patients with EI for studies of EI cell pathology and the effects of chemical chaperones as putative therapies. Methods We derived keratinocytes from three patients with EI and one healthy control and established immortalized keratinocytes using human papillomavirus 16-E6/E7. Growth and differentiation characteristics, ability to regenerate organotypic epidermis, keratin expression, formation of cytoskeletal aggregates, and responses to heat shock and chemical chaperones were assessed. Results The cell lines EH11 (K1-p.Val176-Lys197del), EH21 (K10-p.156Arg>Gly), EH31 (K10-p.Leu161-Asp162del) and NKc21 (wild-type) currently exceed 160 population doublings and differentiate when exposed to calcium. At resting state, keratin aggregates were detected in 9% of calcium-differentiated EH31 cells, but not in any other cell line. Heat stress further increased this proportion to 30% and also induced aggregates in 3% of EH11 cultures. Treatment with trimethylamine N-oxide and 4-phenylbutyrate (4-PBA) reduced the fraction of aggregate-containing cells and affected the mRNA expression of keratins 1 and 10 while 4-PBA also modified heat shock protein 70 (HSP70) expression. Furthermore, in situ proximity ligation assay suggested a colocalization between HSP70 and keratins 1 and 10. Reconstituted epidermis from EI cells cornified but EH21 and EH31 cells produced suprabasal cytolysis, closely resembling the in vivo phenotype. Conclusions These immortalized cell lines represent a useful model for studying EI biology and novel therapies.

     

    Place, publisher, year, edition, pages
    British Association of Dermatologists, 2011
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-123067 (URN)10.1111/j.1365-2133.2010.10092.x (DOI)000286668300009 ()20977447 (PubMedID)
    Available from: 2010-04-23 Created: 2010-04-23 Last updated: 2017-12-12Bibliographically approved
  • 19.
    Chamcheu, Jean Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Lorié, Elizabeth Pavez
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Akgul, Baki
    Centre for Cutaneous Research, ICMS, Bart's and London Queen Mary's School of Medicine and Dentistry, London, United Kingdom.
    Bannbers, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Virtanen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Gammon, Luke
    Centre for Cutaneous Research, ICMS, Bart's and London Queen Mary's School of Medicine and Dentistry, London, United Kingdom.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Navsaria, Harshad
    Centre for Cutaneous Research, ICMS, Bart's and London Queen Mary's School of Medicine and Dentistry, London, United Kingdom.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition2009In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 53, no 3, p. 198-206Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Epidermolysis bullosa simplex (EBS) is an autosomal inherited mechano-bullous disease, characterized by intraepidermal blistering and skin fragility caused by mutations in the keratin (KRT) 5 or 14 genes. Despite a vast knowledge about the intermediate filament pathology in this disease, the progress in therapy has been slow. Animal models and well-characterized continuous cell culture models of EBS are needed prior to clinical testing.

    OBJECTIVES: Our aim was to generate immortalized cell lines as an in vitro model for the study of EBS and test a chemical chaperone, trimethylamine N-oxide (TMAO), as a putative novel therapy.

    METHODS: We generated four immortalized cell lines, two each from an EBS patient with a KRT5-mutation (V186L) and a healthy control, using human papillomavirus 16 (HPV16) E6E7 as transducer. Cell lines were established in serum-free and serum-containing medium and assessed for growth characteristics, keratin expression profiles, ability to differentiate in organotypic cultures, and response to heat stress with and without the presence of TMAO.

    RESULTS: All cell lines have been expanded >160 population doublings and their cellular characteristics are similar. However, the formation of cytoplasmic keratin filament aggregates in response to heat-shock treatment differed between EBS and normal cell lines. Notably, serum-free established EBS-cell line was most vulnerable to heat shock but both cell lines exhibited significant reduction in the number of keratin aggregates containing cells by TMAO.

    CONCLUSION: The immortalized cell lines represent a suitable model for studying novel therapies for EBS. TMAO is a promising new agent for future development as a novel EBS therapy.

  • 20.
    Chamcheu, Jean Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Navsaria, Harshad
    Pihl-Lundin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Liovic, Mirjana
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Chemical Chaperones Protect Epidermolysis Bullosa Simplex Keratinocytes from Heat Stress-Induced Keratin Aggregation: Involvement of Heat Shock Proteins and MAP Kinases2011In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 131, no 8, p. 1684-1691Article in journal (Refereed)
    Abstract [en]

    Epidermolysis bullosa simplex (EBS) is a blistering skin disease caused by mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In other protein-folding disorders, involvement of molecular chaperones and the ubiquitin-proteasome system may modify disease severity. In this study, the effects of heat stress on keratin aggregation in immortalized cells from two patients with EBS (KRT5) and a healthy control were examined with and without addition of various test compounds. Heat-induced (43 °C, 30 minutes) aggregates were observed in all cell lines, the amount of which correlated with the donor phenotype. In EBS cells pre-exposed to proteasome inhibitor, MG132, and p38-mitogen-activated protein kinase (MAPK) inhibitor, SB203580, the proportion of aggregate-positive cells increased, suggesting a role of proteasomes and phosphorylation in removing mutated keratin. In contrast, aggregates were reduced by pretreatment with two chemical chaperones, trimethylamine N-oxide (TMAO) and 4-phenylbutyrate (4-PBA). TMAO also modulated stress-induced p38/c-jun N-terminal kinase (JNK) activation and expression of heat shock protein (HSPA1A), the latter of which colocalized with phosphorylated keratin 5 in EBS cells. Taken together, our findings suggest therapeutic targets for EBS and other keratinopathies.

  • 21.
    Chamcheu, Jean Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Navsaria, Harshad
    Bart's and London Queen Mary's University School of Medicine and Dentistry .
    Pihl-Lundin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Liovic, Mirjana
    University of Ljubjana, Institute of Chemistry and Centre for Molecular Biology.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation::  Involvement of heat shock proteins and MAP kinasesIn: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747Article in journal (Refereed)
    Abstract [en]

    Epidermolysis bullosa simplex (EBS) is an inherited epithelial tissue fragility disorder due to mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In some protein folding disorders such as cystic fibrosis and Alzheimer’s disease, chaperones and the ubiquitin-proteasome system modify disease severity, suggesting a novel therapeutic approach even for EBS. In this study, the effects of two chemical chaperones (trimethylamine-N oxide (TMAO) and 4-phenylbutyrate (4-PBA)) on heat stress-induced keratin aggregation responses were examined in newly and previously established immortalized control and EBS patient-derived keratinocyte cell lines. Heat-induced keratin-positive aggregates were observed in all EBS cells, which were most prominent in severe keratin-defective cell lines and less so in normal cells. The proportion of cells containing aggregates were dramatically reduced by TMAO and 4-PBA pretreatment. Furthermore, heat stress greatly induced MAP kinase activation (p38 and JNK) and increased Hsp70/Hsc70 expression, and TMAO was able to transiently modulate these effects. The results suggest that TMAO rescue may involve components of the endogenous chaperone and MAPK machineries, which may represent novel targets for the development of more effective treatments for EBS and other keratin-related genetic disorders.

  • 22.
    Chamcheu, Jean Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Pihl-Lundin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Eteti Mouyobo, Cedrique
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Gester, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Virtanen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Navsaria, Harshad
    Centre for Cutaneous Research, Queen Mary’s School of Medicine and Dentistry, London E1 2AT, U.K..
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype: A useful in vitro model for testing new treatments2011In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 164, no 2, p. 263-272Article in journal (Refereed)
    Abstract [en]

    Background: Epidermolytic ichthyosis (EI) is a skin fragility disorder caused by mutations in genes encoding suprabasal keratins 1 and 10. While the aetiology of EI is known, model systems are needed for pathophysiological studies and development of novel therapies. Objectives To generate immortalized keratinocyte lines from patients with EI for studies of EI cell pathology and the effects of chemical chaperones as putative therapies. Methods We derived keratinocytes from three patients with EI and one healthy control and established immortalized keratinocytes using human papillomavirus 16-E6/E7. Growth and differentiation characteristics, ability to regenerate organotypic epidermis, keratin expression, formation of cytoskeletal aggregates, and responses to heat shock and chemical chaperones were assessed. Results The cell lines EH11 (K1-p.Val176-Lys197del), EH21 (K10-p.156Arg>Gly), EH31 (K10-p.Leu161-Asp162del) and NKc21 (wild-type) currently exceed 160 population doublings and differentiate when exposed to calcium. At resting state, keratin aggregates were detected in 9% of calcium-differentiated EH31 cells, but not in any other cell line. Heat stress further increased this proportion to 30% and also induced aggregates in 3% of EH11 cultures. Treatment with trimethylamine N-oxide and 4-phenylbutyrate (4-PBA) reduced the fraction of aggregate-containing cells and affected the mRNA expression of keratins 1 and 10 while 4-PBA also modified heat shock protein 70 (HSP70) expression. Furthermore, in situ proximity ligation assay suggested a colocalization between HSP70 and keratins 1 and 10. Reconstituted epidermis from EI cells cornified but EH21 and EH31 cells produced suprabasal cytolysis, closely resembling the in vivo phenotype. Conclusions These immortalized cell lines represent a useful model for studying EI biology and novel therapies.

     

  • 23.
    Chamcheu, Jean Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Virtanen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Navsaria, Harshad
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Immortalized keratinocytes from Epidermolytic Ichthyosis-patients reproduce the disease phenotype in vitro2010In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 130, p. S83-S83Article in journal (Other academic)
  • 24.
    Chamcheu, Jean Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Virtanen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Navsaria, Harshad
    Centre for Cutaneous Research, ICMS, Bart’s and London School of Medicine and Dentistry, Queen Mary University of London.
    Bowden, Paul E.
    Cardiff University, School of Medicine, Department of Dermatology.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Epidermolysis bullosa simplex due to KRT5 mutations: mutation-related differences in cellular fragility and the protective effects of trimethylamine N-oxide in cultured primary keratinocytes2010In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 162, no 5, p. 980-989Article in journal (Refereed)
    Abstract [en]

    Summary Background Epidermolysis bullosa simplex (EBS) is a mechanobullous skin fragility disease characterized by cytolysis of basal keratinocytes and intraepidermal blistering often caused by mutations in keratin genes (KRT5 or KRT14). No remedies exist for these disorders presenting a need for development of novel therapies. Objectives To identify new genotype-phenotype relationships in vivo and in cultured primary EBS keratinocytes in vitro, and to study the cytoskeletal stabilizing effects of trimethylamine N-oxide (TMAO) in heat-stressed EBS cells. Methods Genomic DNA and cDNA samples from three Swedish patients with EBS were analysed for keratin mutations. Primary EBS keratinocyte cultures were established, heat stressed with and without added TMAO, followed by evaluation of cellular fragility. Results In addition to the previously reported KRT5 mutation (V186L) in one patient, two patients were found to have a novel I183M and recurrent E475G replacements in KRT5. Cultured EBS keratinocytes did not exhibit keratin aggregates or cell loss, except in the patient with the p.I183M mutation who showed 3% aggregates and 2% cell loss. Upon transient heat stress the number of aggregate-containing cells increased to 21%, 27% and 13%, respectively, in the p.I183M, p.E475G and p.V186L mutant cells. Interestingly, pretreatment with TMAO prior to heat stress, dose dependently reduced the number of aggregate-containing cells and cell loss. Conclusion These results revealed a genotype-phenotype correlation in EBS keratinocytes upon heat stress and suggest protein stabilization as a new therapeutic strategy.

  • 25. Charlesworth, A.
    et al.
    Chiaverini, C.
    Chevrant-Breton, J.
    DelRio, M.
    Diociaiuti, A.
    Dupuis, R. P.
    El Hachem, M.
    Le Fiblec, B.
    Sankari-Ho, A. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Valhquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Wierzbicka, E.
    Lacour, J. P.
    Meneguzzi, G.
    Epidermolysis bullosa simplex with PLEC mutations: new phenotypes and new mutations2013In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 168, no 4, p. 808-814Article in journal (Refereed)
    Abstract [en]

    Background Genetic mutations in the plectin gene (PLEC) cause autosomal recessive forms of epidermolysis bullosa simplex (EBS) associated with either muscular dystrophy (EBS-MD) or pyloric atresia (EBS-PA). Phenotype-genotype analysis has suggested that EBS-MD is due mostly to genetic mutations affecting the central rod domain of plectin, and EBS-PA to mutations outside this domain. Objectives This study aimed to describe new phenotypes of patients with EBS-MD and EBS-PA, to identify novel PLEC mutations and to establish genotype-phenotype correlations. Methods Seven patients with a suspicion of EBS linked to PLEC mutations were included. A standardized clinical questionnaire was sent to the physicians in charge of each patient. Immunofluorescence studies of skin biopsies followed by molecular analysis of PLEC were performed in all patients. Results We report the first case of nonlethal EBS-PA improving with age, the first multisystemic involvement in a patient with lethal EBS-PA, and the first patients with EBS-MD with involvement of either the bladder or oesophagus. Eleven novel PLEC mutations are also reported. Conclusions Our results confirm that EBS-PA is linked to mutations in the distal exons 1-30 and 32 of PLEC. Long-term survival is possible, with skin improvement, but a delayed onset of MD is probable. While EBS-MD is linked to PLEC mutations in all exons, in most cases one of the mutations affects exon 31. The precocity of MD seems to be linked to the type and localization of the PLEC mutation(s), but no correlation with mucosal involvement has been found.

  • 26.
    Craiglow, Brittany G.
    et al.
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA.
    Boyden, Lynn M.
    Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.
    Hu, Ronghua
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA.
    Virtanen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Su, John
    Univ Melbourne, Murdoch Childrens Res Inst, Dept Pediat, Melbourne, Vic, Australia;Monash Univ, Eastern Hlth, Dept Dermatol, Melbourne, Vic, Australia.
    Rodriguez, Gabriela
    Univ Costa Rica, Dept Dermatol, San Jose, Costa Rica.
    McCarthy, Catherine
    Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.
    Luna, Paula
    Ramos Mejia Hosp, Dept Pediat Dermatol, Buenos Aires, DF, Argentina.
    Larralde, Margarita
    Ramos Mejia Hosp, Dept Pediat Dermatol, Buenos Aires, DF, Argentina.
    Humphrey, Stephen
    Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA.
    Holland, Kristen E.
    Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA.
    Hogeling, Marcia
    Univ Calif Los Angeles, David Geffen Sch Med, Div Dermatol, Los Angeles, CA 90095 USA.
    Hidalgo-Matlock, Benjamin
    Univ Costa Rica, Dept Dermatol, San Jose, Costa Rica.
    Ferrari, Bruno
    Ramos Mejia Hosp, Dept Pediat Dermatol, Buenos Aires, DF, Argentina.
    Fernandez-Faith, Esteban
    Ohio State Univ, Med Ctr, Dept Pediat & Dermatol, Columbus, OH 43210 USA;Nationwide Childrens Hosp, Dept Pediat & Dermatol, Columbus, OH USA.
    Drolet, Beth
    Nationwide Childrens Hosp, Dept Pediat & Dermatol, Columbus, OH USA.
    Cordoro, Kelly M.
    Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA;Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA.
    Bowcock, Anne M.
    Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Genet & Genome Sci, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA.
    Antaya, Richard J.
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA;Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA.
    Ashack, Kurt
    Univ Illinois, Coll Med, Dept Dermatol, Chicago, IL 60680 USA.
    Ashack, Richard J.
    Dermatol Associates West Michigan, Grand Rapids, MI USA.
    Lifton, Richard P.
    Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.
    Milstone, Leonard M.
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA.
    Paller, Amy S.
    Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA;Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA.
    Choate, Keith A.
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA;Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA;Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.
    CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris2018In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 79, no 3, p. 487-494Article in journal (Refereed)
    Abstract [en]

    Background: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-alpha inhibitors. Objective: We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14. Methods: Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed. Results: We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab. Limitations: Relatively small sample size. Conclusions: Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.

  • 27.
    Dahlin, Jakob
    et al.
    Skane Univ Hosp, Dept Occupat & Environm Dermatol, SE-20502 Malmo, Sweden..
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Med Prod Agcy, Dept Cosmet, S-75103 Uppsala, Sweden..
    Duner, Kari
    Blekinge Hosp, Dept Dermatol, S-37185 Karlskrona, Sweden..
    Hosseiny, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Matura, Mihaly
    SLSO, Unit Occupat & Environm Dermatol, Ctr Occupat & Environm Med, S-11365 Stockholm, Sweden..
    Nyman, Gunnar
    Hudlakarmottagningen Telegrafen, S-50330 Boras, Sweden..
    Tammela, Monica
    Med Prod Agcy, Dept Cosmet, S-75103 Uppsala, Sweden..
    Isaksson, Marlene
    Skane Univ Hosp, Dept Occupat & Environm Dermatol, SE-20502 Malmo, Sweden..
    Several cases of undesirable effects caused by methacrylate ultraviolet-curing nail polish for non-professional use2016In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 75, no 3, p. 151-156Article in journal (Refereed)
    Abstract [en]

    BackgroundUltraviolet (UV)-curing nail polishes based on acrylates or methacrylates are currently also available for non-professional use. The Swedish Medical Products Agency recently prohibited one brand of UV-curing polish, because several consumers reported undesirable effects after using it. ObjectivesTo investigate whether consumers with undesirable effects after using the UV-curing nail polish that was later prohibited were contact allergic to the polish and its individual ingredients. Materials/MethodsEight patients who had reported severe skin reactions after the use of the UV-curing polish were patch tested with two coatings of the nail polish and its ingredients at five dermatology departments in Sweden. ResultsAll patients tested except one showed contact allergic reactions to one or several of the acrylate-based or methacrylate-based ingredients in the nail polish. ConclusionsThe non-professional use of UV-curing nail polishes poses a risk of sensitization from acrylates and methacrylates.

  • 28.
    Dahlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Badhai, Jitendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 1, p. e29471-Article in journal (Refereed)
    Abstract [en]

    Keratosis linearis with ichthyosis congenita and keratoderma (KLICK) is an autosomal recessive skin disorder associated with a single-nucleotide deletion in the 5'untranslated region of the proteasome maturation protein (POMP) gene. The deletion causes a relative switch in transcription start sites for POMP, predicted to decrease levels of POMP protein in terminally differentiated keratinocytes. To investigate the pathophysiology behind KLICK we created an in vitro model of the disease using siRNA silencing of POMP in epidermal air-liquid cultures. Immunohistochemical analysis of the tissue constructs revealed aberrant staining of POMP, proteasome subunits and the skin differentiation marker filaggrin when compared to control tissue constructs. The staining patterns of POMP siRNA tissue constructs showed strong resemblance to those observed in skin biopsies from KLICK patients. Western blot analysis of lysates from the organotypic tissue constructs revealed an aberrant processing of profilaggrin to filaggrin in samples transfected with siRNA against POMP. Knock-down of POMP expression in regular cell cultures resulted in decreased amounts of proteasome subunits. Prolonged silencing of POMP in cultured cells induced C/EBP homologous protein (CHOP) expression consistent with an activation of the unfolded protein response and increased endoplasmic reticulum (ER) stress. The combined results indicate that KLICK is caused by reduced levels of POMP, leading to proteasome insufficiency in differentiating keratinocytes. Proteasome insufficiency disturbs terminal epidermal differentiation, presumably by increased ER stress, and leads to perturbed processing of profilaggrin. Our findings underline a critical role for the proteasome in human epidermal differentiation.

  • 29.
    Dahlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ichthyin/NIPAL4 localizes to keratins and desmosomes in epidermis and Ichthyin mutations affect epidermal lipid metabolism2012In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 304, no 5, p. 377-386Article in journal (Refereed)
    Abstract [en]

    Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by abnormal desquamation of the skin and a disrupted epidermal water barrier. Ichthyin/NIPAL4 gene mutations have been identified in a subgroup of ARCI patients, but the role of ichthyin in epidermis remains elusive. In order to obtain new insights concerning the characteristics of ichthyin and the ARCI pathogenesis, we studied the expression and localization of ichthyin and related epidermal components in cultured keratinocytes and skin sections from patients with Ichthyin mutations and healthy controls. We observed an up-regulation of Ichthyin mRNA levels after in vitro differentiation of keratinocytes from both a patient with Ichthyin mutations and controls. Confocal and electron microscopy analyses of immunolabeled skin sections revealed that ichthyin localizes to desmosomes and keratins in both patients with mutant Ichthyin and controls, with an increased immunolabeling in patients. Nile red lipid analysis of skin sections exposed intra-cellular lipid accumulations in cells of the granular and cornified layers in patients but not in controls, consistent with the pathognomonic lipid membrane structures previously identified in epidermis from patients. Our combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies. These results provide new clues to the understanding of the epidermal water barrier and the pathogenesis in ARCI.

  • 30.
    Dahlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy.
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Ichthyin Localizes to Keratins and Desmosomes in Epidermis and is Involved in Lipid MetabolismManuscript (preprint) (Other academic)
  • 31.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. KI.
    Clinical and immunological characteristics of Autoimmune Addison’s disease in Sweden: a nationwide multicenter analysis of 660 patientsManuscript (preprint) (Other academic)
  • 32.
    Dalin, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Adamus, Grazyna
    Oregon Hlth & Sci Univ, Casey Eye Inst, Ocular Immunol Lab, Portland, OR 97201 USA..
    Yang, Sufang
    Oregon Hlth & Sci Univ, Casey Eye Inst, Ocular Immunol Lab, Portland, OR 97201 USA..
    Landgren, Eva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hallgren, Åsa
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hugosson, Therese
    Lund Univ, Dept Clin Sci, Ophthalmol, Lund, Sweden..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Eriksson, Daniel
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Andreasson, Sten
    Lund Univ, Dept Clin Sci, Ophthalmol, Lund, Sweden..
    Tabbara, Khalid F.
    Ctr Eye, Riyadh, Saudi Arabia..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy2016In: Ophthalmology (Rochester, Minn.), ISSN 0161-6420, E-ISSN 1549-4713, Vol. 123, no 6, p. 1401-1404Article in journal (Other academic)
  • 33.
    Dalin, Frida
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Adamus, Grazyna
    Yang, Sufang
    Landgren, Eva
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hallgren, Åsa
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hugosson, Therése
    Landegren, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Daniel
    Andreasson, Sten
    Tabbara, Khalid F.
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Alimohammadi, Mohammad
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy2016In: Ophthalmology (Rochester, Minn.), ISSN 0161-6420, E-ISSN 1549-4713, Vol. 123, no 6, p. 1401-1404Article in journal (Refereed)
  • 34.
    Dalin, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Nordling Eriksson, Gabriel
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Hallgren, Åsa
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Wahlberg, Jeanette
    Linkoping Univ, Div Endocrinol, Dept Med & Hlth Sci, Fac Hlth Sci, SE-58183 Linkoping, Sweden.
    Ekwall, Olov
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Söderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Olcén, Per
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Winqvist, Ola
    Karolinska Inst, Karolinska Univ Hosp, Translat Immunol, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Kriström, Berit
    Umea Univ, Inst Clin Sci, Pediat, SE-90736 Umea, Sweden.
    Laudius, Maria
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Halldin Stenlid, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Gebre-Medhin, Gennet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Björnsdottir, Sigridur
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Janson, Annika
    Karolinska Inst, Dept Womens & Childrens Hlth, SE-17176 Stockholm, Sweden.
    Åkerman, Anna-Karin
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Åman, Jan
    Univ Orebro, Dept Pediat, Fac Med & Hlth, SE-70281 Orebro, Sweden.
    Duchen, Karel
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Bergthorsdottir, Ragnhildur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Johannsson, Gudmundur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Lindskog, Emma
    Univ Gothenburg, Dept Pediat, Inst Clin Sci, SE-40530 Gothenburg, Sweden.
    Landin-Olsson, Mona
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Elfving, Maria
    Lund Univ, Dept Pediat, Pediat Endocrinol, Clin Sci, SE-22362 Lund, Sweden.
    Waldenström, Erik
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Hulting, Anna-Lena
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Bensing, Sophie
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 379-389Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

    OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

    DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

    MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

    RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

    CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

  • 35.
    Domeika, Marius
    et al.