Carl Gustaf Winge,MD PhD

All Publications

• Advances in cutaneous squamous cell carcinoma. Nature reviews. Cancer Winge, M. C., Kellman, L. N., Guo, K., Tang, J. Y., Swetter, S. M., Aasi, S. Z., Sarin, K. Y., Chang, A. L., Khavari, P. A. 2023

  Abstract

  Human malignancies arise predominantly in tissues of epithelial origin, where the stepwise transformation from healthy epithelium to premalignant dysplasia to invasive neoplasia involves sequential dysregulation of biological networks that govern essential functions of epithelial homeostasis. Cutaneous squamous cell carcinoma (cSCC) is a prototype epithelial malignancy, often with a high tumour mutational burden. A plethora of risk genes, dominated by UV-induced sun damage, drive disease progression in conjunction with stromal interactions and local immunomodulation, enabling continuous tumour growth. Recent studies have identified subpopulations of SCC cells that specifically interact with the tumour microenvironment. These advances, along with increased knowledge of the impact of germline genetics and somatic mutations on cSCC development, have led to a greater appreciation of the complexity of skin cancer pathogenesis and have enabled progress in neoadjuvant immunotherapy, which has improved pathological complete response rates. Although measures for the prevention and therapeutic management of cSCC are associated with clinical benefit, the prognosis remains poor for advanced disease. Elucidating how the genetic mechanisms that drive cSCC interact with the tumour microenvironment is a current focus in efforts to understand, prevent and treat cSCC.

  View details for DOI 10.1038/s41568-023-00583-5

  View details for PubMedID 37286893

  View details for PubMedCentralID 4833641

• Single-Cell and Spatial Transcriptomic Analysis of Human Skin Delineates Intercellular Communication and Pathogenic Cells. The Journal of investigative dermatology Thrane, K., Winge, M. C., Wang, H., Chen, L., Guo, M. G., Andersson, A., Abalo, X. M., Yang, X., Kim, D. S., Longo, S. K., Soong, B. Y., Meyers, J. M., Reynolds, D. L., McGeever, A., Demircioglu, D., Hasson, D., Mirzazadeh, R., Rubin, A. J., Bae, G. H., Karkanias, J., Rieger, K., Lundeberg, J., Ji, A. L. 2023

  Abstract

  Epidermal homeostasis is governed by a balance between keratinocyte proliferation and differentiation with contributions from cell-cell interactions, but conserved or divergent mechanisms governing this equilibrium across species, and how an imbalance contributes to skin disease, are largely undefined. To address these questions, human skin single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) data were integrated and compared to mouse skin data. Human skin cell type annotation was improved by using matched ST data, highlighting the importance of spatial context in cell type identity, and ST refined cellular communication inference. In cross-species analyses, we identified a human spinous keratinocyte subpopulation that exhibited proliferative capacity and a heavy-metal processing signature, which was absent in mouse and may account for species differences in epidermal thickness. This human subpopulation was expanded in psoriasis and zinc-deficiency dermatitis, attesting to disease relevance and suggesting a paradigm of subpopulation dysfunction as a hallmark of disease. To assess additional potential subpopulation drivers of skin diseases, we performed cell-of-origin enrichment analysis within genodermatoses, nominating pathogenic cell subpopulations and their communication pathways, which highlighted multiple potential therapeutic targets. This integrated dataset is encompassed in a publicly available web resource to aid mechanistic and translational studies of normal and diseased skin.

  View details for DOI 10.1016/j.jid.2023.02.040

  View details for PubMedID 37142187

• New-onset pemphigus vegetans and pemphigus foliaceus following SARS-CoV-2 vaccination: a case series. JAAD case reports Gui, H., Young, P. A., Sox, J., Pol-Rodriguez, M., Rieger, K. E., Lewis, M. A., Winge, M. C., Bae, G. H. 2022

  View details for DOI 10.1016/j.jdcr.2022.07.002

  View details for PubMedID 35845348

• NUTRITIONAL DEFICIENCY CONTRIBUTING TO REFRACTORY ERYTHRODERMA IN HEMATOPOETIC CELL TRANSPLANT PATIENTS: DISTINCTIVE CLINICAL AND HISTOPATHOLOGICAL FINDINGS. Journal of the American Academy of Dermatology Winge, M. C., Rieger, K. E., Kim, J., Weng, W., Johnston, L. J., Miklos, D. B., Strelo, J., Zaba, L. C., Pugliese, S. B., Novoa, R. A., Kwong, B. Y. 2021

  View details for DOI 10.1016/j.jaad.2021.07.077

  View details for PubMedID 34450206

• Telescope punch biopsy of normal-appearing skin to diagnose intravascular lymphoma. The British journal of dermatology Winge, M. C., Iberri, D. J., Novoa, R. A., Kwong, B. Y., Zaba, L. C. 2021

  View details for DOI 10.1111/bjd.19711

  View details for PubMedID 33523506

• ITK and RLK Inhibitor PRN694 Improves Skin Disease in Two Mouse Models of Psoriasis. The Journal of investigative dermatology Fuhriman, J. M., Winge, M. C., Haberstock-Debic, H., Funk, J. O., Bradshaw, J. M., Marinkovich, M. P. 2018; 138 (4): 864–71

  Abstract

  The chronic and highly prevalent skin disorder psoriasis vulgaris is characterized by a hyperproliferative epidermis and aberrant immune activity. Many studies have highlighted the role of differentiated T lymphocytes in psoriasis progression. Several biologics are currently available that target proinflammatory cytokines produced by T lymphocytes, but the need for improved therapies persists. The small molecule PRN694 covalently binds ITK and RLK, two Tec kinases activated downstream of T-lymphocyte activation, both of which are up-regulated in psoriatic skin. These Tec kinases are involved in signaling cascades mediating T-lymphocyte proliferation, differentiation, and migration and proinflammatory cytokine production. Invitro analysis showed that PRN694 effectively inhibited IL-17A production from murine T helper type 17-differentiated T lymphocytes. Additionally, PRN694 effectively reduced the psoriasis-like phenotype severity and reduced epidermal proliferation and thickness in both the Rac1V12 and imiquimod mouse models of psoriasis. PRN694 also inhibited CD3+ T-cell and gammadelta T-cell infiltration into skin regions. Inhibition of ITK and RLK attenuated psoriasis-associated signaling pathways, indicating that PRN694 is an effective psoriasis therapeutic.

  View details for PubMedID 29129599

• ITK and RLK Inhibitor PRN694 Improves Skin Disease in Two Mouse Models of Psoriasis JOURNAL OF INVESTIGATIVE DERMATOLOGY Fuhriman, J. M., Winge, M. G., Haberstock-Debic, H., Funk, J., Bradshaw, J., Marinkovich, M. 2018; 138 (4): 864–71

  View details for DOI 10.1016/j.jid.2017.10.029

  View details for Web of Science ID 000428135400024

• Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis Marinkovich, M. P., et al 2018

  Abstract

  Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12-/+/Srb1-/-/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis.

  View details for DOI 10.1172/jci.insight.97179

  View details for PubMedCentralID PMC5821196

• Intragenic Copy Number Variation in the Filaggrin Gene in Ethiopian Patients with Atopic Dermatitis PEDIATRIC DERMATOLOGY Fernandez, K., Asad, S., Taylan, F., Wahlgren, C., Bilcha, K. D., Nordenskjold, M., Winge, M. G., Bradley, M. 2017; 34 (3): E140-E141

  Abstract

  Genetic variants in filaggrin (FLG) involving truncating mutations or intragenic copy number variation are strongly associated with the risk of developing atopic dermatitis (AD) in European and Asian populations. Few loss-of-function mutations have been identified in Africans, although an association between FLG copy number variation and AD severity in a small African American cohort has been proposed. We studied the association between FLG copy number and AD in 132 Ethiopians and found no association between AD severity and FLG copy number, suggesting that other, still unidentified genetic factors are of more importance in predisposing Ethiopians to AD.

  View details for DOI 10.1111/pde.13095

  View details for Web of Science ID 000401722200010

  View details for PubMedID 28295514

• Epidermal activation of the small GTPase Rac1 in psoriasis pathogenesis. Small GTPases Winge, M. C., Marinkovich, M. P. 2017: 1-6

  Abstract

  The small GTPase Ras-related C3 botulinum toxin substrate 1 (RAC1) plays a central role in skin homeostasis, including barrier function, wound healing and inflammatory responses. Psoriasis is a common skin disease characterized by deregulation of these functions, and affected skin exhibit keratinocyte hyperproliferation, inflammation and immune cell infiltration. Although psoriasis is often triggered by environmental stimulus, there is a strong genetic association with genes expressed in both immune cells and keratinocytes, of which several are linked to Rac1 signaling. Rac1 is highly active in human psoriatic lesional skin and keratinocytes, and keratinocyte-specific overexpression of an activated mutant of Rac1, Rac1(V12), in a transgenic mouse model closely mimics the presentation of human psoriasis. Both Rac1 activation in keratinocytes and immune derived stimulus are required to drive psoriasiform signaling in transgenic mouse and human xenograft models of psoriasis. Therefore, understanding how increased Rac1 activation in psoriatic epidermis is regulated is central to understanding how the abnormal crosstalk between keratinocytes and immune cells is maintained.

  View details for DOI 10.1080/21541248.2016.1273861

  View details for PubMedID 28055293

• The tight junction gene Claudin-1 is associated with atopic dermatitis among Ethiopians JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY Asad, S., Winge, M. G., Wahlgren, C., Bilcha, K. D., Nordenskjold, M., Taylan, F., Bradley, M. 2016; 30 (11): 1939-1941

  Abstract

  The strong association between epidermal barrier gene variants and Atopic Dermatitis (AD) highlights that impaired skin barrier is a key feature in the pathogenesis of AD. Although the filaggrin (FLG) gene is the major AD risk gene in European and Asian populations, disease-associated variants remain elusive in African populations.A previous study has reported that variants in the tight junction gene CLDN1 have been associated with AD susceptibility and disease severity in African-Americans. Our aim was therefore to investigate the association of CLDN1 with AD in the Ethiopian population.To investigate how CLDN1 variants may be involved in increasing the risk of AD in the Ethiopian population, we analysed whole exome sequencing (WES) data for all exons in CLDN1, and in addition, assayed four SNPs (rs17501010, rs9290927, rs9290929 and rs893051) which had previously showed association in African-American AD patients.No damaging variants were detected through WES in 22 Ethiopian samples. Genotyping of disease-associated CLDN1 SNPs in Ethiopian cases and control material showed no overall association. However, significant association was seen for rs893051 in patients who developed AD before the age of 5 years (P < 0.03).Taken together, we demonstrate that tight junction genes and, in particular, CLDN1 rather than variants in FLG may be involved in the susceptibility of AD in the Ethiopian population.

  View details for DOI 10.1111/jdv.13806

  View details for Web of Science ID 000386941300052

  View details for PubMedID 27581203

• Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI insight Kennedy Crispin, M., Ko, J. M., Craiglow, B. G., Li, S., Shankar, G., Urban, J. R., Chen, J. C., Cerise, J. E., Jabbari, A., Winge, M. C., Marinkovich, M. P., Christiano, A. M., Oro, A. E., King, B. A. 2016; 1 (15)

  Abstract

  Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8(+) T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined.This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome.Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment.At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease.ClinicalTrials.gov NCT02197455 and NCT02312882.This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

  View details for PubMedID 27699252

• Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata JCI INSIGHT Crispin, M., Ko, J. M., Craiglow, B. G., Li, S., Shankar, G., Urban, J. R., Chen, J. C., Cerise, J. E., Jabbari, A., Winge, M. G., Marinkovich, M., Christiano, A. M., Oro, A. E., King, B. A. 2016; 1 (15)

  View details for DOI 10.1172/jci.insight.89776

  View details for Web of Science ID 000387123200013

• RAC1 activation drives pathologic interactions between the epidermis and immune cells JOURNAL OF CLINICAL INVESTIGATION Winge, M. C., Ohyama, B., Dey, C. N., Boxer, L. M., Li, W., Ehsani-Chimeh, N., Truong, A. K., Wu, D., Armstrong, A. W., Makino, T., Davidson, M., Starcevic, D., Kislat, A., Nguyen, N. T., Hashimoto, T., Homey, B., Khavari, P. A., Bradley, M., Waterman, E. A., Marinkovich, M. P. 2016; 126 (7): 2661-2677

  Abstract

  Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RACV12) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1V12-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NFκB, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions.

  View details for DOI 10.1172/JCI85738

  View details for Web of Science ID 000379094800028

  View details for PubMedID 27294528

  View details for PubMedCentralID PMC4922704

• Translating Ribosome Affinity Purification for Qualitative Assessment of Human Neural Stem Cells Transcripts in the Ischemic Rat Brain. Azevedo-Pereira, R. L., Manley, N. C., Winge, M. C., Berryn, J., Sun, G., Bliss, T., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000399956100296

• Optogenetic Stimulation of Neural Grafts Enhances Neurotransmission and Downregulates the Inflammatory Response in Experimental Stroke Model. Cell transplantation Daadi, M. M., Klausner, J. Q., Bajar, B., Goshen, I., Lee-Messer, C., Lee, S. Y., Winge, M. C., Ramakrishnan, C., Lo, M., Sun, G., Deisseroth, K., Steinberg, G. K. 2016; 25 (7): 1371-1380

  Abstract

  Compelling evidence suggests that transplantation of neural stem cells (NSCs) from multiple sources ameliorates motor deficits after stroke. However, it is currently unknown to what extent the electrophysiological activity of grafted NSC progeny participates in the improvement of motor deficits and whether excitatory phenotypes of the grafted cells are beneficial or deleterious to sensorimotor performances. To address this question, we used optogenetic tools to drive the excitatory outputs of the grafted NSCs and assess the impact on local circuitry and sensorimotor performance. We genetically engineered NSCs to express the Channelrhodopsin-2 (ChR2), a light-gated cation channel that evokes neuronal depolarization and initiation of action potentials with precise temporal control to light stimulation. To test the function of these cells in a stroke model, rats were subjected to an ischemic stroke and grafted with ChR2-NSCs. The grafted NSCs identified with a human-specific nuclear marker survived in the peri-infarct tissue and coexpressed the ChR2 transgene with the neuronal markers TuJ1 and NeuN. Gene expression analysis in stimulated versus vehicle-treated animals showed a differential upregulation of transcripts involved in neurotransmission, neuronal differentiation, regeneration, axonal guidance, and synaptic plasticity. Interestingly, genes involved in the inflammatory response were significantly downregulated. Behavioral analysis demonstrated that chronic optogenetic stimulation of the ChR2-NSCs enhanced forelimb use on the stroke-affected side and motor activity in an open field test. Together these data suggest that excitatory stimulation of grafted NSCs elicits beneficial effects in experimental stroke model through cell replacement and non-cell replacement, anti-inflammatory/neurotrophic effects.

  View details for DOI 10.3727/096368915X688533

  View details for PubMedID 26132738

• Whole-exome sequencing of Ethiopian patients with ichthyosis vulgaris and atopic dermatitis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Taylan, F., Nilsson, D., Asad, S., Lieden, A., Wahlgren, C., Winge, M. G., Bilcha, K., Nordenskjold, M., Bradley, M. 2015; 136 (2): 507-+

  View details for DOI 10.1016/j.jaci.2015.02.010

  View details for Web of Science ID 000359004900042

  View details for PubMedID 25819062

• Maternal Filaggrin Mutations Increase the Risk of Atopic Dermatitis in Children: An Effect Independent of Mutation Inheritance PLOS GENETICS Esparza-Gordillo, J., Matanovic, A., Marenholz, I., Bauerfeind, A., Rohde, K., Nemat, K., Lee-Kirsch, M., Nordenskjold, M., Winge, M. G., Keil, T., Krueger, R., Lau, S., Beyer, K., Kalb, B., Niggemann, B., Huebner, N., Cordell, H. J., Bradley, M., Lee, Y. 2015; 11 (3): e1005076

  Abstract

  Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10-36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10-8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring's susceptibility to a common human disease.

  View details for DOI 10.1371/journal.pgen.1005076

  View details for Web of Science ID 000352197100055

  View details for PubMedID 25757221

  View details for PubMedCentralID PMC4355615

• Moisturizing treatment of patients with atopic dermatitis and ichthyosis vulgaris improves dry skin, but has a modest effect on gene expression regardless of FLG genotype JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY Hoppe, T., Winge, M. G., Bradley, M., Nordenskjold, M., Vahlquist, A., Torma, H., Berne, B. 2015; 29 (1): 174-177

  Abstract

  Loss-of-function mutations in FLG (encoding filaggrin) are a predisposing factor for atopic dermatitis (AD) and cause ichthyosis vulgaris (IV). Patients with AD and IV display impaired skin barrier and dry skin, and altered epidermal expression of genes in pro-inflammatory and lipid metabolic pathways are often evident.To evaluate the effect of three different moisturizers on skin barrier function and epidermal gene expression in patients with AD/IV in relation to FLG mutation status.Patients (n = 43) were classified according to their FLG status: AD with FLG+/+ (n = 14), AD with FLG+/- (n = 14), and AD/IV with FLG-/- (n = 15). Dryness score and transepidermal water loss (TEWL) were monitored on volar forearms, and punch biopsies were taken for analysis of gene expression. Measurements were repeated after 4 weeks of treatment with either of two moisturizers on each forearm.Treatment with any of the three moisturizers significantly reduced dryness score and TEWL in the group as a whole. FLG-/- patients displayed the largest reduction in dryness score. Only minute changes occurred in the mRNA expression of 15 selected epidermal genes.Moisturizing treatment improves dry skin and certain aspects of abnormal skin barrier function, especially in patients with AD/IV and dual FLG mutations, but does not normalize the epidermal gene expression profile.

  View details for DOI 10.1111/jdv.12333

  View details for Web of Science ID 000346733800028

  View details for PubMedID 24330146

• Atopic dermatitis severity and skin barrier impairment BRITISH JOURNAL OF DERMATOLOGY Winge, M. G. 2014; 170 (3): 490-491

  View details for DOI 10.1111/bjd.12869

  View details for Web of Science ID 000332586100002

  View details for PubMedID 24617425

• A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis HUMAN MOLECULAR GENETICS Weidinger, S., Willis-Owen, S. G., Kamatani, Y., Baurecht, H., Morar, N., Liang, L., Edser, P., Street, T., Rodriguez, E., O'Regan, G. M., Beattie, P., Foelster-Holst, R., Franke, A., Novak, N., Fahy, C. M., Winge, M. G., Kabesch, M., Illig, T., Heath, S., Soderhall, C., Melen, E., Pershagen, G., Kere, J., Bradley, M., Lieden, A., Nordenskjold, M., Harper, J. I., Mclean, W., Brown, S. J., Cookson, W. C., Lathrop, G., Irvine, A. D., Moffatt, M. F. 2013; 22 (23): 4841-4856

  Abstract

  Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.

  View details for DOI 10.1093/hmg/ddt317

  View details for Web of Science ID 000326973000016

  View details for PubMedID 23886662

  View details for PubMedCentralID PMC3820131

• Genetic Variation in the Inflammasome and Atopic Dermatitis Susceptibility JOURNAL OF INVESTIGATIVE DERMATOLOGY Bivik, C., Verma, D., Winge, M. C., Lieden, A., Bradley, M., Rosdahl, I., Soderkvist, P. 2013; 133 (10): 2486-2489

  View details for DOI 10.1038/jid.2013.168

  View details for Web of Science ID 000324899100028

  View details for PubMedID 23563199

• Lack of association between filaggrin gene mutations and onset of psoriasis in childhood JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY Winge, M. G., Suneson, J., Lysell, J., Nikamo, P., Lieden, A., Nordenskjold, M., Wahlgren, C. F., Bradley, M., Stahle, M. 2013; 27 (1): e124-e127

  Abstract

  Atopic dermatitis (AD; OMIM#603165) and psoriasis (OMIM#177900) are two common inflammatory skin disorders. Both are genetically complex, multifactorial and do not follow a Mendelian pattern of inheritance. Both diseases share several genetic susceptibility loci such as the epidermal differentiation complex (EDC) on chromosome 1q21. Within the EDC, mutations in the filaggrin (FLG) gene are strongly associated with AD whereas no association has been replicated with psoriasis. However, reduced levels of filaggrin have been reported in psoriatic skin. Further, filaggrin deficiency was shown to be a modifying factor for the phenotype in another epidermal skin disorder, X-linked recessive ichthyosis. Altogether, this raises the question if FLG mutations may modify the disease course in other epidermal skin diseases such as psoriasis. Psoriasis is a highly heterogeneous disease and so far genetic studies have not taken the distinct sub-phenotype childhood onset into account.To determine if FLG mutations modify the onset of psoriasis.A total of 241 children with onset of psoriasis below 15 years of age and 314 healthy controls were identified at the Dermatology clinic, Karolinska University Hospital and diagnosed by the same dermatologist (JL). Blood samples were taken and medical history was recorded. FLG was genotyped in all patients and controls using allelic discrimination (n = 555) and sequencing (n = 20).No association between FLG mutations and early onset of psoriasis was demonstrated (P = 0.57) and no novel mutations were detected, indicating that FLG loss-of-function variants do not have a strong effect on the onset of psoriasis in childhood.

  View details for DOI 10.1111/j.1468-3083.2011.04403.x

  View details for Web of Science ID 000312655900036

  View details for PubMedID 22182180

• Characterization of EGFR and ErbB2 expression in atopic dermatitis patients ARCHIVES OF DERMATOLOGICAL RESEARCH Saaf, A., Pivarcsi, A., Winge, M. G., Wahlgren, C., Homey, B., Nordenskjold, M., Tengvall-Linder, M., Bradley, M. 2012; 304 (10): 773-780

  Abstract

  Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases in industrialized countries. To identify candidate genes involved in the pathogenesis of AD, we previously undertook a genome-wide approach using DNA microarrays. A transcript encoding the epidermal growth factor receptor (EGFR) was found to be among the down-regulated transcripts in AD skin. Here, we further investigated the expression pattern of two EGFR family members (EGFR and ErbB2) in AD skin on a protein level. Immunohistochemical (IHC) analysis of EGFR and ErbB2 showed decreased expression of EGFR and ErbB2 proteins in AD lesional skin as compared to skin from healthy individuals. Interestingly, we found that EGFR and ErbB2 were reciprocally expressed in an in vitro model of keratinocyte proliferation and differentiation, paralleling the expression patterns found in epidermis of healthy skin. The highest levels of EGFR transcripts were found in proliferating cells, while ErbB2 was found in differentiated cells. We show that blocking EGFR activity combined with co-stimulation of the Th2-cytokine IL4 in keratinocytes leads to induction of the inflammatory chemokine CCL26/eotaxin-3 in vitro. Accordingly, increased CCL26 transcriptional levels were observed in AD lesional skin. Taken together, suppression of EGFR may contribute to the pathogenesis of AD via the regulation of inflammatory chemokines.

  View details for DOI 10.1007/s00403-012-1242-4

  View details for Web of Science ID 000311495600001

  View details for PubMedID 22552355

• Genetic Variation in the Epidermal Transglutaminase Genes Is Not Associated with Atopic Dermatitis PLOS ONE Lieden, A., Winge, M. G., Saaf, A., Kockum, I., Ekelund, E., Rodriguez, E., Foelster-Holst, R., Franke, A., Illig, T., Tengvall-Linder, M., Baurecht, H., Weidinger, S., Wahlgren, C., Nordenskjold, M., Bradley, M. 2012; 7 (11): e49694

  Abstract

  Atopic dermatitis (AD) is a common chronic inflammatory skin disorder where epidermal barrier dysfunction is a major factor in the pathogenesis. The identification of AD susceptibility genes related to barrier dysfunction is therefore of importance. The epidermal transglutaminases (TGM1, TGM3 and TGM5) encodes essential cross-linking enzymes in the epidermis.To determine whether genetic variability in the epidermal transglutaminases contributes to AD susceptibility.Forty-seven single nucleotide polymorphisms (SNPs) in the TGM1, TGM3 and TGM5 gene region were tested for genetic association with AD, independently and in relation to FLG genotype, using a pedigree disequilibrium test (PDT) in a Swedish material consisting of 1753 individuals from 539 families. In addition, a German case-control material, consisting of 533 AD cases and 1996 controls, was used for in silico analysis of the epidermal TGM regions. Gene expression of the TGM1, TGM3 and TGM5 gene was investigated by relative quantification with Real Time PCR (qRT-PCR). Immunohistochemical (IHC) analysis was performed to detect TG1, TG3 and TG5 protein expression in the skin of patients and healthy controls.PDT analysis identified a significant association between the TGM1 SNP rs941505 and AD with allergen-specific IgE in the Swedish AD family material. However, the association was not replicated in the German case-control material. No significant association was detected for analyzed SNPs in relation to FLG genotype. TG1, TG3 and TG5 protein expression was detected in AD skin and a significantly increased TGM3 mRNA expression was observed in lesional skin by qRT-PCR.Although TGM1 and TGM3 may be differentially expressed in AD skin, the results from the genetic analysis suggest that genetic variation in the epidermal transglutaminases is not an important factor in AD susceptibility.

  View details for DOI 10.1371/journal.pone.0049694

  View details for Web of Science ID 000311929800032

  View details for PubMedID 23189155

  View details for PubMedCentralID PMC3506648

• X-linked recessive ichthyosis: an impaired barrier function evokes limited gene responses before and after moisturizing treatments BRITISH JOURNAL OF DERMATOLOGY Hoppe, T., Winge, M. G., Bradley, M., Nordenskjold, M., Vahlquist, A., Berne, B., Torma, H. 2012; 167 (3): 514-522

  Abstract

  X-linked recessive ichthyosis (XLRI) is due to deletions or inactivating mutations in the steroid sulfatase (STS) gene. This results in an accumulation of cholesterol sulphate affecting the packing of intercorneocyte lipids. XLRI is characterized by dry, scaly skin and increased skin barrier permeability; patients are often dependent on daily use of moisturizers.To examine the biophysical and molecular changes in the skin of patients with XLRI compared with healthy volunteers, and to analyse the effects of moisturizers on the patients' barrier function.Patients with XLRI (n=14) and healthy controls (n=14) were included in the study. Skin dryness score, transepidermal water loss (TEWL) and skin surface pH were monitored at baseline, and punch biopsies were obtained for mRNA expression profiles determined by oligonucleotide arrays. Measurements were repeated in the patients with XLRI after a 4-week treatment with three different moisturizers on the volar forearms.Patients with XLRI showed, compared with healthy controls, increased dryness and TEWL, equal skin pH and altered expression of 27 genes. There were no signs of activation of inflammation or repair pathways. Five selected genes were significantly altered also on quantitative polymerase chain reaction analysis. Treatment with the moisturizers showed similar effects: they improved skin dryness but had no effect on TEWL, pH or expression of selected genes.Despite a dysfunctional skin barrier, the limited number of genes altered in XLRI skin suggests that no inflammatory or repair mechanisms are triggered. Treatment with moisturizers does not have any major impact on the skin barrier properties of patients with XLRI.

  View details for DOI 10.1111/j.1365-2133.2012.10979.x

  View details for Web of Science ID 000308130900011

  View details for PubMedID 22486194

• Filaggrin Genotype Determines Functional and Molecular Alterations in Skin of Patients with Atopic Dermatitis and Ichthyosis Vulgaris PLOS ONE Winge, M. G., Hoppe, T., Berne, B., Vahlquist, A., Nordenskjold, M., Bradley, M., Torma, H. 2011; 6 (12): e28254

  Abstract

  Several common genetic and environmental disease mechanisms are important for the pathophysiology behind atopic dermatitis (AD). Filaggrin (FLG) loss-of-function is of great significance for barrier impairment in AD and ichthyosis vulgaris (IV), which is commonly associated with AD. The molecular background is, however, complex and various clusters of genes are altered, including inflammatory and epidermal-differentiation genes.The objective was to study whether the functional and molecular alterations in AD and IV skin depend directly on FLG loss-of-function, and whether FLG genotype determines the type of downstream molecular pathway affected.Patients with AD/IV (n = 43) and controls (n = 15) were recruited from two Swedish outpatient clinics and a Swedish AD family material with known FLG genotype. They were clinically examined and their medical history recorded using a standardized questionnaire. Blood samples and punch biopsies were taken and trans-epidermal water loss (TEWL) and skin pH was assessed with standard techniques. In addition to FLG genotyping, the STS gene was analyzed to exclude X-linked recessive ichthyosis (XLI). Microarrays and quantitative real-time PCR were used to compare differences in gene expression depending on FLG genotype. Several different signalling pathways were altered depending on FLG genotype in patients suffering from AD or AD/IV. Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression.We emphasize further the role of FLG in skin-barrier integrity and the complex compensatory activation of signalling pathways. This involves inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion in response to FLG-dependent skin-barrier dysfunction.

  View details for DOI 10.1371/journal.pone.0028254

  View details for Web of Science ID 000298171400054

  View details for PubMedID 22164253

  View details for PubMedCentralID PMC3229525

• Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis BRITISH JOURNAL OF DERMATOLOGY Winge, M. G., Bilcha, K. D., Lieden, A., Shibeshi, D., Sandilands, A., Wahlgren, C., McLean, W. I., Nordenskjold, M., Bradley, M. 2011; 165 (5): 1074-1080

  Abstract

  Filaggrin is a key protein involved in maintaining skin barrier function and hydration. Mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and are a major predisposing factor for atopic dermatitis (AD) in individuals of European and Asian descent. It has been proposed that FLG mutations are population specific and a difference in the spectra of mutations between different ancestral groups has been described. However, it is unknown whether FLG mutations in the African population are a causative genetic factor for IV and predispose to AD, or whether other mechanisms are more prominent.The present aim was to investigate the role of FLG mutations as predisposing factors for IV or AD among individuals from Ethiopia.A case series of Ethiopian patients with AD (n = 103) and IV (n = 7) together with controls (n = 103; subjects without past or present history of AD, dry skin or atopic manifestations) was collected at the outpatient dermatology clinics at ALERT Dermatology Hospital, Tikur Anbessa Hospital and Gondar University Hospital, Ethiopia. AD was diagnosed by a dermatologist using the U.K. Working Party's diagnostic criteria. The IV diagnosis was based on clinical examination and genetic testing of the steroid sulphatase gene to exclude X-linked recessive ichthyosis. Patients were studied with direct sequencing (n = 40) and/or allelic discrimination (n = 110). Immunohistochemical analysis was performed for filaggrin expression in the skin of patients (n = 7) and controls (n = 2).The Ethiopian patients and controls were genotyped for the four previously described common European FLG null mutations (R501X, 2282del4, S3247X, R2447X) and no carriers were found. In one patient with AD a novel heterozygous 2-bp deletion, 632del2, leading to a premature stop codon was revealed by direct sequencing. No additional carrier of this deletion or other mutations was found. In addition, no difference in filaggrin expression was detected in AD or IV skin compared with healthy control skin.Our results indicate that FLG loss-of-function-variants are less common in patients with IV and AD in the Ethiopian population, suggesting that other factors may be of importance in the pathogenesis in this ethnic group.

  View details for DOI 10.1111/j.1365-2133.2011.10475.x

  View details for Web of Science ID 000297318700023

  View details for PubMedID 21692775

• Novel point mutation in the STS gene in a patient with X-linked recessive ichthyosis JOURNAL OF DERMATOLOGICAL SCIENCE Winge, M. G., Hoppe, T., Lieden, A., Nordenskjold, M., Vahlquist, A., Wahlgren, C., Torma, H., Bradley, M., Berne, B. 2011; 63 (1): 62-64

  View details for DOI 10.1016/j.jdermsci.2011.03.011

  View details for Web of Science ID 000291846500009

  View details for PubMedID 21530180

• Combs and Hair-trimming Tools as Reservoirs for Dermatophytes in Juvenile Tinea Capitis ACTA DERMATO-VENEREOLOGICA Winge, M. G., Chryssanthou, E., Wahlgren, C. 2009; 89 (5): 536-537

  View details for DOI 10.2340/00015555-0694

  View details for Web of Science ID 000270423400026

  View details for PubMedID 19734990