TY - JOUR AB - Introduction: Atopic dermatitis (AD) is an inflammatory skin disorder characterized by disrupted skin barrier, increased skin pH and elevated skin Staphylococcus aureus colonization. The complex interplay between skin microenvironment and microbiome in AD is not yet fully understood. Here we investigated the influence of topical corticosteroids (TCS) and of pH-lowering emollient on the skin physiology and microbiome in real-life AD setting. Methods: A double-blinded, placebo-controlled study was performed in 29 mild-moderate AD patients. TCS was applied for two weeks, followed by pH-lowering verum and placebo emollients on opposite bodysides for six weeks. Clinical, skin physiology and skin microbiome data was collected every 2-4 weeks. Skin microbiome composition was analyzed by 16S sequencing. Skin S. aureus absolute numbers were quantified by standardized qPCR. Results: TCS significantly lowered SCORAD in all patients, in correlation with transepidermidal water loss (TEWL) drecrease in patients with high baseline TEWL. Skin pH and hydration were not afftected by TCS. Lesional skin S. aureus abundance, both relative and absolute, significantly declined after TCS therapy in patients with hight baseline S. aureus abundance. Skin pH was significantly reduced by the pH-lowering verum, to significantly lower pH than placebo. Skin hydration was significantly increased by both verum and placebo emollients. However, S. aureus abundance increased back to baseline during both the verum and placebo emollient application, independent of the skin pH decline. Conclusions: Our findings provide valuable longitudinal data on treatment responses and microbiome dynamics in real-life setting. Topical corticosteroid therapy positively modulated the skin barrier and decreased S. aureus skin colonization with no effect on skin pH. Skin pH reduction by pH-lowering emollient did not control skin Staphylococcus aureus colonization compared to placebo. Thus, changing the skin pH might be irrelevant in balancing AD skin microbiome. Future studies should validate these findings in cohorts enriched for severe AD. AU - Berk, B.* AU - Rohayem, R.* AU - Reiger, M. AU - Klepper, L. AU - Ranieri, C.* AU - Gülzow, C.* AU - Seide, C.* AU - Worthmann, A.* AU - Schölermann, A.M.* AU - Rippke, F.* AU - Traidl-Hoffmann, C. AU - Hülpüsch, C.* AU - Neumann, A.U. C1 - 76029 C2 - 58345 SP - e74 - e74 TI - 270 Impact of topical corticosteroids and pH-modulating emollients on skin physiology and skin microbiome in atopic dermatitis patients. JO - J. Invest. Dermatol. VL - 145 IS - 11 PY - 2025 SN - 0022-202X ER - TY - JOUR AB - Phenotypic heterogeneity in atopic dermatitis (AD) remains poorly defined. This study advances the identification and characterization of AD endotypes using skin transcriptomes. We analyzed transcriptomic profiles from 765 lesional (ADL), 535 non-lesional (ADNL) and 164 healthy control (HC) skin samples. Using machine learning, we identified and replicated 2 distinct AD endotypes defined by 108 markers and characterized by clinical, microbial, histological and cytometric parameters. In vitro experiments were conducted in cell and tissue culture to explore endotype-specific pathways. We demonstrate that the endotype-distinguishing signature is temporally stable with only a small subset of patients switching endotypes following AD treatment. ADL endotype 2 (ADLE2) was characterized by increased severity, Staphylococcus aureus (SA) load, M1 macrophage, granulocyte count and elevated expression of innate immunity genes (e.g. IL6 and IL1B) compared to ADLE1. In 2D keratinocyte cultures we observed synergistic gene expression changes for endotype/AD markers (CXCL3, TNFAIP6, CCL2, CCL26) by co-stimulation of Th2 cytokines (IL4, IL13) with IL-6/IL-1β. In 3D organotypic skin cultures, IL-6/ IL-1β addition to the Th2 cytokine cocktail aggravated epidermal hallmarks of acute AD with spongiosis, acanthosis, terminal differentiation defects and poor skin barrier function. SA exposure of keratinocytes upregulated IL6/IL1B, further amplified by adding Th2 cytokines. Expression of endotype/AD markers normalized with addition of AD drugs. In conclusion, our study reveals distinct AD endotypes defined by presence/absence of an inflammatory component driven by innate immunity, highlighting potential treatment options for a subgroup of patients. AU - Hübenthal, M.* AU - Klijnhout, J.* AU - Bogaard, E.v.d.* AU - Langreder, N.* AU - Eyerich, S. AU - Strotton, M.* AU - Hartmann, J.* AU - Rintala, T.* AU - Fortino, V.* AU - Xing, H.* C1 - 76143 C2 - 58428 SP - S318 - S318 TI - 292 Role of innate immunity in molecular differentiation and mechanistic validation of endotypes of Atopic Dermatitis. JO - J. Invest. Dermatol. VL - 145 IS - 12 PY - 2025 SN - 0022-202X ER - TY - JOUR AB - Lichen planus (LP) is a chronic inflammatory disease affecting the skin, mucosa, nail, and hair. Previous studies demonstrated a pivotal role of type 1 immunity in LP because infiltrating T cells trigger apoptosis and necroptosis in the epidermis. In this study, we investigated the role of DAPK1 in LP with special focus on its role in mediating cell death and inflammation. Bulk RNA sequencing of skin biopsies revealed a high expression of DAPK1 in LP compared with that in psoriasis and atopic dermatitis. DAPK1 expression in human keratinocytes was induced by IFN-g, TNF, and IL-32. CRISPR/Cas9-mediated DAPK1 knockout led to a decreased rate of cell death and induction of proapoptotic proteins (BAX, cPARP) in human keratinocytes upon stimulation with the supernatant T cells derived from LP skin biopsies. Meanwhile, DAPK1 knockout resulted in an induction of kinases involved in necroptosis (RIPK3) and an upregulation of inflammatory genes (CXCL9, CXCL10, CXCL11, IL32, CCL2) after stimulation with LP supernatant T cells. In summary, we demonstrate that DAPK1 mediates keratinocyte apoptosis under type 1 inflammatory conditions and thereby counteracts necroptosis and regulation of inflammatory genes. These findings point toward previously unreported therapeutic approaches for activating or stabilizing DAPK1 in LP. AU - Kurzen, N.* AU - Mubarak, M.* AU - Eigemann, J. AU - Seiringer, P.* AU - Wasserer, S.* AU - Hillig, C. AU - Menden, M.P. AU - Biedermann, T.* AU - Schmidt-Weber, C.B. AU - Eyerich, K.* AU - Jargosch, M. AU - Eyerich, S. AU - Lauffer, F.* C1 - 75459 C2 - 58014 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 1921-1929.e13 TI - Death-associated protein kinase 1 dampens keratinocyte necroptosis and expression of genes in lichen planus. JO - J. Invest. Dermatol. VL - 145 IS - 8 PB - Elsevier Science Inc PY - 2025 SN - 0022-202X ER - TY - CONF AU - Scala, E.* AU - Hillig, C. AU - Mercurio, L.* AU - Fania, L.* AU - Gubinelli, E.* AU - Madonna, S.* AU - Menden, M.P. AU - Eyerich, K.* AU - Eyerich, S. AU - Albanesi, C.* C1 - 76141 C2 - 58427 SP - S324 - S324 TI - 331 IL-34 expression and function in hidradenitis suppurativa and psoriasis. JO - J. Invest. Dermatol. VL - 145 IS - 12 PY - 2025 SN - 0022-202X ER - TY - JOUR AU - Schneider, M.R.* AU - Meier, M. C1 - 74901 C2 - 57711 TI - Bringing high-resolution spatial order to sebaceous glands. JO - J. Invest. Dermatol. PY - 2025 SN - 0022-202X ER - TY - JOUR AB - Lichen planus (LP) is a chronic inflammatory disease (ISD) affecting skin, mucosa, nail, and hair. Previous studies demonstrated a pivotal role of type 1 immunity in LP, as infiltrating T cells trigger apoptosis and necroptosis in the epidermis. In this study, we investigated the role of DAPK1 in LP with special focus on its role in mediating cell death and inflammation. Bulk RNA seq of skin biopsies revealed a high expression of DAPK1 in LP compared to psoriasis and atopic dermatitis (AD). DAPK1 expression in human keratinocytes was induced by IFN-γ, TNF and IL-32. CRISPR/Cas9 mediated DAPK1 knock-out (KO) led to a decreased rate of cell death and induction of pro-apoptotic proteins (BAX, cPARP) in human keratinocytes upon stimulation with the supernatant T cells derived from LP skin biopsies (LP-TCS). Meanwhile, DAPK1 KO resulted in an induction of kinases involved in necroptosis (RIPK3) and an upregulation of inflammatory genes (CXCL9, CXCL10, CXCL11, IL32, CCL2) after stimulation with LP-TCS. In summary, we demonstrate that DAPK1 mediates keratinocyte apoptosis under type 1 inflammatory conditions and thereby counteracts necroptosis and regulation of inflammatory genes. These findings point towards previously unreported therapeutic approaches for activating or stabilizing DAPK1 in LP. AU - Kurzen, N.* AU - Mubarak, M.* AU - Eigemann, J. AU - Seiringer, P.* AU - Wasserer, S.* AU - Hillig, C. AU - Menden, M.P. AU - Biedermann, T.* AU - Schmidt-Weber, C.B. AU - Eyerich, K.* AU - Jargosch, M. AU - Eyerich, S. AU - Lauffer, F.* C1 - 72935 C2 - 56758 TI - Death associated protein kinase 1 dampens keratinocyte necroptosis and expression of inflammatory genes in lichen planus. JO - J. Invest. Dermatol. PY - 2024 SN - 0022-202X ER - TY - JOUR AB - Single-cell technologies have become essential to driving discovery in both basic and translational investigative dermatology. Despite the multitude of available datasets, a central reference atlas of normal human skin, which can serve as a reference resource for skin cell types, cell states, and their molecular signatures, is still lacking. For any such atlas to receive broad acceptance, participation by many investigators during atlas construction is an essential prerequisite. As part of the Human Cell Atlas project, we have assembled a Skin Biological Network to build a consensus Human Skin Cell Atlas and outline a roadmap toward that goal. We define the drivers of skin diversity to be considered when selecting sequencing datasets for the atlas and list practical hurdles during skin sampling that can result in data gaps and impede comprehensive representation and technical considerations for tissue processing and computational analysis, the accounting for which should minimize biases in cell type enrichments and exclusions and decrease batch effects. By outlining our goals for Atlas 1.0, we discuss how it will uncover new aspects of skin biology. AU - Almet, A.A.* AU - Yuan, H.* AU - Annusver, K.* AU - Ramos, R.* AU - Liu, Y.* AU - Wiedemann, J.* AU - Sorkin, D.H.* AU - Landén, N.X.* AU - Sonkoly, E.* AU - Haniffa, M.* AU - Nie, Q.* AU - Lichtenberger, B.M.* AU - Luecken, M. AU - Andersen, B.* AU - Tsoi, L.C.* AU - Watt, F.M.* AU - Gudjonsson, J.E.* AU - Plikus, M.V.* AU - Kasper, M.* C1 - 67965 C2 - 54443 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 1667-1677 TI - A Roadmap for a consensus human skin cell atlas and single-cell data standardization. JO - J. Invest. Dermatol. VL - 143 IS - 9 PB - Elsevier Science Inc PY - 2023 SN - 0022-202X ER - TY - JOUR AU - Filipp, F.V. C1 - 68099 C2 - 54577 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 1342-1347 TI - Spatial cancer systems biology resolves heterotypic interactions and identifies disruption of spatial hierarchy as a pathological driver event. JO - J. Invest. Dermatol. VL - 143 IS - 8 PB - Elsevier Science Inc PY - 2023 SN - 0022-202X ER - TY - JOUR AB - Highly effective targeted therapies are available to treat noncommunicable chronic inflammatory skin diseases. In contrast, the exact diagnosis of noncommunicable chronic inflammatory skin diseases is complicated by its complex pathogenesis and clinical and histological overlap. Particularly, the differential diagnosis of psoriasis and eczema can be challenging in some cases, and molecular diagnostic tools need to be developed to support a gold standard diagnosis. The aim of this work was to develop a real-time PCR-based molecular classifier to distinguish psoriasis from eczema in formalin-fixed and paraffin-embedded-fixed skin samples and to evaluate the use of minimally invasive microbiopsies and tape strips for molecular diagnosis. In this study, we present a formalin-fixed and paraffin-embedded-based molecular classifier that determines the probability for psoriasis with a sensitivity/specificity of 92%/100%, respectively, and an area under the curve of 0.97, delivering comparable results to our previous published RNAprotect-based molecular classifier. The psoriasis probability, as well as levels of NOS2 expression, positively correlated with the disease hallmarks of psoriasis and negatively with eczema hallmarks. Furthermore, minimally invasive tape strips and microbiopsies were effectively used to differentiate psoriasis from eczema. In summary, the molecular classifier offers broad usage in pathology laboratories as well as outpatient settings and can support the differential diagnosis of noncommunicable chronic inflammatory skin diseases on a molecular level using formalin-fixed and paraffin-embedded tissue, microbiopsies, and tape strips. AU - Fischer, F. AU - Doll, A.* AU - Uereyener, D. AU - Roenneberg, S.* AU - Hillig, C. AU - Weber, L.* AU - Hackert, V.* AU - Meinel, M. AU - Farnoud, A. AU - Seiringer, P.* AU - Thomas, J. AU - Anand, P.* AU - Graner, L.* AU - Schlenker, F.* AU - Zengerle, R.* AU - Jonsson, P.* AU - Jargosch, M. AU - Theis, F.J. AU - Schmidt-Weber, C.B. AU - Biedermann, T.* AU - Howell, M.* AU - Reich, K.* AU - Eyerich, K.* AU - Menden, M.P. AU - Garzorz-Stark, N.* AU - Lauffer, F.* AU - Eyerich, S. C1 - 67747 C2 - 54057 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 1461-1469.e5 TI - Gene expression-based molecular test as diagnostic aid for the differential diagnosis of psoriasis and eczema in formalin-fixed and paraffin-embedded tissue, microbiopsies, and tape strips. JO - J. Invest. Dermatol. VL - 143 IS - 8 PB - Elsevier Science Inc PY - 2023 SN - 0022-202X ER - TY - JOUR AU - Correa-Gallegos, D. AU - Machens, H.G.* AU - Rinkevich, Y. C1 - 65505 C2 - 52376 SP - 1767-1770 TI - States and fates of skin fibroblasts revealed through chromatin accessibility. JO - J. Invest. Dermatol. VL - 142 IS - 7 PY - 2022 SN - 0022-202X ER - TY - JOUR AB - Deep skin wounds rapidly heal by mobilizing extracellular matrix and cells from the fascia, deep beneath the dermal layer of the skin, to form scars. Despite wounds being an extensively studied area and an unmet clinical need, the biochemistry driving this patch-like repair remains obscure. Lacking also are efficacious therapeutic means to modulate scar formation in vivo. Here, we identify a central role for p120 in mediating fascia mobilization and wound repair. Injury triggers p120 expression, largely within engrailed-1 lineage positive fibroblasts (EPFs) of the fascia that exhibit a supra-cellular organization. Using adeno-associated virus (AAV) mediated gene silencing, we show that p120 establishes the supracellular organization of fascia EPFs, without which fascia mobilization is impaired. Gene silencing of p120 in fascia fibroblasts disentangles their supracellular organization, reducing the transfer of fascial cells and extracellular matrix into wounds, and augments wound healing. Our findings place p120 as essential for fascia mobilization, opening a new therapeutic avenue for targeted intervention in the treatment of a variety of skin scar conditions. AU - Rajendran, V. AU - Ramesh, P. AU - Dai, R. AU - Kalgudde Gopal, S. AU - Ye, H. AU - Machens, H.G.* AU - Adler, H. AU - Jiang, D. AU - Rinkevich, Y. C1 - 66852 C2 - 53323 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - Therapeutic silencing of p120 in fascia fibroblasts ameliorate tissue repair. JO - J. Invest. Dermatol. VL - 143 IS - 5 PB - Elsevier Science Inc PY - 2022 SN - 0022-202X ER - TY - JOUR AB - T cells are key drivers of autoimmunity in numerous noncommunicable inflammatory skin diseases by directly harming host tissue or through helping B cells in producing autoantibodies. Technological advances have contributed to identifying autoantigens, the Holy Grail of autoimmunity, in many inflammatory disorders of the skin. Novel therapeutic approaches such as chimeric (auto)antibody receptor T cells are a milestone on the way to finding individualized, well-tolerated, targeted therapies. This review summarizes the current knowledge on pathogenesis, immune response pattern‒related ontology, diagnostic approaches, and treatment options of autoimmune skin diseases. AU - Seiringer, P. AU - Garzorz-Stark, N.* AU - Eyerich, K.* C1 - 63037 C2 - 51218 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 804-810 TI - T-cell‒mediated autoimmunity: Mechanisms and future directions. JO - J. Invest. Dermatol. VL - 142 IS - 3 PT B PB - Elsevier Science Inc PY - 2022 SN - 0022-202X ER - TY - JOUR AB - Reactivation of latent Epstein-Barr virus (EBV) and/or Cytomegalovirus (CMV) infection is a dreaded complication in immunocompromised patients receiving hematopoietic stem cell transplantation. Evidence is sparse if subclinical reactivation of viral infection may also be of clinical relevance in dermatological patients. We screened patients (n= 206) suffering from chronic skin diseases for subclinical reactivation of EBV and CMV infection. We found that immunocompromised patients with therapy-refractory chronic skin diseases showed higher rates of subclinical reactivation of CMV and EBV infection (6.7 % vs. 0 % for EBV and 16.7 % vs. 5.6% for CMV) and higher prevalence of virus specific DNA in skin tissue (30.8 % vs. 0% for EBV and 21.4% vs. 0% for CMV) as compared to non-immunocompromised patients with chronic skin diseases. T cells isolated from lesional skin exhibited up to 14-fold increased proliferation with production of Th1 and Th17 cytokines upon stimulation with viral proteins providing evidence for possible aggravation of the underlying skin diseases by viral infection. Improvement of skin lesions in patients with reactivation of CMV infection (n=4) was observed upon anti-viral treatment. Our data suggests that subclinical reactivation of EBV and/or CMV infection is an under-recognized condition in the dermatological patient population with chronic skin diseases. AU - Speth, P.* AU - Jargosch, M.* AU - Seiringer, P.* AU - Schwamborn, K.* AU - Bauer, T. AU - Scheerer, C.* AU - Protzer, U. AU - Schmidt-Weber, C.B. AU - Biedermann, T.* AU - Eyerich, S. AU - Garzorz-Stark, N.* C1 - 62955 C2 - 51203 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 549-558.e6 TI - Immunocompromised patients with therapy-refractory chronic skin diseases show reactivation of latent EBV and CMV infection. JO - J. Invest. Dermatol. VL - 142 IS - 3 PT A PB - Elsevier Science Inc PY - 2022 SN - 0022-202X ER - TY - JOUR AU - Thomas, J. AU - Wang, R.* AU - Batra, R. AU - Böhner, A.* AU - Garzorz-Stark, N.* AU - Eberlein, B.* AU - Theis, F.J. AU - Biedermann, T.* AU - Schmidt-Weber, C.B. AU - Zink, A.* AU - Eyerich, K.* AU - Eyerich, S. C1 - 61109 C2 - 49840 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 681-685.e6 TI - CD23 levels on B cells determine long-term therapeutic response in patients with atopic eczema treated with selective IgE immune apheresis. JO - J. Invest. Dermatol. VL - 141 IS - 3 PB - Elsevier Science Inc PY - 2021 SN - 0022-202X ER - TY - JOUR AU - Chuah, S.Y.* AU - Attia, A.B.E.* AU - Ho, C.J.H.* AU - Li, X.* AU - Lee, J.S.* AU - Tan, M.W.P.* AU - Yong, A.A.* AU - Tan, A.W.M.* AU - Razansky, D. AU - Olivo, M.* AU - Thng, S.T.G.* C1 - 54331 C2 - 45515 CY - 360 Park Ave South, New York, Ny 10010-1710 Usa SP - 481-485 TI - Volumetric multispectral optoacoustic tomography for 3-dimensional reconstruction of skin tumors: A further evaluation with histopathologic correlation. JO - J. Invest. Dermatol. VL - 139 IS - 2 PB - Elsevier Science Inc PY - 2019 SN - 0022-202X ER - TY - JOUR AU - Eyerich, K.* AU - Eyerich, S. C1 - 53569 C2 - 44749 SP - S16-S16 TI - Immune response patterns in chronic inflammatory skin diseases a basis of targeted therapy. JO - J. Invest. Dermatol. VL - 138 IS - 5 PY - 2018 SN - 0022-202X ER - TY - JOUR AB - Melanoma cells share many biological properties with neural crest stem cells. Here we show that the homeodomain transcription factor Msh homeobox 1 (MSX1), which is significantly correlated with melanoma disease progression, reprograms melanocytes and melanoma cells towards a neural crest precursor-like state. MSX1-reprogrammed normal human melanocytes express the neural crest marker p75 and become multipotent. MSX1 induces a phenotypic switch in melanoma, which is characterized by an oncogenic transition from an E-cadherin-high non-migratory state towards a ZEB1-high invasive state. ZEB1 up-regulation is responsible for the MSX1-induced migratory phenotype in melanoma cells. Depletion of MSX1 significantly inhibits melanoma metastasis in vivo. These results demonstrate that neural crest-like reprogramming achieved by a single factor is a critical process for melanoma progression. AU - Heppt, M.V.* AU - Wang, J.X.* AU - Hristova, D.M.* AU - Wei, Z.* AU - Li, L.* AU - Evans, B.* AU - Beqiri, M.* AU - Zaman, S.* AU - Zhang, J.* AU - Irmler, M. AU - Berking, C.* AU - Besch, R.* AU - Beckers, J. AU - Rauscher, F.J.* AU - Sturm, R.A.* AU - Fisher, D.E.* AU - Herlyn, M.* AU - Fukunaga-Kalabis, M.* C1 - 51946 C2 - 43601 CY - New York SP - 141-149 TI - MSX1-induced neural crest-like reprogramming promotes melanoma progression. JO - J. Invest. Dermatol. VL - 138 IS - 1 PB - Elsevier Science Inc PY - 2018 SN - 0022-202X ER - TY - JOUR AU - Hiller, J. AU - Hagl, B. AU - Effner, R. AU - Puel, A.* AU - Schaller, M.* AU - Mascher, B.* AU - Eyerich, S. AU - Eyerich, K.* AU - Jansson, A.F.* AU - Ring, J.J.* AU - Casanova, J.L.* AU - Renner, E.D. AU - Traidl-Hoffmann, C. C1 - 52171 C2 - 43801 CY - New York SP - 711-714 TI - STAT1 gain-of-function and dominant negative STAT3 mutations impair IL-17 and IL-22 immunity associated with CMC. JO - J. Invest. Dermatol. VL - 138 IS - 3 PB - Elsevier Science Inc PY - 2018 SN - 0022-202X ER - TY - JOUR AU - Jargosch, M.* AU - Lauffer, F.* AU - Paetzold, K.* AU - Krause, L. AU - Garzorz-Stark, N. AU - Biedermann, T.* AU - Eyerich, S. AU - Eyerich, K.* C1 - 53570 C2 - 44748 SP - S116-S116 TI - Necroptosis as special type of cell death in inflammatory skin diseases. JO - J. Invest. Dermatol. VL - 138 IS - 5 PY - 2018 SN - 0022-202X ER - TY - JOUR AB - Interface dermatitis is a characteristic histological pattern that occurs in autoimmune and chronic inflammatory skin diseases. It is unknown whether a common mechanism orchestrates this distinct type of skin inflammation. Here we investigated the overlap of two different interface dermatitis positive skin diseases, lichen planus and lupus erythematosus. The shared transcriptome signature pointed toward a strong type I immune response, and biopsy-derived T cells were dominated by IFN-γ and tumor necrosis factor alpha (TNF-α) positive cells. The transcriptome of keratinocytes stimulated with IFN-γ and TNF-α correlated significantly with the shared gene regulations of lichen planus and lupus erythematosus. IFN-γ TNF-α or mixed supernatant of lesional T cells induced signs of keratinocyte cell death in three-dimensional skin equivalents. We detected a significantly enhanced epidermal expression of receptor-interacting-protein-kinase 3, a key regulator of necroptosis, in interface dermatitis. Phosphorylation of receptor-interacting-protein-kinase 3 and mixed lineage kinase domain like pseudokinase was induced in keratinocytes on stimulation with T-cell supernatant—an effect that was dependent on the presence of either IFN-γ or TNF-α in the T-cell supernatant. Small hairpin RNA knockdown of receptor-interacting-protein-kinase 3 prevented cell death of keratinocytes on stimulation with IFN-γ or TNF-α. In conclusion, type I immunity is associated with lichen planus and lupus erythematosus and induces keratinocyte necroptosis. These two mechanisms are potentially involved in interface dermatitis. AU - Lauffer, F.* AU - Jargosch, M.* AU - Krause, L. AU - Garzorz-Stark, N.* AU - Franz, R.* AU - Roenneberg, S.* AU - Böhner, A.* AU - Müller, N.S. AU - Theis, F.J. AU - Schmidt-Weber, C.B. AU - Biedermann, T.* AU - Eyerich, S. AU - Eyerich, K.* C1 - 53238 C2 - 44505 SP - 1785-1794 TI - Type I immune response induces keratinocyte necroptosis and is associated with interface dermatitis. JO - J. Invest. Dermatol. VL - 138 IS - 8 PY - 2018 SN - 0022-202X ER - TY - JOUR AB - Fibroblast growth factor-binding protein 1 (FGFBP1, FGF-BP) is a secreted chaperone that mobilizes paracrine-acting FGFs, stored in the extracellular matrix, and presents them to their cognate receptors. FGFBP1 enhances FGF signaling including angiogenesis during cancer progression, and is upregulated in various cancers. Here we evaluated the contribution of endogenous FGFBP1 to development and homeostasis as well as to skin pathologies utilizing Fgfbp1-knockout (KO) mice. Relative to wild-type (WT) littermates KO mice showed no gross pathologies. Still, in KO mice a significant thickening of the epidermis associated with a decreased transepidermal water loss and increased pro-inflammatory gene expression in the skin was detected. Also, skin carcinogen challenge by DMBA/TPA resulted in delayed and reduced papillomatosis in KO mice. This was paralleled by delayed healing of skin wounds and reduced angiogenic sprouting in subcutaneous matrigel plugs. Heterozygous GFP-knock-in mice revealed rapid induction of gene expression during papilloma induction and during wound healing. Examination of WT skin grafted onto Fgfbp1 GFP knockin reporter hosts and bone marrow transplants from the GFP reporter model into WT hosts revealed that circulating Fgfbp1-expressing cells migrate into healing wounds. We conclude that tissue-resident and circulating Fgfbp1-expressing cells modulate skin carcinogenesis and inflammation. AU - Schmidt, M.O.* AU - Garman, K.A.* AU - Lee, Y.G.* AU - Zuo, C.* AU - Beck, P.J.* AU - Tan, M.W.P.* AU - Aguilar-Pimentel, A. AU - Ollert, M.* AU - Schmidt-Weber, C.B. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Hrabě de Angelis, M. AU - Tassi, E.* AU - Riegel, A.T.* AU - Wellstein, A.* AU - German Mouse Clinic Consortium (Zimprich, A. AU - Becker, L. AU - Vernaleken, A. AU - Adler, T. AU - Treise, I. AU - Horsch, M. AU - Beckers, J. AU - Moreth, K. AU - Garrett, L. AU - Hölter, S.M. AU - Wurst, W. AU - Brommage, R. AU - Hans, W. AU - Amarie, O.V. AU - Graw, J. AU - Rozman, J. AU - Calzada-Wack, J. AU - Da Silva-Buttkus, P. AU - Neff, F. AU - Rácz, I. AU - Rathkolb, B. AU - Östereicher, M.A. AU - Steinkamp, R. AU - Lengger, C. AU - Maier, H. AU - Stoeger, C. AU - Leuchtenberger, S.) C1 - 51790 C2 - 43516 CY - New York SP - 179-188 TI - The role of Fibroblast growth factor binding protein 1 in skin carcinogenesis and inflammation. JO - J. Invest. Dermatol. VL - 138 IS - 1 PB - Elsevier Science Inc PY - 2018 SN - 0022-202X ER - TY - JOUR AB - Various haptens trigger innate immune pathways and/or induce cytotoxicity as a part of sensitization. Adam et al. decipher in vitro the mechanisms by which chromium(VI) induces inflammation, the likely prerequisites for toxicity, sensitization, and allergic contact dermatitis against chromium(VI). Importantly, and in line with other observations, chromium(VI), but not chromium(III) (or Ni(II)), induces mitochondrial reactive oxygen species accumulation. Mitochondrial reactive oxygen species in turn activate the NLRP3 inflammasome, allowing increased IL-1 beta processing and secretion, which likely underlies both chromium(VI)-induced cutaneous toxicity and sensitization. Interrupting this mechanism, perhaps with reducing agents or inhibitors of the NLRP3/IL-1 axis, may be a new option to prevent occupational chromium toxicity and allergy. AU - Buters, J.T.M. AU - Biedermann, T.* C1 - 50468 C2 - 42298 CY - New York SP - 274-277 TI - Chromium(VI) contact dermatitis: Getting closer to understanding the underlying mechanisms of toxicity and sensitization! JO - J. Invest. Dermatol. VL - 137 IS - 2 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AB - We sought to examine the relationship globally between UV dose exposure and current eczema prevalences. ISAAC Phase Three provided data on eczema prevalence for 13-14 year-olds in 214 centres in 87 countries and for 6-7 year-olds in 132 centres in 57 countries. Linear and non-linear associations between (natural log transformed) eczema prevalence and the mean, maximum, minimum, standard deviation and range of monthly UV dose exposures were assessed using linear mixed-effects regression models. For the 13-14 year olds, the country-level eczema prevalence was positively and linearly associated with country-level monthly mean (prevalence ratio: 1.31, 95% confidence interval: [1.05, 1.63] per kJ/m(2)) and minimum (1.25 [1.06, 1.47] per kJ/m(2)) UV dose exposure. Linear and non-linear associations were also observed for other metrics of UV. Results were similar in trend, but non-significant, for the fewer centres with 6-7 year-olds (e.g. 1.24 [0.96, 1.59] per kJ/m(2) for country-level monthly mean UV). No consistent within-country associations were observed (e.g. 1.05 [0.89, 1.23] and 0.92 [0.71, 1.18] per kJ/m(2) for center-level monthly mean UV, for the 13-14 and 6-7 year-olds, respectively). These ecological results support a role for UV exposure in explaining some of the variation in global childhood eczema prevalence. AU - Fuertes, E.* AU - Flohr, C.* AU - Silverberg, J.I.* AU - Standl, M. AU - Strachan, D.P.* C1 - 50619 C2 - 42625 SP - 1248-1256 TI - Global associations between UVR exposure and current eczema prevalence in children from ISAAC Phase Three. JO - J. Invest. Dermatol. VL - 137 IS - 6 PY - 2017 SN - 0022-202X ER - TY - JOUR AU - Garzorz-Stark, N.* AU - Lauffer, F.* AU - Krause, L. AU - Gross, O.* AU - Traidl-Hoffmann, C.* AU - Theis, F.J. AU - Schmidt-Weber, C.* AU - Biedermann, T.* AU - Eyerich, S.* AU - Eyerich, K.* C1 - 51918 C2 - 43565 CY - New York SP - S275-S275 TI - TLR7/8 agonists stimulate plasmacytoid dendritic cells to initiate a Th17-deviated acute contact dermatitis in humans. JO - J. Invest. Dermatol. VL - 137 IS - 10 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AU - Guttman-Yassky, E.* AU - Khattri, S.* AU - Brunner, P.M.* AU - Neumann, A.U. AU - Malik, K.A.* AU - Fuentes-Duculan, J.* AU - Garcet, S.* AU - Suárez-Fariñas, M.* AU - Lebwohl, M.* AU - Krueger, J.G.* C1 - 51727 C2 - 43359 CY - New York SP - S53-S53 TI - A pathogenic role for Th22/IL-22 in atopic dermatitis is established by a placebo-controlled trial with an anti IL-22/ILV-094 mAb. JO - J. Invest. Dermatol. VL - 137 IS - 5 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AB - miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In the present study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in lesional skin of psoriasis patients. The expression of miR-146a was about 2-fold higher than that of miR-146b in healthy human skin and it was more strongly induced by stimulation of pro-inflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of psoriasis patients, among which FERMT1 was verified as direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in miR-146a gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a-/- and skin fibroblasts from miR-146a-/- and miR-146b-/- mice stimulated with psoriasis-associated cytokines as compared to wild type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin. AU - Hermann, H.* AU - Runnel, T.* AU - Aab, A.* AU - Baurecht, H.* AU - Rodriguez, E.* AU - Magilnick, N.* AU - Urgard, E.* AU - Šahmatova, L.* AU - Prans, E.* AU - Maslovskaja, J.* AU - Abram, K.* AU - Karelson, M.* AU - Kaldvee, B.* AU - Reemann, P.* AU - Haljasorg, U.* AU - Rückert, B.* AU - Wawrzyniak, P.* AU - Weichenthal, M.* AU - Mrowietz, U.* AU - Franke, A.* AU - Gieger, C. AU - Barker, J.* AU - Trembath, R.* AU - Tsoi, L.C.* AU - Elder, J.T.* AU - Tkaczyk, E.R.* AU - Kisand, K.* AU - Peterson, P.* AU - Kingo, K.* AU - Boldin, M.* AU - Weidinger, S.* AU - Akdis, C.A.* AU - Rebane, A.* C1 - 51280 C2 - 43120 CY - New York SP - 1945-1954 TI - miR-146b probably assists miRNA-146a in the suppression of keratinocyte proliferation and inflammatory responses in psoriasis. JO - J. Invest. Dermatol. VL - 137 IS - 9 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AB - Growing interest in microbial contributions to human health and disease has increasingly led investigators to examine the microbiome in both healthy skin and cutaneous disorders, including acne, psoriasis, and atopic dermatitis. The need for common language, effective study design, and validated methods is critical for high-quality standardized research. Features, unique to skin, pose particular challenges when conducting microbiome research. This review discusses microbiome research standards and highlights important factors to consider, including clinical study design, skin sampling, sample processing, DNA sequencing, control inclusion, and data analysis. AU - Kong, H.H.* AU - Andersson, B.* AU - Clavel, T.* AU - Common, J.E.* AU - Jackson, S.A.* AU - Olson, A.D.* AU - Segre, J.A.* AU - Traidl-Hoffmann, C. C1 - 50557 C2 - 42352 CY - New York SP - 561-568 TI - Performing skin microbiome research: A method to the madness. JO - J. Invest. Dermatol. VL - 137 IS - 3 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AU - Laemmermann, I.* AU - Terlecki-Zaniewicz, L.* AU - Weinmuellner, R.* AU - Schosserer, M.* AU - Berlin, I.* AU - Morizot, F.* AU - Lejeune, F.* AU - Fuzzati, N.* AU - Almaraz, J.C.H. AU - Scheideler, M. AU - Rietveld, M.* AU - El Ghalbzouri, A.* AU - Tschachler, E.* AU - Gruber, F.* AU - Grillari, J.* C1 - 51917 C2 - 43564 CY - New York SP - S311-S311 TI - Blocking negative effects of senescence in human skin fibroblasts with a plant extract. JO - J. Invest. Dermatol. VL - 137 IS - 10 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AU - Lauffer, F.* AU - Jargosch, M.* AU - Krause, L. AU - Garzorz-Stark, N.* AU - Franz, R.* AU - Roenneberg, S.* AU - Biedermann, T.* AU - Theis, F.J. AU - Schmidt-Weber, C. AU - Eyerich, S. AU - Eyerich, K.* C1 - 51919 C2 - 43566 CY - New York SP - S254-S254 TI - Interface Dermatitis is characterized by a type I immune response and an epidermal reaction to IFN-gamma and TNF-alpha. JO - J. Invest. Dermatol. VL - 137 IS - 10 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AB - Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease (CVD). Therefore, we investigate associations and potential underlying pathways of AD and CVD in large cohort studies: the AOK PLUS cohort (n=1.2Mio), the GINIplus/LISAplus birth cohorts (n=2286), and the KORA F4 cohort (n=2990). Additionally, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed. Longitudinal analysis of AD patients in AOK PLUS showed slightly increased risk for incident angina pectoris (AP) (adjusted risk ratio 1.17; 95%-confidence interval 1.12-1.23), hypertension (1.04 (1.02-1.06)) and peripheral arterial disease (PAD) (1.15 (1.11-1.19)) but not for myocardial infarction (MI) (1.05 (0.99-1.12) and stroke (1.02 (0.98-1.07)). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors (CVRFs) and no differences in metabolite levels were detected. There was no robust evidence for shared genetic risk variants of AD and CVD. This study indicates only a marginally increased risk for AP, hypertension and PAD and no increased risk for MI or stroke in AD patients. Relevant associations of AD with CVRFs reported in US-populations could not be confirmed. Likewise, AD patients did not have increased genetic risk factors for CVD. AU - Standl, M. AU - Tesch, F.* AU - Baurecht, H.* AU - Rodriguez, E.* AU - Müller-Nurasyid, M. AU - Gieger, C. AU - Peters, A. AU - Wang-Sattler, R. AU - Prehn, C. AU - Adamski, J. AU - Kronenberg, F.* AU - Schulz, H. AU - Koletzko, S.* AU - Schikowski, T.* AU - von Berg, A.* AU - Lehmann, I.* AU - Berdel, D.* AU - Heinrich, J. AU - Schmitt, J.* AU - Weidinger, S.* C1 - 50428 C2 - 42264 CY - New York SP - 1074-1081 TI - Association of atopic dermatitis with cardiovascular risk factors and diseases. JO - J. Invest. Dermatol. VL - 137 IS - 5 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AU - Terlecki-Zaniewicz, L.* AU - Pils, V.* AU - Laemmermann, I.* AU - Latreille, J.* AU - Pum, D.* AU - Scheideler, M. AU - Almaraz, J.C.H. AU - Morizot, F.* AU - Gruber, F.* AU - Grillari, J.* C1 - 51920 C2 - 43567 CY - New York SP - S250-S250 TI - Senescent human fibroblasts selectively secrete miRNAs in extracellular vesicles and modulate keratinocyte functionality during skin aging. JO - J. Invest. Dermatol. VL - 137 IS - 10 PB - Elsevier Science Inc PY - 2017 SN - 0022-202X ER - TY - JOUR AU - Aguirre Bueno, J. AU - Schwarz, M. AU - Garzorz-Stark, N.* AU - Lauffer, F.* AU - Soliman, D. AU - Bühler, A. AU - Eyerich, S.* AU - Ntziachristos, V. C1 - 49644 C2 - 40763 SP - S217-S217 TI - Assessment of psoriasis using label-free ultra-broadband optoacoustic mesoscopy. JO - J. Invest. Dermatol. VL - 136 IS - 9 PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Altunbulakli, C.* AU - Neumann, A.* AU - Giner, F.C.* AU - Garzorz-Stark, N.* AU - Reiger, M. AU - Akdis, M.* AU - Traidl-Hoffmann, C. AU - Akdis, C.A.* C1 - 49651 C2 - 40796 CY - New York SP - S177-S177 TI - Transcriptomic analysis of epidermal barrier molecules, cytokines and growth factors in atopic dermatitis lesions. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Bounas-Pyrros, N. AU - Todorova, A. AU - Biedermann, T.* AU - Hofmann, H.* AU - Traidl-Hoffmann, C. C1 - 49652 C2 - 40795 CY - New York SP - S232-S232 TI - Establishing and validating a new flow cytometric method for diagnosis of Lyme borreliosis. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Buters, J.T.M. AU - Bartusel, E. AU - Kupresanin, D. AU - Weil, C. AU - Pusch, G. AU - Oteros, J. AU - Traidl-Hoffmann, C. AU - Schmidt-Weber, C.B. C1 - 49664 C2 - 40821 CY - New York SP - S235-S235 TI - Differences in the biological exposome between Munich, Germany and Davos, Switzerland. Report of a 4 year period of daily outdoor levels. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Dietz, K. AU - de los Reyes Jimenez, M. AU - Gollwitzer, E.S.* AU - Schmidt-Weber, C.B. AU - Chaker, A.* AU - Marsland, B.J.* AU - Esser-von Bieren, J. C1 - 49656 C2 - 40816 CY - New York SP - S225-S225 TI - Age dictates a steroid resistant cascade of wnt5a, transglutaminase-2 and leukotrienes in inflamed airways. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Dittlein, D.C. AU - Gilles, S. AU - Frank, U. AU - Gross, O.* AU - Traidl-Hoffmann, C. C1 - 49649 C2 - 40797 CY - New York SP - S220-S220 TI - Pollen and UV-B: A couple modulating human skin barrier and immune function. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Effner, R. AU - Hiller, J. AU - Eyerich, S. AU - Traidl-Hoffmann, C. AU - Brockow, K.* AU - Triggiani, M.* AU - Behrendt, H. AU - Schmidt-Weber, C.B. AU - Buters, J.T.M. C1 - 49658 C2 - 40827 CY - New York SP - S232-S232 TI - Cytochrome P450s are deactivators of the aryl hydrocarbon receptor in human immune cells. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AB - Visualizing anatomical and functional features of hair follicle development in their unperturbed environment is key in understanding complex mechanisms of hair pathophysiology and in discovery of novel therapies. Of particular interest is in-vivo visualization of the intact pilosebaceous unit, vascularization of the hair bulb and evaluation of the hair cycle particularly in humans. Furthermore, non-invasive visualization of the sebaceous glands could offer crucial insight into pathophysiology of follicle-related diseases, dry or seborrhoic skin, in particular by combining in-vivo imaging with other phenotyping, genotyping and microbial analyses. The available imaging techniques are limited in their ability for deep tissue in-vivo imaging of hair follicles and lipid-rich sebaceous glands in their entirety without biopsy. We developed a non-invasive, painless and risk-free volumetric multispectral optoacoustic tomography (vMSOT) method for deep tissue three-dimensional visualization of whole hair follicles and surrounding structures with high spatial resolution below 70μm. Herein we demonstrate on-the-fly assessment of key morphometric parameters of follicles and lipid content as well as functional oxygenation parameters of the associated capillary bed. The ease of handheld operation and versatility of the newly-developed approach poise it as an indispensable tool for early diagnosis of disorders of the pilosebaceous unit and surrounding structures, and for monitoring the efficacy of cosmetic and therapeutic interventions. AU - Ford, S.J. AU - Bigliardi, P.L.* AU - Sardella, T.C.* AU - Urich, A.* AU - Burton, N.C.* AU - Kacprowicz, M.* AU - Bigliardi, M.* AU - Olivo, M.* AU - Razansky, D. C1 - 47661 C2 - 39718 CY - New York SP - 753-761 TI - Structural and functional analysis of intact hair follicles and pilosebaceous units by volumetric multispectral optoacoustic tomography. JO - J. Invest. Dermatol. VL - 136 IS - 4 PB - Nature Publishing Group PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Graessel, A. AU - Hauck, S.M. AU - von Toerne, C. AU - Kloppmann, E.* AU - Goldberg, T.* AU - Koppensteiner, H. AU - Schindler, M.* AU - Krause, L. AU - Schmidt-Weber, C.B. AU - Blank, S. C1 - 49655 C2 - 40794 CY - New York SP - S232-S232 TI - Identification of new cell surface targets on human T helper cells. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Jakwerth, C.A. AU - Zissler, U.M. AU - Guerth, F.M. AU - Hajdu, Z.* AU - Schmidt-Weber, C.B. AU - Chaker, A.* C1 - 49666 C2 - 40819 CY - New York SP - S225-S225 TI - Grass pollen-specific immunotherapy entails systemic increase of regulatory B cells and shift in Th17 cell compartments. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Kuepper, M.K.* AU - Thomas, J. AU - Garzorz-Stark, N.* AU - Krause, L. AU - Müller, N.S. AU - Biedermann, T.* AU - Theis, F.J. AU - Schmidt-Weber, C.B. AU - Eyerich, K.* AU - Eyerich, S. C1 - 49660 C2 - 40825 CY - New York SP - S217-S217 TI - Characterization of multiple B cell subsets in peripheral blood of psoriasis patients identifies a correlation of regulatory B cells and disease severity. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Lauffer, F.* AU - Krause, L. AU - Franz, R.* AU - Garzorz-Stark, N.* AU - Biedermann, T.* AU - Theis, F.J. AU - Schmidt-Weber, C.B. AU - Eyerich, S. AU - Eyerich, K.* C1 - 49647 C2 - 40798 CY - New York SP - S219-S219 TI - Interface dermatitis shows a distinctive molecular signature independent from individual disease background. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Lovaszi, M.* AU - Mattii, M. AU - Eyerich, K.* AU - Kovács, D.* AU - Zouboulis, C.C.* AU - Stahle, M.* AU - Eyerich, S. AU - Torocsik, D.* C1 - 49667 C2 - 40818 CY - New York SP - S231-S231 TI - Characterization of the immunomodulatory effects of sebocytes on macrophages. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AB - Gene mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes chromosome 11 open reading frame 30 (C11orf30) and leucine rich repeat containing 32 (LRRC32). Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the glycoprotein A repetitions predominantly (GARP), a receptor on activated regulatory T cells that binds latent TGFβ. Subsequent association testing in more than 2,000 atopic dermatitis cases and 2,000 controls revealed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modelling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4(+)CD25(-) T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T cell subtypes obtained from AD patients revealed a significantly reduced surface expression of GARP, and a reduced conversion of CD4(+)CD25(-) T cells into regulatory T cells along with lower expression of latency-associated protein (LAP) upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of TGFβ signalling with atopic dermatitis risk. AU - Manz, J. AU - Rodriguez, E.* AU - El Sharawy, A.* AU - Oesau, E.M.* AU - Petersen, B.S.* AU - Baurecht, H.* AU - Mayr, G.* AU - Weber, S. AU - Harder, J.* AU - Reischl, E. AU - Schwarz, A.* AU - Novak, N.* AU - Franke, A.* AU - Weidinger, S.* C1 - 49172 C2 - 41689 CY - New York SP - 2380-2386 TI - Targeted resequencing and functional testing identifies low-frequency missense variants in the gene encoding GARP as significant contributors to atopic dermatitis risk. JO - J. Invest. Dermatol. VL - 136 IS - 12 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Musiol, S. AU - Kulig, P.* AU - Freiberger, S.* AU - Schreiner, B.* AU - Gyulveszi, G.* AU - Russo, G.* AU - Kishihara, K.* AU - Alessandrini, F. AU - Becher, B.* AU - Haak, S. C1 - 49662 C2 - 40823 CY - New York SP - S261-S261 TI - The Ying & Yang of IL23p40 in psoriatic plaque formation. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Russkamp, D. AU - Aguilar-Pimentel, A.* AU - Gailus-Durner, V. AU - Fuchs, H. AU - Schiener, M. AU - Ollert, M.* AU - Hrabě de Angelis, M. AU - Schmidt-Weber, C.B. AU - Blank, S. C1 - 49657 C2 - 40828 CY - New York SP - S231-S231 TI - Alum-free thermosensitive hydrogel as subcutaneous matrix for immunomodulators and allergens during specific immunotherapy. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Schlumprecht, C. AU - Dittlein, D.C. AU - van Bergenhenegouwen, J.* AU - Garssen, J.* AU - Haller, D.* AU - Traidl-Hoffmann, C. C1 - 49663 C2 - 40822 CY - New York SP - S208-S208 TI - Immuno-modulatory effects of pre-/probiotics and active microbial structures on human primary keratinocytes. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Standl, M. AU - Rodriguez, E.* AU - Baurecht, H.* AU - Peters, A. AU - Schmitt, J.* AU - Weidinger, S.* C1 - 49648 C2 - 40829 CY - New York SP - S165-S165 TI - Association of atopic dermatitis with cardiometabolic diseases and risk factor. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Wang, R.* AU - Eyerich, K.* AU - Eyerich, S. AU - Zink, A.* AU - Thomas, J. AU - Biedermann, T.* AU - Schmidt-Weber, C.B. C1 - 49661 C2 - 40824 CY - New York SP - S168-S168 TI - Cellular mechanism of action of IgE-specific immunoadsorption in treatment of patients with severe atopic eczema. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AU - Wimmer, M. AU - Alessandrini, F. AU - Gilles, S. AU - Frank, U. AU - Ernst, D. AU - Ohnmacht, C. AU - Schmidt-Weber, C.B. AU - Traidl-Hoffmann, C. AU - Gutermuth, J. C1 - 49668 C2 - 40800 CY - New York SP - S229-S229 TI - Pollen-derived adenosine plays an important role in induction of ragweed allerg. JO - J. Invest. Dermatol. VL - 136 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 0022-202X ER - TY - JOUR AB - Impaired re-epithelialization, imbalanced expression of cytokines and growth factors and vascular disease contribute to healing impairment in diabetes. Interleukin-22 (IL-22), a pro-inflammatory cytokine mediating crosstalk between immune system and epithelial cells, has been shown to play a role in repair processes. In this study we aimed to investigate IL-22 regenerative potential in the poor healing context of diabetic wounds. By using streptozotocin-induced diabetic mice, we demonstrated that IL-22 wound treatment significantly accelerated the healing process, by promoting re-epithelialization, and granulation tissue formation and vascularization. Improved re-epithelialization was associated with increased keratinocyte proliferation and STAT3 activation. We showed that endogenous IL-22 content was reduced at both mRNA and protein level during the inflammatory phase of diabetic wounds, with fewer IL-22-positive cells infiltrating the granulation tissue. We demonstrated that IL-22 treatment promoted proliferation and injury repair of hyperglycemic keratinocytes and induced activation of STAT3 and ERK transduction pathways in keratinocytes grown in hyperglycemic condition or isolated from diabetic patients. Finally, we demonstrated that IL-22 treatment was able to inhibit diabetic keratinocyte differentiation while promoting VEGF release. Our data indicate a pro-healing role of IL-22 in diabetic wounds, suggesting a therapeutic potential for this cytokine in diabetic ulcer management. AU - Avitabile, S.* AU - Odorisio, T.* AU - Madonna, S.* AU - Eyerich, S. AU - Guerra, L.* AU - Eyerich, K.* AU - Zambruno, G.* AU - Cavani, A.* AU - Cianfarani, F.* C1 - 46325 C2 - 37592 SP - 2862-2870 TI - Interleukin-22 promotes wound repair in diabetes by improving keratinocyte pro-healing functions. JO - J. Invest. Dermatol. VL - 135 IS - 11 PY - 2015 SN - 0022-202X ER - TY - JOUR AU - Baurecht, H.* AU - Schmitt, J.* AU - Rodriguez, E.* AU - Lieb, W.* AU - Gieger, C. AU - Irvine, A.D.* AU - Novak, N.* AU - Weidinger, S.* C1 - 46699 C2 - 37753 CY - New York SP - S63 TI - Epidemiologic and genetic association between atopic dermatitis, rheumatoid arthritis, inflammatory bowel disease, and type-1 diabetes. JO - J. Invest. Dermatol. VL - 135 PB - Nature Publishing Group PY - 2015 SN - 0022-202X ER - TY - JOUR AU - Brosch, S.* AU - Dietze-Schwonberg, K.* AU - Lopez Kostka, S.* AU - Lorenz, B.* AU - Haak, S. AU - Becher, B.* AU - von Stebut, E.* C1 - 31738 C2 - 34704 SP - 308-311 TI - Disease control in cutaneous leishmaniasis is independent of IL-22. JO - J. Invest. Dermatol. VL - 135 IS - 1 PY - 2015 SN - 0022-202X ER - TY - JOUR AB - Melanoma cells share many biological properties with neural crest cells. Here, we show that the homeodomain transcription factor Msh homeobox 1 (MSX1), which is essential for neural crest specification, reprograms melanocytes towards a neural crest precursor-like state. MSX1-reprogrammed melanocytes express the neural crest marker p75 and are able to differentiate into neuronal and mesenchymal lineages. Mechanistically, MSX1 suppresses the proximal promoter of microphthalmia-associated transcription factor (MITF), the master transcriptional regulator of melanogenesis. MSX1 expression is also significantly correlated with melanoma progression. MSX1 prompts melanoma cell motility and depletion of MSX1 significantly inhibits melanoma metastasis. These results demonstrate that not only can neural crest-like reprogramming in melanocytes be achieved by a single factor, but also that similar dedifferentiation is a critical process for melanoma progression. AU - Fukunaga-Kalabis, M.* AU - Heppt, M.* AU - Wang, J.* AU - Hristova, D.* AU - Wei, Z.* AU - Irmler, M. AU - Berking, C.* AU - Besch, R. AU - Beckers, J. AU - Rauscher, F.J.* AU - Fisher, D.E.* AU - Herlyn, M.* C1 - 44692 C2 - 37021 CY - New York SP - S111 TI - MSX1-induced neural crest-like reprograming promotes melanoma progression. JO - J. Invest. Dermatol. VL - 135 PB - Nature Publishing Group PY - 2015 SN - 0022-202X ER - TY - JOUR AU - Garzorz, N.V.* AU - Krause, L. AU - Lauffer, F.* AU - Atenhan, A.* AU - Thomas, J.* AU - Theis, F.J. AU - Biedermann, T.* AU - Schmidt-Weber, C.B. AU - Eyerich, S. AU - Eyerich, K.* C1 - 46702 C2 - 37750 CY - New York SP - S1 TI - Molecular diagnostics of psoriasis and eczema-a novel approach to establish personalised therapy. JO - J. Invest. Dermatol. VL - 135 PB - Nature Publishing Group PY - 2015 SN - 0022-202X ER - TY - JOUR AB - Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study (n=4.185) and a prospective cohort of German Health Insurance beneficiaries (n=1.811.098). A potential genetic overlap was explored using genome-wide data from >22.000 coronary artery disease (CAD) and >4.000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3.717 controls. Controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odd's ratio OR=2.36; 95% confidence interval CI=1.26-4.41) and myocardial infarction (MI, OR=2.26, 95% CI=1.03-4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk RR=1.11; 95%CI=1.08-1.14) and MI (RR=1.14; 95%CI=1.06-1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the MHC, there was no evidence for genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct. AU - Koch, M.* AU - Baurecht, H.* AU - Ried, J.S. AU - Rodriguez, E.* AU - Schlesinger, S.* AU - Volks, N.* AU - Gieger, C. AU - Rückert, I.-M. AU - Heinrich, L.* AU - Willenborg, C.* AU - Smith, C.* AU - Peters, A. AU - Thorand, B. AU - Koenig, W.* AU - Lamina, C.* AU - Jansen, H.* AU - Kronenberg, F.* AU - Seissler, J.* AU - Thiery, J.* AU - Rathmann, W.* AU - Schunkert, H.* AU - Erdmann, J.* AU - Barker, J.* AU - Nair, R.P.* AU - Tsoi, L.C.* AU - Elder, J.T.* AU - Mrowietz, U.* AU - Weichenthal, M.* AU - Mucha, S.* AU - Schreiber, S.* AU - Franke, A.* AU - Schmitt, J.* AU - Lieb, W.* AU - Weidinger, S.* C1 - 43128 C2 - 36300 CY - New York SP - 1283-1293 TI - Psoriasis and cardiometabolic traits: Modest association but distinct genetic architectures. JO - J. Invest. Dermatol. VL - 135 IS - 5 PB - Nature Publishing Group PY - 2015 SN - 0022-202X ER - TY - JOUR AU - Paternoster, L.* AU - Standl, M. AU - Baurecht, H.* AU - Evans, D.M* AU - Weidinger, S.* C1 - 46701 C2 - 37751 CY - New York SP - S56 TI - Multi-ethnic genome-wide association study of 21,000 cases and 95,000 controls identifies 11 novel risk loci for atopic dermatitis. JO - J. Invest. Dermatol. VL - 135 PB - Nature Publishing Group PY - 2015 SN - 0022-202X ER - TY - JOUR AU - Rodriguez, E.* AU - Manz, J. AU - Petersen, B.S.* AU - Baurecht, H.* AU - Mayr, G.* AU - Harder, J.* AU - Schwarz, A.E.* AU - Franke, A.* AU - El Sharawy, A.* AU - Weidinger, S.* C1 - 46700 C2 - 37752 CY - New York SP - S58 TI - Targeted resequencing and finemapping identifies functional low-frequency missense variants in LRRC32 as risk factors for atopic dermatitis. JO - J. Invest. Dermatol. VL - 135 PB - Nature Publishing Group PY - 2015 SN - 0022-202X ER - TY - JOUR AU - Garzorz, N.V.* AU - Quaranta, M. AU - Knapp, B. AU - Mattii, M. AU - Andres, C.* AU - Theis, F.J. AU - Ring, J.* AU - Schmidt-Weber, C.B. AU - Eyerich, S. AU - Eyerich, K.* C1 - 32173 C2 - 35924 CY - New York SP - S1 TI - Intra-individual genome expression analysis reveals a specific molecular signature of psoriasis and eczema. JO - J. Invest. Dermatol. VL - 134 PB - Nature Publishing Group PY - 2014 SN - 0022-202X ER - TY - JOUR AU - Kretschmer, A. AU - Prokisch, H. AU - Eyerich, S.* AU - Hauck, S.M. AU - Peters, A. AU - Adamski, J. AU - Reischl, E. AU - Weidinger, S.* C1 - 32174 C2 - 35241 CY - New York SP - S55 TI - A common atopy-associated variant in the Th2 cytokine locus control region impacts transcriptional regulation and alters SMAD3 and SP1 binding. JO - J. Invest. Dermatol. VL - 134 PB - Nature Publishing Group PY - 2014 SN - 0022-202X ER - TY - JOUR AB - Even though aging and cellular senescence appear to be linked the biological mechanisms interconnecting these two processes remain to be unravelled. Therefore, miRNA profiles were analyzed ex vivo by gene array in fibroblasts isolated from young and old human donors. Expression of several miRNAs was positively correlated with donor age. Among those miR-23a-3p was shown to target hyaluronan-synthase 2. Hyaluronan (HA) is a polysaccharide of the extracellular matrix that critically regulates the phenotype of fibroblasts. Indeed, both aged and senescent fibroblasts showed increased miR-23a-3p expression and secreted significantly lower amounts of HA compared to young and non senescent fibroblasts. Ectopic overexpression of miR-23a-3p in non senescent fibroblasts led to decreased HAS2 mediated HA-synthesis, upregulation of senescence associated markers and decreased proliferation. In addition, siRNA mediated downregulation of HAS2 and pharmacologic inhibition of HA-synthesis by 4-methylumbelliferone mimicked the effects of miR-23a-3p. In vivo, miR-23a-3p was upregulated and HAS2 was downregulated in the skin of old mice versus young mice. Inhibition of HA-synthesis by 4-methylumbelliferone in mice reduced dermal hydration and viscoelasticity thereby mimicking an aged skin phenotype. Taken together, these findings appear to link miR-23a-3p and the HA-microenvironment as effector mechanisms in both dermal aging and senescence. AU - Röck, K.* AU - Tigges, J.* AU - Sass, S. AU - Schütze, A.* AU - Florea, A.M.* AU - Fender, A.C.* AU - Theis, F.J. AU - Krutmann, J.* AU - Boege, F.* AU - Fritsche, E.* AU - Reifenberger, G.* AU - Fischer, J.W.* C1 - 32405 C2 - 35027 CY - New York SP - 369-377 TI - miR-23a-3p causes cellular senescence by targeting hyaluronan synthase2: Possible implication for skin aging. JO - J. Invest. Dermatol. VL - 135 IS - 2 PB - Nature Publishing Group PY - 2014 SN - 0022-202X ER - TY - JOUR AB - Epigenetic alterations are increasingly recognized as mechanisms for disease-associated changes in genome function and important risk factors for complex diseases. The epigenome differs between cell types and so far has been characterized in few human tissues only. In order to identify disease-associated DNA methylation differences for atopic dermatitis (AD), we investigated DNA from whole blood, T cells, B cells, as well as lesional and non-lesional epidermis from AD patients and healthy controls. To elicit functional links, we examined epidermal mRNA expression profiles. No genome-wide significant DNA methylation differences between AD cases and controls were observed in whole blood, T cells, and B cells, and, in general, intra-individual differences in DNA methylation were larger than interindividual differences. However, striking methylation differences were observed between lesional epidermis from patients and healthy control epidermis for various CpG sites, which partly correlated with altered transcript levels of genes predominantly relevant for epidermal differentiation and innate immune response. Significant DNA methylation differences were discordant in skin and blood samples, suggesting that blood is not an ideal surrogate for skin tissue. Our pilot study provides preliminary evidence for functionally relevant DNA methylation differences associated with AD, particularly in the epidermis, and represents a starting point for future investigations of epigenetic mechanisms in AD. AU - Rodriguez, E.* AU - Baurecht, H.* AU - Wahn, A.F.* AU - Kretschmer, A. AU - Hotze, M.* AU - Zeilinger, S. AU - Klopp, N.* AU - Illig, T.* AU - Schramm, K. AU - Prokisch, H. AU - Kühnel, B. AU - Gieger, C. AU - Harder, J.* AU - Cifuentes, L.* AU - Novak, N.* AU - Weidinger, S.* C1 - 31082 C2 - 34134 CY - New York SP - 1873-1883 TI - An integrated epigenetic and transcriptomic analysis reveals distinct tissue-specific patterns of DNA methylation associated with atopic dermatitis. JO - J. Invest. Dermatol. VL - 134 IS - 7 PB - Nature Publishing Group PY - 2014 SN - 0022-202X ER - TY - JOUR AB - Mutations in neurofibromin (NF1) cause the dominant genetic disorder neurofibromatosis type 1. Neurofibromatosis is characterized by Schwann cell-based tumors and skin hyperpigmentation, resulting from both haploinsufficiency and loss of heterozygosity. The fact that some pigment cells (melanocytes) arise from Schwann cell precursors suggests that neurofibromin could be required during the common precursor stage. In this study, we found a missense mutation in neurofibromin in Dark skin 9 (Dsk9) mutant mice, revealing that Nf1 mutations cause skin hyperpigmentation in mice, as they do in humans. Using tissue-specific knockouts, we found that haploinsufficiency of neurofibromin in melanocytes via Mitf-cre is insufficient to cause darker skin, whereas haploinsufficiency in bipotential Schwann cell-melanoblast precursors via Plp1-creER is sufficient. These findings suggest that there is a narrow developmental window during which Nf1 haploinsufficiency acts on pigment cells. Using fate mapping, we discovered differences in the colonization of the dermis and epidermis by melanocytes that arise from Schwann cell precursors, an unexpected complexity of melanocyte development. As homozygous knockout of Nf1 via Mitf-cre is sufficient to cause darker skin, we conclude that reduced gene dosage can act by a mechanism different from complete gene loss, even when the end result of both is very similar. AU - Deo, M.* AU - Huang, J. L.-Y.* AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - van Raamsdonk, C. D.* C1 - 10456 C2 - 30251 SP - 49-58 TI - Differential effects of neurofibromin gene dosage on melanocyte development. JO - J. Invest. Dermatol. VL - 133 IS - 1 PB - Nature Publishing Group PY - 2013 SN - 0022-202X ER - TY - JOUR AB - Selenoproteins are essential molecules for the mammalian antioxidant network. We previously demonstrated that targeted loss of all selenoproteins in mouse epidermis disrupted skin and hair development, and caused premature death. In the current study, we targeted specific selenoproteins for epidermal deletion to determine whether similar phenotypes developed. Keratinocyte-specific knockout mice lacking either the glutathione peroxidase 4 (GPx4) or thioredoxin reductase 1 (TR1) gene were generated by cre-lox technology using K14-cre. TR1 knockout mice had a normal phenotype in resting skin, whereas GPx4 loss in the epidermis caused epidermal hyperplasia, dermal inflammatory infiltrate, dysmorphic hair follicles, and alopecia in perinatal mice. Unlike epidermal ablation of all selenoproteins, mice ablated for GPx4 recovered after 5 weeks and had a normal life span. GPx1 and TR1 were upregulated in the skin and keratinocytes of GPx4-knockout mice. GPx4 deletion reduces keratinocyte adhesion in culture and increases lipid peroxidation and cyclooxygenase-2 (COX-2) levels in cultured keratinocytes and whole skin. Feeding a COX-2 inhibitor to nursing mothers partially prevents development of the abnormal skin phenotype in knockout pups. These data link the activity of cutaneous GPx4 to the regulation of COX-2 and hair follicle morphogenesis, and provide insight into the function of individual selenoprotein activity in maintaining cutaneous homeostasis. AU - Sengupta, A.* AU - Lichti, U.F.* AU - Carlson, B.A.* AU - Cataisson, C.* AU - Ryscavage, A.O.* AU - Mikulec, C.* AU - Conrad, M. AU - Fischer, S.M.* AU - Hatfield, D.L.* AU - Yuspa, S.H.* C1 - 24560 C2 - 31574 SP - 1731-1741 TI - Targeted disruption of glutathione peroxidase 4 in mouse skin epithelial cells impairs postnatal hair follicle morphogenesis that is partially rescued through inhibition of COX-2. JO - J. Invest. Dermatol. VL - 133 IS - 7 PB - Nature Publishing PY - 2013 SN - 0022-202X ER - TY - JOUR AB - Tissue inhibitors of metalloproteinases exhibit diverse physiological/biological functions including moderation of the proteolytic processing of growth factors and turnover of extracellular matrix. These various biological activities are linked in part to the stoichiometry of tissue inhibitor of metalloprotein/matrix metalloprotein (TIMP/MMP)/surface protein interactions. TIMP-1, a secreted protein, can be detected on the cell surface only through its interaction with surface-bound proteins. Proteins anchored by glycosylphosphatidylinositol (GPI), when purified and added to cells or tissues, are efficiently incorporated into their surface membranes. A GPI anchor was fused to TIMP-1 to focus defined concentrations of the inhibitory protein independently on the surface of primary dermal fibroblast cells. Exogenously added recombinant TIMP-1-GPI effectively inserted into the cell membrane of fibroblasts blocked the secretion of MMPs and markedly altered the stoichiometry of MMP association with the cell surface. TIMP-1-GPI treatment resulted in inhibition of fibroblast-reduced proliferation, and transiently reduced expression of fibrosis-associated genes. These effects were dose dependent. Treated cells also showed a more proapoptotic phenotype based on apoptotic assays and western blot analysis for apoptosis-associated protein expression. GPI-anchored TIMP-1 may represent a more effective version of the protein for use in therapeutic approaches to help control fibrosis and scar formation.Journal of Investigative Dermatology advance online publication, 25 October 2012; doi:10.1038/jid.2012.375. AU - Djafarzadeh, R.* AU - Notohamiprodjo, S.* AU - Rieth, N.* AU - Hofstetter, M.* AU - Nößner, E. AU - Nelson, P.J.* C1 - 11837 C2 - 30826 SP - 803-811 TI - Treatment of dermal fibroblasts with GPI-anchored human TIMP-1 protein moderates processes linked to scar formation. JO - J. Invest. Dermatol. VL - 133 IS - 3 PB - Nature Publishing Group PY - 2012 SN - 0022-202X ER - TY - JOUR AB - Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25 to 1% of the general population. To identify common susceptibility loci, we performed a meta-analysis of three imputed genome-wide association studies (GWAS) on psoriasis, stratified for PsA. A total of 1,160,703 single-nucleotide polymorphisnns (SNPs) were analyzed in the discovery set consisting of 535 PsA cases and 3,432 controls from Germany, the United States, and Canada. We followed up two SNPs in 1,931 PsA cases and 6,785 controls comprising six independent replication panels from Germany, Estonia, the United States, and Canada. In the combined analysis, a genome-wide significant association was detected at 2p16 near the REL locus encoding c-Rel (rs13017599, P=1.18 x 10(-8), odds ratio (OR) =1.27, 95% confidence interval (CI)=1.18-1.35). The rs13017599 polymorphism is known to associate with rheumatoid arthritis (RA), and another SNP near REL (rs702873) was recently implicated in PsV susceptibility. However, conditional analysis indicated that rs13017599, rather than rs702873, accounts for the PsA association at REL. We hypothesize that c-Rel, as a member of the Rel/NF-kappa B family, is associated with PsA in the context of disease pathways that involve other identified PsA and PsV susceptibility genes including TNIP1, TNFAIP3, and NF kappa BIA. AU - Ellinghaus, E.* AU - Stuart, P.E.* AU - Ellinghaus, D.* AU - Nair, R.P.* AU - Debrus, S.* AU - Raelson, J.V.* AU - Belouchi, M.* AU - Tejasvi, T.* AU - Li, Y.* AU - Tsoi, L.C.* AU - Onken, A.T.* AU - Esko, T.* AU - Metspalu, A.* AU - Rahman, P.* AU - Gladman, D.D.* AU - Bowcock, A.M.* AU - Helms, C.* AU - Krueger, G.G.* AU - Kõks, S.* AU - Kingo, K.* AU - Gieger, C. AU - Wichmann, H.-E. AU - Mrowietz, U.* AU - Weidinger, S.* AU - Schreiber, S.* AU - Abecasis, G.R.* AU - Elder, J.T.* AU - Weichenthal, M.* AU - Franke, A.* C1 - 7975 C2 - 29942 SP - 1133-1140 TI - Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL. JO - J. Invest. Dermatol. VL - 132 IS - 4 PB - Nature Publishing Group PY - 2012 SN - 0022-202X ER - TY - JOUR AB - no Abstract AU - Metz, M.* AU - Gilles, S. AU - Geldmacher, A.* AU - Behrendt, H. AU - Traidl-Hoffmann, C. AU - Maurer, M.* C1 - 7111 C2 - 29597 SP - 987-990 TI - Evidence for non-allergic mast cell activation in pollen-associated inflammation. JO - J. Invest. Dermatol. VL - 131 IS - 4 PB - Nature Publishing Group PY - 2011 SN - 0022-202X ER - TY - JOUR AB - Atopic dermatitis (AD) and psoriasis are common skin diseases characterized by cutaneous inflammation and disturbed epidermal differentiation. Genome-wide analyses have shown overlapping susceptibility loci, such as the epidermal differentiation complex on chromosome 1q21. Recently, a deletion on 1q21 (LCE3C_LCE3B-del), comprising LCE3B and LCE3C, two members of the late cornified envelope (LCE) gene cluster, was found to be associated with psoriasis. Although the mechanistic role of LCE proteins in psoriasis has not been identified, these proteins are putatively involved in skin barrier formation and repair. Considering the potential genetic overlap between the two diseases and the recent finding that mutations in the skin barrier protein filaggrin are associated with AD, we investigated a possible association between LCE3C_LCE3B-del and AD. Evaluation of four different cohorts of European ancestry, containing a total of 1075 AD patients and 1658 controls, did not provide evidence for such an association. Subgroup analysis did not reveal an association with concomitant asthma. Our data suggest that the potential roles of skin barrier defects in the pathogenesis of AD and psoriasis are based on distinct genetic causes. AU - Bergboer, J.G.M.* AU - Zeeuwen, P.L.* AU - Irvine, A.D.* AU - Weidinger, S.* AU - Giardina, E.* AU - Novelli, G.* AU - den Heijer, M.* AU - Rodriguez, E.* AU - Illig, T. AU - Riveira-Munoz, E.* AU - Campbell, L.E.* AU - Tyson, J.* AU - Dannhauser, E.N.* AU - O'Regan, G.M.* AU - Galli, E.* AU - Klopp, N. AU - Koppelman, G.H.* AU - Novak, N.* AU - Estivill, X.* AU - McLean, W.H.* AU - Postma, D.S.* AU - Armour, J.A.* AU - Schalkwijk, J.* C1 - 714 C2 - 27884 SP - 2057-2061 TI - Deletion of Late Cornified Envelope 3B and 3C genes is not associated with atopic dermatitis. JO - J. Invest. Dermatol. VL - 130 IS - 8 PB - Nature Publ. Group PY - 2010 SN - 0022-202X ER - TY - JOUR AB - Epithelial cells of both the respiratory tract and the skin form a tight barrier against environmental harm. They represent the site of first contact for airborne allergen carriers. Consequently, in this study, we analyzed the uptake of grass pollen allergens by epithelial cells: Phl p 1 was selected as a glycosylated allergen containing disulfide bridges whereas Phl p 6 lacks post-translational modifications. Allergen uptake by the respiratory epithelial cell line A549 reached a plateau at 2 hours, and both allergens were localized intracellularly in non-acidic vesicles. In addition, in A549 cells allergens were exocytosed, suggesting a transcytosis mechanism in the passage of allergens over the respiratory epithelial barrier. In contrast, allergens were predominately localized in lysosomes in keratinocytes, and allergen uptake did not reach a plateau up to 24 hours. Notably, keratinocytes from atopic patients showed a significantly increased uptake of Phl p 1 as compared with healthy donors. Preincubation of epithelial cells with IL-4 and/or IFN-gamma to simulate inflammatory status led to an increased allergen uptake only in keratinocytes. This higher engulfment of allergens by inflammatory-type keratinocytes suggests a higher susceptibility of inflamed skin for the uptake of allergens and consequently a potentially higher risk for sensitization under natural exposure conditions, such as chronic atopic eczema. AU - Blume, C. AU - Foerster, S. AU - Gilles, S. AU - Becker, W.M.* AU - Ring, J.* AU - Behrendt, H. AU - Petersen, A.* AU - Traidl-Hoffmann, C. C1 - 48570 C2 - 41191 SP - 1935-1944 TI - Human epithelial cells of the respiratory tract and the skin differentially internalize grass pollen allergens. JO - J. Invest. Dermatol. VL - 129 IS - 8 PY - 2009 SN - 0022-202X ER - TY - JOUR AB - Chronic mucocutaneous candidiasis (CMC) constitutes a selective inability to clear infection with the yeast Candida, resulting in persistent debilitating inflammation of skin, nails, and mucous membranes. The underlying defect is unknown. Only recently, IL-17-producing T cells have been reported to be involved in clearing Candida infections. In order to characterize T cellular immune response to Candida, we analyzed T-cell cytokine secretion to Candida antigen and mitogenic stimuli in CMC patients, immunocompetent patients suffering from acute Candida infection, and healthy volunteers. Peripheral blood mononuclear cells (PBMCs) from CMC patients produced significantly lower amounts of IL-17 and IL-22 mRNA and protein when stimulated with Candida albicans or mitogen in vitro compared with that in matched healthy individuals. Additionally, PBMCs from immunocompetent Candida-infected patients secreted more IL-17 and IL-22 than those of both CMC patients and healthy, non-infected controls. Flow cytometry revealed a decreased number of CCR6+ IL-17-producing T cells in CMC patients, whereas the amount of CCR6+/CCR4+ cells was not altered. Levels of differentiating cytokines for human Th17 cells, IL-1beta and IL-6, tended to be higher in CMC patients. The inability to clear C. albicans in CMC patients could be due to a defect in the immune response of IL-17-producing T cells.Journal of Investigative Dermatology advance online publication. AU - Eyerich, K. AU - Foerster, S. AU - Rombold, S.* AU - Seidl, H.P.* AU - Behrendt, H. AU - Hofmann, H.* AU - Ring, J. AU - Traidl-Hoffmann, C. C1 - 2133 C2 - 25589 SP - 2640–2645 TI - Patients with Chronic Mucocutaneous Candidiasis Exhibit Reduced Production of Th17-Associated Cytokines IL-17 and IL-22. JO - J. Invest. Dermatol. VL - 128 IS - 11 PB - Nature Publ. Group PY - 2008 SN - 0022-202X ER - TY - JOUR AB - Allergic contact dermatitis is one of the most frequent dermatological problems affecting 7% of the general population. Impaired skin barrier function facilitates the penetration of contact allergens and irritants into the epidermal layer and is regarded as an important cofactor promoting the process of allergic contact sensitization. Filaggrin is crucial for the maintenance of the skin barrier function. Loss-of-function mutations within the filaggrin (FLG) gene are associated with skin barrier diseases such as ichthyosis vulgaris and atopic eczema (AE). To assess the impact of FLG on allergic contact sensitization and plausible intermediate traits, the two prevalent FLG mutations R501X and 2282del4 were typed in 1,502 individuals of the KORA C population-based cohort with extensive dermatologic phenotyping. Associations of FLG mutations with AE could be replicated. Strong associations were seen with dry skin, palmar hyperlinearity, and keratosis pilaris. In addition, an association with contact sensitization to nickel and contact sensitization to nickel combined with intolerance to fashion jewelry, but not with other contact allergens, was observed. From these data, we conclude that a genetically determined FLG deficiency manifests as dry skin and features of ichthyosis vulgaris. In addition, FLG deficiency may also represent a risk factor for contact sensitization to allergens. AU - Novak, N. AU - Baurecht, H.* AU - Schäfer, T.* AU - Rodriguez, E. AU - Wagenpfeil, S.* AU - Klopp, N. AU - Heinrich, J. AU - Behrendt, H. AU - Ring, J. AU - Wichmann, H.-E. AU - Illig, T. AU - Weidinger, S. C1 - 3196 C2 - 25393 SP - 1430-1435 TI - Loss-of-function mutations in the filaggrin gene and allergic contact sensitization to nickel. JO - J. Invest. Dermatol. VL - 128 IS - 6 PB - Nature Publ. Group PY - 2008 SN - 0022-202X ER - TY - JOUR AB - Human neuroimaging studies on the physiology of itch have been hampered by the lack of reproducible "on-off" stimuli. Using a previously established biphasic temperature stimulus model, we investigated the cerebral activation pattern of itch processing in 12 healthy volunteers with functional magnetic resonance imaging. Itch was provoked on the right forearm with skin prick application of 1% histamine-dihydrochloride. Local temperature modulation allowed reproducible itch provocation above scratch threshold (defined as 33/100 on a visual analogue scale) during 25 degrees C, whereas itch declined below scratch threshold during the 32 degrees C stimulation period. No itch sensation was reported using 0.9% saline with temperature modulation. Itch sensation above scratch threshold was associated with increased activation of the thalamus, presupplementary motor area, anterior insular, inferior parietal, and dorsolateral prefrontal cortex, and decreased activation of the orbitofrontal, medial frontal, mid-cingulate, and primary motor cortex in comparison to saline. The biphasic temperature model allows rapid modulation of histamine-induced itch. The evoked itch sensation above scratch threshold is processed by a network of brain regions contributing to the encoding of sensory, emotional, attention-dependent, cognitive-evaluative and motivational aspects of itch. AU - Valet, M.* AU - Pfab, F. AU - Sprenger, T.* AU - Wöller, A.* AU - Zimmer, C.* AU - Behrendt, H. AU - Ring, J. AU - Darsow, U. AU - Tölle, T.R.* C1 - 2518 C2 - 25724 SP - 426-433 TI - Cerebral processing of histamine-induced itch using short-term alternating temperature modulation - an FMRI study. JO - J. Invest. Dermatol. VL - 128 IS - 2 PB - Nature Publ. Group PY - 2008 SN - 0022-202X ER - TY - JOUR AU - Weidinger, S. AU - Rodriguez, E. AU - Stahl, C.* AU - Wagenpfeil, S.* AU - Klopp, N. AU - Illig, T. AU - Novak, N. C1 - 2525 C2 - 24689 SP - 724-726 TI - Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. JO - J. Invest. Dermatol. VL - 127 IS - 3 PB - Nature Publ. Group PY - 2007 SN - 0022-202X ER - TY - JOUR AB - With the goal of increasing the number of genetic entry points for studying physiologic processes and human disease, large-scale, systematic, chemical mutagenesis projects in mice have been initiated in several different centers. We have been studying mouse mutants that exhibit dominantly inherited defects in either skin and/or hair color. Here, we describe a bright coat color mutant, Bright coat color 1 (Bcc1), which develops light-colored hair at 4 weeks of age, and when homozygous exhibits oral leukoplakia and blistering, and growth retardation. We identified a missense mutation in mutant animals that predicts an N154S amino-acid substitution in the 1A domain of Keratin 4 (encoded by the Krt2-4 gene), a region known to be mutated in human patients with white sponge nevus (WSN). Bcc1 recapitulates the gross pathologic, histologic, and genetic aspects of the human disorder, WSN. © 2006 The Society for Investigative Dermatology. AU - McGowan, K.A.* AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Barsh, G.S.* C1 - 4753 C2 - 23771 SP - 60-64 TI - Identification of a Keratin 4 mutation in a chemically induced mouse mutant that models white sponge nevus. JO - J. Invest. Dermatol. VL - 127 IS - 1 PY - 2006 SN - 0022-202X ER - TY - JOUR AU - McGowan, K.A.* AU - Aradhya, S.* AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Barsh, G.S.* C1 - 5738 C2 - 23807 SP - 1013-1016 TI - A mouse Keratin 1 mutation causes dark skin and epidermolytic hyperkeratosis. JO - J. Invest. Dermatol. VL - 126 IS - 5 PY - 2006 SN - 0022-202X ER - TY - JOUR AU - Pfab, F.* AU - Valet, M.* AU - Sprenger, T.* AU - Toelle, T.R.* AU - Athanasiadis, G.I.* AU - Behrendt, H. AU - Ring, J.* AU - Darsow, U.* C1 - 1210 C2 - 24230 SP - 2673-2678 TI - Short-term alternating temperature enhances histamine-induced itch: A biphasic stimulus model. JO - J. Invest. Dermatol. VL - 126 PY - 2006 SN - 0022-202X ER - TY - JOUR AU - Schäfer, T.* AU - Merkl, J.* AU - Klemm, E.* AU - Wichmann, H.-E. AU - Ring, J.* C1 - 2915 C2 - 24273 SP - 1490-1496 TI - The epidemiology of nevi and signs of skin aging in the adult general population: Results of the KORA-Survey 2000. JO - J. Invest. Dermatol. VL - 126 PY - 2006 SN - 0022-202X ER - TY - JOUR AU - Krämer, U.* AU - Weidinger, S.* AU - Darsow, U.* AU - Möhrenschlager, M.* AU - Ring, J.* AU - Behrendt, H. C1 - 5404 C2 - 22967 SP - 514-523 TI - Seasonality in symptom severity influenced by temperature or grass pollen: Results of a panel study children with eczema. JO - J. Invest. Dermatol. VL - 124 PY - 2005 SN - 0022-202X ER - TY - JOUR AU - Alessandrini, F. AU - Pfister, S. AU - Kremmer, E. AU - Gerber, J.-K. AU - Ring, J.* AU - Behrendt, H. C1 - 2477 C2 - 22537 SP - 1030-1036 TI - Alterations of glucosylceramide-ß-glucosidase levels in the skin of patients with psoriasis vulgaris. JO - J. Invest. Dermatol. VL - 123 PY - 2004 SN - 0022-202X ER - TY - JOUR AU - Giehl, K.* AU - Eckstein, G.N. AU - Benet-Pagès, A. AU - Tosti, A.* AU - de Berker, D.A.R.* AU - Meitinger, T. AU - Müller-Myhsok, B.* AU - Strom, T.M. C1 - 3625 C2 - 22208 SP - 1073-1077 TI - A gene locus responsible for the familial hair shaft abnormality pili annulati maps to chromosome 12q24.32-24.33. JO - J. Invest. Dermatol. VL - 123 PY - 2004 SN - 0022-202X ER - TY - JOUR AU - Mempel, M.* AU - Voelcker, V.* AU - Köllisch, G. AU - Plank, Ch.* AU - Rad, R.* AU - Gerhard, M.* AU - Schnopp, Ch.* AU - Fraunberger, P.* AU - Walli, A.K.* AU - Ring, J.* AU - Abeck, D.* AU - Ollert, M. C1 - 10071 C2 - 21768 SP - 1389-1396 TI - Toll-like receptor expression in human keratinocytes : Nuclear factor kB controlled gene activation by Staphylococcus aureus is toll-like receptor 2 but not toll-like receptor 4 or platelet activating factor receptor dependent. JO - J. Invest. Dermatol. VL - 121 PY - 2003 SN - 0022-202X ER - TY - JOUR AB - Reduced coat 3 (Rco3) is a new spontaneous autosomal recessive mutation with defects in hair structure and progressive alopecia. Here we describe chromosomal mapping and molecular identification of the Rco3 mutation. The murine Rco3 locus maps to a 2-Mb interval on chromosome 15 encompassing the keratin type II gene cluster. Recently, mK6irs1 was described as a type II keratin expressed in Henle's and Huxley's layer of the murine inner root sheath. Genomic sequencing revealed a 10-bp deletion in exon 1 of mK6irs1 resulting in a frameshift after 58 amino acid residues and, therefore, the absence of 422 carboxy-terminal amino acid residues containing the complete α-helical rod domain. Henle's and Huxley's layers show no immunoreactivity with mK6irs1-specific antibodies and the absence of intermediate filament formation in electron microscopic images. These results indicate that the expression of functional mK6irs1 is indispensable for intermediate filament formation in the inner root sheath and highlights the importance of the keratinization of the inner root sheath in the normal formation of the hair shaft. AU - Peters, T.H.* AU - Sedlmeier, R.* AU - Büssow, H.* AU - Runkel, F.* AU - Lüers, G.H.* AU - Korthaus, D.* AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Stumm, G.* AU - Russ, A.P.* AU - Porter, R.M.* AU - Augustin, M.A.* AU - Franz, T.J. C1 - 33162 C2 - 21454 SP - 674-680 TI - Alopecia in a Novel Mouse Model RCO3 Is Caused by mK6irs1 Deficiency. JO - J. Invest. Dermatol. VL - 121 IS - 4 PY - 2003 SN - 0022-202X ER - TY - JOUR AU - Schaller, M.* AU - Mailhammer, R. AU - Grassl, G.* AU - Sander, C.A.* AU - Hube, B.* AU - Korting, H.C.* C1 - 21972 C2 - 20496 SP - 652-657 TI - Infection of Human Oral Epithelia with Candida Species Induces Cytokine Expression Correlated to the Degree of Virulence. JO - J. Invest. Dermatol. VL - 118 PY - 2002 SN - 0022-202X ER - TY - JOUR AU - Alessandrini, F. AU - Stachowitz, S. AU - Ring, J.* AU - Behrendt, H. C1 - 21860 C2 - 20061 SP - 394-400 TI - The Level of Prosaposin is Decreased in the Skin of Patients with Psoriasis Vulgaris. JO - J. Invest. Dermatol. VL - 116 PY - 2001 SN - 0022-202X ER - TY - JOUR AU - Darsow, U. AU - Drzezga, A.* AU - Frisch, M. AU - Munz, F.* AU - Weilke, F.* AU - Bartenstein, P.* AU - Schwaiger, M.* AU - Ring, J.* C1 - 21855 C2 - 20067 SP - 1029-1033 TI - Processing of Histamine-Induced Itch in the Human Cerebral Cortex : A Correlation Analysis with Dermal Reactions. JO - J. Invest. Dermatol. VL - 115 PY - 2000 SN - 0022-202X ER - TY - JOUR AU - Hohenadl, C. AU - Germaier, H. AU - Walchner, M.* AU - Hagenhofer, M.* AU - Hermann, M.* AU - Stürzl, M. AU - Kind, P. AU - Hehlmann, R.* AU - Erfle, V. AU - Leib-Mösch, C. C1 - 21385 C2 - 19503 SP - 587-594 TI - Transcriptional Activation of Endogenous Retroviral Sequences in Human Epidermal Keratinocytes by UVB Irradiation. JO - J. Invest. Dermatol. VL - 113 PY - 1999 SN - 0022-202X ER - TY - JOUR AB - In a recent gene-trap screen, we identified the gene coding for Epidermal Bullous Pemphigoid Antigen 1 (BPAG1) as a putative transcriptional target of Engrailed and of other homeoproteins with a glutamine in position 50 of their homeodomain. We now show that the nuclear addressing of the homeodomains of Engrailed (EnHD) and Antennapedia (AntpHD) upregulates BPAG1e transcription in immortalized human keratinocytes (GMA24FIA) expressing En1. This upregulation is not observed with AntpHD-Q50A, a variant of AntpHD in which a single mutation abolishes its high-affinity binding to target DNA, thus strongly suggesting that BPAG1e upregulation homeodomains reflects their specific recognition of homeoprotein-binding sites in the BPAG1e locus. This is further confirmed by DNase I footprinting and electrophoretic mobility shift assays that reveal, within the cloned BPAG1e promoter, several sites of direct interaction with EnHD and Engrailed. Co-transfection experiments in GMA24FIA human keratinocytes, COS-7 simian fibroblasts, and CHP-100 human neuroepithelial cells show that Engrailed, Hoxa-5, and Hoxc-8 regulate BPAG1e promoter activity and that this regulation is context-dependent. Finally, using a mouse line with LacZ inserted within the En1 locus, we identify the keratinocytes of the ventral paws, including the epithelial cells of the eccrine tubules, as a strong site of En1 expression throughout adulthood. We therefore propose that BPAG1e, a 230 kDa keratin-binding protein expressed in keratinocytes and participating in the maintenance of hemidesmosomes at the dermis-epidermis border, is directly regulated by homeoprotein transcription factors. AU - Mainguy, G.* AU - Ernø, H.* AU - Montesinos, M.L.* AU - Lesaffre, B.* AU - Wurst, W. AU - Volovitch, M.* AU - Prochiantz, A.* C1 - 22863 C2 - 31157 SP - 643-650 TI - Regulation of epidermal Bullous Pemphigoid Antigen 1 (BPAG1) synthesis by homeoprotein transcription factors. JO - J. Invest. Dermatol. VL - 113 IS - 4 PB - Nature Publishing PY - 1999 SN - 0022-202X ER -