Journal of Investigative Dermatology (J Investig Dermatol)

Publications in this journal

• Article: Circulating Melanoma Cells as a Predictive Biomarker.

  Giorgos Karakousis, Ruifeng Yang, Xiaowei Xu
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  ABSTRACT: The prognosis of patients with metastatic melanoma has improved significantly with targeted therapeutic agents and immunotherapies. Detection of early melanoma recurrence after treatment will be beneficial to switch patients who fail on one therapy to different modalities. Circulating tumor cells (CTCs) are cancer cells released by a tumor into the peripheral blood. These cells hold potential as prognostic, predictive, and pharmacodynamic biomarkers for treatment. In this issue, Khoja et al. report that melanoma CTCs can be detected using Melcam and high molecular weight melanoma-associated antibody. They found that in 101 stage IV melanoma patients, CTC numbers ranged between 0 and 36/7.5 ml blood; 26% of the patients had 2 CTCs at baseline. The CTC number (2 CTCs) at baseline was significantly prognostic for median overall survival (OS) in univariate and multivariate analysis. Patients receiving treatment where CTC numbers remained 2 CTCs during their treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, hazard ratio 0.34, 95% confidence interval 0.14-0.81, log-rank test P=0.015). The implications of this work are substantial in counseling patients about their prognosis and in helping to assess responses to systemic therapies.
  Journal of Investigative Dermatology 06/2013; 133(6):1460-1462.
• Article: Recapitulating Atopic Dermatitis in Three Dimensions: Cross Talk between Keratinocytes and Nerve Fibers.

  Carlo Pincelli, Martin Steinhoff
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  ABSTRACT: Roggenkamp et al. (2013) report a significant advance in the in vitro reconstruction of atopic dermatitis (AD) by coculturing lesional human keratinocytes with sensory nerve fibers. This work has important implications for understanding the interaction between the resident skin cells and the peripheral nervous system in AD, and it sheds light on the pathways leading to the pruritus that typifies this disease.
  Journal of Investigative Dermatology 06/2013; 133(6):1465-1467.
• Article: Genome-Wide Epigenetics.

  Brian C Capell, Shelley L Berger
  Journal of Investigative Dermatology 06/2013; 133(6):e9.
• Article: Pseudoxanthoma Elasticum: Progress in Research Toward Treatment: Summary of the 2012 PXE International Research Meeting.

  Jouni Uitto, Andras Váradi, Lionel Bercovitch, Patrick F Terry, Sharon F Terry
  Journal of Investigative Dermatology 06/2013; 133(6):1444-1449.
• Article: Phenotypic Heterogeneity in Hidradenitis Suppurativa (Acne Inversa): Classification Is an Essential Step Toward Personalized Therapy.

  John R Ingram, Vincent Piguet
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  ABSTRACT: Awareness is increasing that there is phenotypic heterogeneity within the hidradenitis suppurativa (HS) disease spectrum. However, the few randomized HS trials that are available have not distinguished between the subtypes of the disease. In this issue, Canoui-Poitrine et al. used latent class (LC) analysis of the largest HS cohort described to date to generate three phenotypic subtypes. LC 1 correlates with "typical" European HS, mainly involving the axilla, groin, and, in women, the inframammary region. "Atypical" HS, which may be linked to γ-secretase gene mutations, was subdivided further into LC2 and LC3 subtypes.
  Journal of Investigative Dermatology 06/2013; 133(6):1453-1456.
• Article: Cutaneous Human Papillomavirus Infection and Basal Cell Carcinoma of the Skin.

  Mina S Ally, Jean Y Tang, Sarah T Arron
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  ABSTRACT: Human papillomavirus (HPV) is ubiquitous in skin and has been associated with nonmelanoma skin cancer. Iannacone et al. investigate the role of HPV in basal cell carcinoma (BCC) by assessing the presence of HPV antibodies, HPV DNA in tumors, and the relationship between these two markers and BCC. In contrast to squamous cell carcinoma (SCC), there is no association between HPV and BCC.
  Journal of Investigative Dermatology 06/2013; 133(6):1456-1458.
• Article: Photosensitivity in the Elderly-Think of Late-Onset Protoporphyria.

  Jorge Frank, Pamela Poblete-Gutiérrez, Norbert J Neumann
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  ABSTRACT: Photosensitivity is the clinical hallmark of both erythropoietic protoporphyria (EPP) and X-linked dominant protoporphyria (XLDPP). Both disorders result from a hereditary dysfunction in heme biosynthesis. Disease onset is usually in early childhood. However, rare patients with late-onset EPP in association with a myeloproliferative disorder or myelodysplastic syndrome have been reported. In this issue, Livideanu et al. describe the first patient with late-onset XLDPP.
  Journal of Investigative Dermatology 06/2013; 133(6):1467-1471.
• Article: Many Paths to Alopecia via Compromised Regeneration of Hair Follicle Stem Cells.

  Ji Li, Ting Xin Jiang, Cheng Ming Chuong
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  ABSTRACT: Alopecia can be caused by defective formation, defective regeneration, or increased destruction of hair follicles. Much work has elucidated the roles of diffusible morphogens in modulating hair follicle stem cell activities. Recent studies have revealed novel molecular events within the nucleus, which are required for the activation and progression of hair stem cells. These studies will provide new clues and targets for designing therapeutic strategies for hair loss.
  Journal of Investigative Dermatology 06/2013; 133(6):1450-1452.
• Article: What Lies Beneath? Scanning Probe Tomography May Have the Answer.

  Michael J Conneely, Paul A Campbell
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  ABSTRACT: Scanning probe microscopy facilitates high-resolution noninvasive imaging of surface topography on even the most delicate of biological structures. Moreover, the local probe nature of the instrument architecture lends itself to the measurement of many important physical properties. To date, biological investigations have largely been constrained to imaging surface (membrane)-borne phenomena; however, the advent of extremely high aspect-ratio 'needle' probe tips, as reported by Beard et al. (2013), suggests that the approach can now be extended to address the particular challenges associated with measuring subsurface microscopic targets, including the intracellular components of the stratum corneum.
  Journal of Investigative Dermatology 06/2013; 133(6):1458-1460.
• Article: The Dark Side of Cyclophosphamide: Cyclophosphamide-Mediated Ablation of Regulatory T Cells.

  Jürgen C Becker, David Schrama
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  ABSTRACT: Cancer immune escape is frequently associated with the induction of an inappropriate immune response, i.e., a response that does not inhibit but perhaps even promotes the tumor. Indeed, increased frequencies of tumor-infiltrating regulatory T cells (Tregs) are associated with an impaired prognosis in several cancers. Thus, depletion of Tregs, e.g., by cyclophosphamide, was proposed as a means to boost immune responses to cancer. In the present issue of the Journal, Sevko et al., however, provide evidence that cyclophosphamide exerted the unexpected effect of induction of myeloid-derived suppressor cells.
  Journal of Investigative Dermatology 06/2013; 133(6):1462-1465.
• Article: JID VisualDx Quiz: June 2013.

  Sadegh Amini, Robert S Kirsner
  Journal of Investigative Dermatology 06/2013; 133(6):e5.
• Article: MAPKAP kinase 2 (MK2)-dependent and independent models of blister formation in pemphigus vulgaris.

  Xuming Mao, Hong Li, Yasuyo Sano, Matthias Gaestel, Jin Mo Park, Aimee S Payne
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  ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by autoantibodies to the keratinocyte adhesion protein desmoglein (Dsg) 3. Previous studies suggest that PV pathogenesis involves p38 mitogen activated protein kinase-dependent and -independent pathways. However, p38 is a difficult protein to study and therapeutically target because it has four isoforms and multiple downstream effectors. In the current study, we identify MAPKAP kinase 2 (MK2) as a downstream effector of p38 signaling in PV and describe MK2-dependent and -independent mechanisms of blister formation using passive transfer of human anti-Dsg IgG4 mAbs to neonatal mice. In human keratinocytes, PV mAbs activate MK2 in a dose-dependent manner. MK2 is also activated in human pemphigus skin blisters, causing translocation of MK2 from the nucleus to the cytosol. Small molecule inhibition of MK2 and silencing of MK2 expression block PV mAb-induced Dsg3 endocytosis in human keratinocytes. Additionally, small molecule inhibition and genetic deletion of p38α and MK2 inhibit spontaneous, but not induced, suprabasal blisters by PV mAbs in mouse passive transfer models. Collectively, these data suggest that MK2 is a key downstream effector of p38 that can modulate PV autoantibody pathogenicity. MK2 inhibition may be a valuable adjunctive therapy for control of pemphigus blistering.Journal of Investigative Dermatology accepted article preview online, 8 May 2013; doi:10.1038/jid.2013.224.
  Journal of Investigative Dermatology 05/2013;
• Article: The US prevalence of common warts in childhood: A population-based study.

  Jonathan I Silverberg, Nanette B Silverberg
  Journal of Investigative Dermatology 05/2013;
• Article: IL-25 Enhances HSV-1 Replication by Inhibiting Filaggrin Expression, and Acts Synergistically with TH2 Cytokines to Enhance HSV-1 Replication.

  Byung Eui Kim, Lianghua Bin, Young-Min Ye, Preveen Ramamoorthy, Donald Y M Leung
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  ABSTRACT: Atopic dermatitis (AD) is characterized by epidermal barrier defects and recurrent microbial skin infections. AD patients with a history of eczema herpeticum (ADEH+) have more severe skin disease and more highly TH2 polarized immune responses as compared to uncomplicated AD (ADEH-). However, the mechanisms linking epidermal barrier defects and viral skin infection are not well understood. Recently, it has been reported that interleukin (IL)-25 may play a role in augmenting TH2 responses. We examined protein expression of IL-25 in the skin biopsies from normal subjects (n=10), ADEH- (n=18), ADEH+ (n=7) and psoriasis (n=9). IL-25 expression was increased in the skin from ADEH-, ADEH+ and psoriasis compared to normal skin, and was significantly greater in lesional ADEH+ skin than in lesional ADEH- skin. Importantly, we demonstrated that IL-25 enhances herpes simplex virus (HSV)-1 and vaccinia virus replication by inhibiting filaggrin expression, and IL-25 acts synergistically with IL-4 and IL-13 to enhance HSV-1 replication in vitro. In contrast, interferon-γ inhibited HSV-1 replication in vitro. Additionally, we demonstrate that filaggrin is a critical protein to inhibit HSV-1 replication because filaggrin small interfering RNA knockdown enhances HSV-1 replication in vitro. Filaggrin breakdown products, however, inhibited HSV-1 replication in vitro.Journal of Investigative Dermatology accepted article preview online, 8 May 2013; doi:10.1038/jid.2013.223.
  Journal of Investigative Dermatology 05/2013;
• Article: Risk of rosacea in patients with diabetes using insulin or oral antidiabetic drugs.

  J Spoendlin, J J Voegel, S S Jick, Ch R Meier
  Journal of Investigative Dermatology 05/2013;
• Article: Indoleamine 2,3-dioxygenase Activity Contributes to Local Immune Suppression in the Skin Expressing Human Papillomavirus Oncoprotein E7.

  D Mittal, A J Kassianos, L S Tran, A S Bergot, C Gosmann, J Hofmann, A Blumenthal, G R Leggatt, I H Frazer
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  ABSTRACT: Chronic infection of anogenital epithelium with human papillomavirus (HPV) promotes development of cancer. Many pathogens evoke immunosuppressive mechanisms to enable persistent infection. We have previously shown that grafted skin expressing HPV16 E7 oncoprotein from a keratin-14 promoter (K14E7) is not rejected by a syngeneic, immunocompetent host. In this study we show that indoleamine 2, 3-dioxygenase (IDO) 1, an IFN-γ inducible immunoregulatory molecule, is more highly expressed by langerin(-ve) dermal dendritic cells from K14E7 skin than nontransgenic control skin. Furthermore, inhibiting IDO activity using 1-D/L-methyl tryptophan promotes K14E7 skin graft rejection. Increased IDO1 expression and activity in K14E7 skin requires IFN-γ and iNKT cells, both of which have been shown to negatively regulate T-cell effector function and suppress K14E7 graft rejection. Further, dendritic cells from K14E7 skin express higher level of IFN-γ receptor (IFN-γR) than dendritic cells from control skin. K14E7 transgenic skin recruits significantly higher number of dendritic cells, independent of IFN-γ and IFN-γR expression. Consistent with these observations in a murine model, we found higher expression of IDO1 and IFN-γ but not IDO2 in the cervical epithelium of patients with HPV-associated cervical intraepithelial neoplasia (CIN) 2/3. Our data support a hypothesis that induction of IDO1 in HPV infected skin contributes to evasion of host immunity.Journal of Investigative Dermatology accepted article preview online, 7 May 2013; doi:10.1038/jid.2013.222.
  Journal of Investigative Dermatology 05/2013;
• Article: Myosin-Va Contributes to Manifestation of Malignant-Related Properties in Melanoma Cells.

  Cleidson P Alves, Milene H Moraes, Josane F Sousa, Carmen Lucia S Pontes, Anelisa Ramão, Satoru Yokoyama, Daniel M Trindade, David E Fisher, Enilza M Espreafico
  Journal of Investigative Dermatology 05/2013;
• Article: Isometric Contraction of Dupuytren's Myofibroblasts is Inhibited by Blocking Intercellular Junctions.

  Jennifer S N Verhoekx, Liaquat S Verjee, David Izadi, James K K Chan, Vicky Nicolaidou, Dominique Davidson, Kim S Midwood, Jagdeep Nanchahal
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  ABSTRACT: Myofibroblasts are responsible for both physiological wound and scar contraction. However, it is not known whether these cells act individually to contract the surrounding matrix or whether they behave in a coordinated manner. Therefore, we studied intercellular junctions of primary human myofibroblasts derived from patients with Dupuytren's disease, a fibrotic disorder of the dermis and subdermal tissues of the palm. The cells were maintained in anchored three-dimensional collagen lattices to closely mimic conditions in vivo. We found that selective blockade of adherens, mechanosensitive or gap junctions effectively inhibited contraction of the collagen matrices and down-regulated the myofibroblast phenotype. Our data indicate that myofibroblasts in part function as a coordinated cellular syncytium and disruption of intercellular communication may provide a therapeutic target in diseases characterized by an overabundance of these contractile cells.Journal of Investigative Dermatology accepted article preview online, 7 May 2013; doi:10.1038/jid.2013.219.
  Journal of Investigative Dermatology 05/2013;
• Article: The Aryl Hydrocarbon Receptor is Involved in UVR-Induced Immunosuppression.

  Fatemeh Navid, Anika Bruhs, Winfried Schuller, Ellen Fritsche, Jean Krutmann, Thomas Schwarz, Agatha Schwarz
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  ABSTRACT: Ultraviolet radiation (UVR) suppresses the immune system via the induction of regulatory T cells (Treg). UVR-induced DNA damage has been recognized as the major molecular trigger involved since reduction of DNA damage by enhanced repair prevents the compromise to the immune system by UVR. Nevertheless, other signaling events may also be involved. The aryl hydrocarbon receptor (AhR) was identified as another target for UVR since UVR activates the AhR and certain UVR effects were not detected in AhR-deficient cells. We studied whether the AhR is involved in UVR-induced local immunosuppression and whether similar effects can be induced by AhR agonists. The AhR antagonist 3-methoxy-4-nitroflavone reduced UVR-mediated immunosuppression and the induction of Treg in murine contact hypersensitivity (CHS). Conversely, activation of the AhR by the agonist 4-n-nonylphenol (NP) suppressed the induction of CHS and induced antigen-specific Treg similar to UVR. This was further confirmed in AhR knock-out mice in which UVR- as well as NP-induced immunosuppression was significantly reduced. Together, this indicates that the AhR is involved in mediating UVR-induced immunosuppression. Activation of the AhR might represent an alternative to modulate the immune system in a similar fashion like UVR but without causing the adverse effects of UVR including DNA damage.Journal of Investigative Dermatology accepted article preview online, 7 May 2013; doi:10.1038/jid.2013.221.
  Journal of Investigative Dermatology 05/2013;
• Article: Plakoglobin as a Regulator of Desmocollin Gene Expression.

  Etienne Tokonzaba, Jiangli Chen, Xing Cheng, Zhining Den, Radhika Ganeshan, Eliane J Műller, Peter J Koch
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  ABSTRACT: Desmosomes are cell adhesion junctions required for the normal development and maintenance of mammalian tissues and organs such as the skin, skin appendages and the heart. The goal of the present study was to investigate how desmocollins (DSC), transmembrane components of desmosomes, are regulated at the transcriptional level. We hypothesized that differential expression of the Dsc2 and Dsc3 genes is a prerequisite for normal development of skin appendages. We demonstrate that plakoglobin (Pg) in conjunction with Lef-1 differentially regulates the proximal promoters of these two genes. Specifically, we found that Lef-1 acts as a switch activating Dsc2 and repressing Dsc3 in the presence of Pg. Interestingly, we also determined that NFκB pathway components, down-stream effectors of the Eda/EDAR signaling cascade, can activate Dsc2 expression. We hypothesize that Lef-1 and Eda/EDAR/NFκB signaling contribute to a shift in Dsc isoform expression from Dsc3 to Dsc2 in placode keratinocytes. It is tempting to speculate that this shift is required for invasive growth of placode keratinocytes into the dermis, a crucial step in skin appendage formation.Journal of Investigative Dermatology accepted article preview online, 7 May 2013; doi:10.1038/jid.2013.220.
  Journal of Investigative Dermatology 05/2013;