Journal Of Investigative Dermatology

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Updated: 1 hour 23 min ago

LB1054 IQGAP3 is involved in keratinocyte response to inflammation

Sun, 2019-09-01 00:00
IQGAP proteins mediate many processes important for the development of hyperproliferative skin diseases, namely the EGF signaling, WNT and MAPK kinase cascades, they are required for cell adhesion and migration processes, tight junction and zonula occludens formation, cell cycle regulation. However, the possible contribution of the IQGAP3 in the development of hyperproliferative psoriatic plaques is unknown. We have shown earlier that IQGAP3 is overexpressed in the lesional skin of patients with psoriasis.

LB1053 Dysregulation of antioxidant enzyme PRDX5 in alopecia areata

Sun, 2019-09-01 00:00
We previously published a genome-wide association study (GWAS) and meta-analysis to search for common alleles that contribute to risk of AA, and identified several genomic regions harboring potential susceptibility genes. One candidate susceptibility gene expressed in the hair follicle (HF) in AA is peroxiredoxin 5 (PRDX5) (p= of 8.7*10-14), which is also a GWAS gene in Crohn’s disease, sarcoidosis, and psoriasis. PRDX5 is a member of the family of antioxidant enzymes that are crucial for regulating oxidative stress.

LB1052 Characterization of the B cell infiltrate in discoid lupus

Sun, 2019-09-01 00:00
Discoid lupus erythematosus (DLE) is a severely disfiguring and difficult to treat autoimmune skin disease for which no new therapies have been FDA-approved in over 60 years. One potential therapeutic target is cutaneous B cells. Though rare in healthy skin, B cells are prevalent in DLE lesions, comprising 10-20% of the robust lymphocytic infiltrate. However, the phenotype and function of this expanded B cell population have not been evaluated in detail and it is unknown whether cutaneous B cells play a role in DLE pathogenesis.

LB1051 A selective TYK2 inhibitor, BMS-986165, decreases the transcriptional signature of Th17, IL-12, and interferon pathways in skin of psoriasis: results from a Phase 2 trial

Sun, 2019-09-01 00:00
Psoriasis, a chronic, immune-mediated disease dependent upon the interleukin (IL)-23/Th17 pathway, is thought to be initiated through plasmacytoid dendritic cell activation and induction of Type I interferons (IFNs). BMS-986165 is a novel oral, selective tyrosine kinase 2 (TYK2) inhibitor that blocks signal transduction of IL-23, IL-12, and Type I IFNs in cellular assays. Its selectivity for TYK2 over Janus kinases 1–3 is driven by binding to the pseudokinase domain, rather than the conserved kinase domain.

LB1050 Qing-Re Chu-Shi Decoction Improves 2,4-dinitrochlorobenzene-induced Atopic Dermatitis-like Skin Lesions via Anti-inflammatory and Immune Regulation

Sun, 2019-09-01 00:00
Atopic dermatitis (AD) is reported to be an allergic dermatitis characterized by eczematous lesions and pruritus. Qing-Re Chu-Shi Decoction (QRCSD) is the herbal formula long used as a complementary and alternative therapy for inflammatory skin diseases in China. However, the role and mechanism of action for QRCSD in AD remained poorly understood. The study was designed to explore the underlying effects of the formula and identify the components accounting for the therapeutic effects in2,4-Dinitrochlorobenzene(DNCB)-induced AD-like model of NC/Nga mice.

LB1049 Prolonged ex vivo exposure to the anti-p19 agent tildrakizumab alters the profile of skin-resident T cells isolated from psoriatic patient lesional skin

Sun, 2019-09-01 00:00
Anti-p19 treatments, such as tildrakizumab, distinguish themselves from existing biological treatments by their capability of inducing long-term remission in psoriasis. The magnitude and particularly the prolonged clinical response seen with tildrakizumab indicates a fundamentally different mechanism of action than other biological treatments, including anti-TNF, anti-IL-17, and anti-p40 treatments. To explore these mechanisms, we utilized a method for isolation and ex vivo culture of skin-resident T cells in the presence of tildrakizumab, etanercept, or IgG isotype control followed by combination single-cell RNA-seq (scRNA-seq) and mass spectrometry (CyTOF) profiling.

LB1048 TGFβ/Smad2/4 signaling pathway is required for epidermal Langerhans cell repopulation under inflammation condition but not for their homeostasis, maturation and migration in the steady state

Sun, 2019-09-01 00:00
Langerhans cells (LC) represent a specialized subset of evolutionarily conserved dendritic cells (DC) in skin, which are essential for induction of skin immunity and tolerance. They self-renew in the skin at steady state, but could repopulate from peripheral blood Gr-1hi monocytes and bone marrow (BM) hematopoietic stem cells at inflammatory state. Transforming growth factor-beta1 (TGFβ1) is a crucial factor in the regulation of LC maintenance and function after birth, however the underlying TGFβ signaling pathways are still unclear.

LB1047 Stat3 activation in epidermal keratinocytes induces Langerhans cell activation to form an essential circuit for psoriasis via IL-23 production

Sun, 2019-09-01 00:00
Background: Psoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial. Objectives: To elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model. Methods: Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice.

LB1046 Keratinocyte metabolic reprogramming promotes self-RNA sensation by dendritic cells in psoriasis

Sun, 2019-09-01 00:00
The maintenance of psoriasis as a skin-confined chronic inflammatory condition requires the abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells. In this context, targeting metabolism of keratinocytes is recently reported to be an approach for treating psoriasis, however whether and how the metabolic adaptations of keratinocytes introduce inflammatory cues are unknown. We report that in psoriatic lesions, Protein Phosphatase 6 (PP6) is diminished in the epidermis, and its levels negatively correlate with the disease severity.

Late-Breaking Abstracts Title Page

Sun, 2019-09-01 00:00
Late-Breaking Abstracts

Keyword Index

Sun, 2019-09-01 00:00
AcneLB1103, LB1108, LB1117, LB1118, LB1131

Author Index

Sun, 2019-09-01 00:00
Abdelaziz, Alexa R.LB1053

Research Techniques Made Simple: Forward Genetic Screening to Uncover Genes Involved in Skin Biology

Sun, 2019-09-01 00:00
The primary goals of modern genetics are to identify disease-causing mutations and to define the functions of genes in biological processes. Two complementary approaches, reverse and forward genetics, can be used to achieve this goal. Reverse genetics is a gene-driven approach that comprises specific gene targeting followed by phenotypic assessment. Conversely, forward genetics is a phenotype-driven approach that involves the phenotypic screening of organisms with randomly induced mutations followed by subsequent identification of the causative mutations (i.e., those responsible for phenotype).

Cross-Talk between Hemidesmosomes and Focal Adhesions: A Primer for Wound Healing, Blistering Skin Disease, and Skin Aging

Sun, 2019-09-01 00:00
Hemidesmosomes and focal adhesions attach keratinocytes to the dermis and act as bidirectional signaling centers to control epidermal renewal. Pora and colleagues (Pora et al., 2019) demonstrate that in migrating primary human keratinocytes, hemidesmosomes cluster as ordered arrays consisting of multiple chevrons, flanked by actin-associated focal adhesions. These and related findings have implications for wound healing, cancer invasion, blistering skin diseases, and skin aging.

Can Combination MEK and Akt Inhibition Slay the Giant Congenital Nevus?

Sun, 2019-09-01 00:00
The clinical management of large and giant congenital melanocytic nevi (lgCMN) relies heavily upon iterative surgical procedures. In this issue Rouille et al. (2019) use lgCMN explants and a newly developed patient-derived xenograft model to show that the local administration of MEK and Akt inhibitors limits the lgCMN proliferative potential. These findings, along with emerging reports, support continued investigation of targeted therapies in lgCMN.

Nicastrin Deficiency Induces Tyrosinase-dependent Depigmentation and Skin Inflammation

Mon, 2019-08-19 00:00
Skin depigmentation diseases, such as vitiligo, are pigmentation disorders that often destroy melanocytes. However, their pathological mechanisms remain unclear and, therefore, promising treatments or prevention have been lacking. Here we demonstrate that a zebrafish insertional mutant showing a significant reduction of nicastrin transcript possesses melanosome maturation defect, Tyrosinase-dependent mitochondrial swelling and melanophore cell death. The depigmentation phenotypes are proven to be a result of γ-secretase inactivation.

Base editor correction of COL7A1 in recessive dystrophic epidermolysis bullosa patient-derived fibroblasts and iPSCs

Mon, 2019-08-19 00:00
Genome editing represents a promising strategy for therapeutic correction of COL7A1 mutations that cause recessive dystrophic epidermolysis bullosa (RDEB). DNA cleavage followed by homology-directed repair (HDR) using an exogenous template has previously been used to correct COL7A1 mutations. HDR rates can be modest and the double-strand DNA breaks that initiate HDR commonly result in accompanying undesired insertions and deletions (indels). To overcome these limitations, we applied an A•T→G•C adenine base editor (ABE) to correct two different COL7A1 mutations in primary fibroblasts derived from RDEB patients.

Transglutaminase 3 promotes skin inflammation in atopic dermatitis by activating monocyte-derived dendritic cells via DC-SIGN

Fri, 2019-08-16 00:00
Atopic dermatitis (AD) is often concomitant with increased level of IgE against not only foreign allergens but also autoallergens. AD patients with autoallergy are likely to be more severe and difficult to treat, and self-reactive IgE might be a contributing factor in the pathogenesis of AD. However, how autoallergens are recognized by immune system and what immune responses are induced subsequently remain largely unknown. We found that the serum level of IgE against Transglutaminase 3 (TGase3) was significantly higher in AD patients than that of healthy individuals, and was positively correlated with disease severity.

Classifying melanoma by TERT promoter mutational status

Fri, 2019-08-16 00:00
While TERT promoter mutations have been associated with a worsened prognosis in melanoma, the relationship between mutation status and downstream telomerase activity and telomere length remains convoluted. Using Sanger sequencing and qPCR-based techniques, we evaluated 60 melanoma cell lines for TERT promoter mutational status, copy number, gene expression, and telomere length in order to provide a comprehensive analysis of the TERT/telomere pathway and establish a classification system whereby the associations between TERT mutations and their downstream molecular manifestations can more easily be ascertained.

Environmental exposures such as smoking and low vitamin D are predictive of poor outcome in cutaneous melanoma rather than other deprivation measures

Fri, 2019-08-16 00:00
Lack of basic resources within a society (deprivation) is associated with increased cancer mortality and this relationship has been described for melanoma. We have previously reported the association of smoking and low vitamin D levels with melanoma death. In this study we further explored the associations of these with melanoma, in addition to deprivation and socio-economic stressors. In this analysis of 2183 population-ascertained primary cutaneous melanoma patients; clinical, demographic and socio-economic variables were assessed as predictors of tumour thickness, melanoma death and overall death.

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