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Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers.
The vast majority of polymorphisms for human dermatologic diseases fall in non-coding DNA regions, leading to difficulty interpreting their functional significance. Recent work utilizing chromosome conformation capture (3C) technology in combination with chromatin immunoprecipitation (ChIP) has provided a systematic means of linking non-coding variants within active enhancer loci to putative gene targets. Here, we apply H3K27ac HiChIP high-resolution contact maps, generated from primary human T-cell subsets (CD4+ Naïve, TH17, and Treg), to 21 dermatologic conditions associated with single nucleotide polymorphisms (SNPs) from 106 genome-wide association studies (GWAS).
Neurological patients have an increased risk for bullous pemphigoid (BP) in which autoantibodies target BP180, a cutaneous basement membrane protein also expressed in the brain. Here we show that 53.6% sera of patients with multiple sclerosis (MS) (n=56) had IgG reactivity against full-length BP180 in immunoblotting, while in BP180-NC16A ELISA (n=143), only 7.7% MS samples studied were positive. Epitope mapping with 13 fusion proteins covering the entire BP180 polypeptide revealed that, in MS and Alzheimer’s disease (AD) patients, IgG autoantibodies target regions located in the intracellular and mid-extracellular parts of BP180, but not the well-known BP epitopes located in the NC16A domain and the distal part of extracellular domain.
The Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity-Score (ABSIS) scores have been proposed to provide an objective measure of pemphigus activity. These scores have been evaluated only on already treated patients mainly with mild to moderate activity. The objective was to assess the interrater reliability of ABSIS and PDAI scores and their correlation with other severity markers in a large international study.Consecutive patients with newly diagnosed pemphigus were enrolled in 31 centers.
Dendritic Cells (DC) are important inducers and regulators of T cell responses. They are able to activate- and modulate the differentiation of CD4+ and CD8+ T cells. In the skin there are at least five phenotypically distinct DC subpopulations that can be distinguished by differential expression of the cell surface markers CD207, CD103 and CD11b. Previous studies have suggested, that dermal CD11b−CD207+ conventional type 1 DC (cDC1) are indispensable for the priming of a skin homing cytotoxic T lymphocyte (CTL) response.
Activation of the Hedgehog (Hh) pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCC), with loss of function of Patched1 (Ptc1) being the most common genomic lesion. Sporadic BCCs also overexpress desmoglein-2 (Dsg2), a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively.
Vitiligo results from CD8+ T cell targeting of melanocytes, leading to patchy depigmentation. Upon cessation of therapy, depigmentation recurs at the same locations, implicating resident autoimmune memory T (TRM) cells. Indeed, Richmond and colleagues found that vitiligo patients have antigen-specific autoreactive TRM cells in lesional skin. As interleukin (IL)-15 is critical for generation of TRM cells, these investigators examined the effects of blocking IL-15 signaling via an antibody to the IL-15 CD122 subunit, which is expressed on autoreactive TRM cells in vitiligo.
Simpson and colleagues examined the clinical and physiological features and serum biomarkers in adult atopic dermatitis (AD) patients with and without Staphylococcus aureus colonization. AD patients colonized by S. aureus exhibited a distinct clinical phenotype and endotype, marked by more severe disease, greater epidermal function impairment, more pronounced defects in permeability and skin hydration, increased immune activation, type 2 immunity, and more extensive tissue damage than non-AD patients colonized by S. aureus.
Animal models have been developed to study the complex cellular and biochemical processes of wound repair and to evaluate the efficacy and safety of potential therapeutic agents. Several factors can influence wound healing. These include aging, infection, medications, nutrition, obesity, diabetes, venous insufficiency, and peripheral arterial disease. Lack of optimal preclinical models that are capable of properly recapitulating human wounds remains a significant translational challenge. Animal models should strive for reproducibility, quantitative interpretation, clinical relevance, and successful translation into clinical use.
The “Research Techniques Made Simple” (RTMS) series has covered nearly 75 research topics in the past 6 years to help readers build a foundation from which to understand the vast array of basic science and clinical research tools used in the field of dermatology. The early RTMS articles published in late 2012 through 2014 covered fundamental techniques including flow cytometry (Jahan-Tigh et al., 2012), PCR (Garibyan and Avashia, 2013), how a transgenic mouse is made (Scharfenberger et al., 2014), and basics of systematic reviews and meta-analyses (Abuabara et al., 2012).
The JID Connector was established to do just that—connect. It was in that spirit that “Research Techniques Made Simple” (RTMS) was born. The initial concept, conceived by Barbara Gilchrest of Harvard University and implemented by Kathy Schwarzenberger of the University of Tennessee Health Science Center, was to increase the accessibility of articles that appeared in the Journal of Investigative Dermatology (JID). It was recognized, however, that to reach trainees, interested clinicians, and non-cognoscenti, the science had to be more accessible and understandable.
“Education is not the filling of a pail, but the lighting of a fire.”—W.B. Yeats
Editorial note: Welcome to the Journal of Investigative Dermatology (JID) Cells to Surgery Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image above, while additional questions concern the findings reported in a JID article by Miller et al (https://doi.org/10.1016/j.jid.2018.02.018).