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ABSTRACT Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a rare genetic disorder that can arise due to mutations in the desmoglein 1 (DSG1) gene and sometimes in the desmoplakin (DSP) gene and is characterized by an autosomal recessive inheritance pattern. Severe dermatitis in most cases is treatment resistant and usually starts in the early postnatal period. Herein, we report a 5‐month‐old male with SAM syndrome that had a homozygous missense variant in exon 8 of the DSG1 gene with c.909G>C (p.Trp303Cys) and presented with pulmonary stenosis—a rare associated finding. [ABSTRACT FROM AUTHOR]

Cong-Li Jia,1 Fu Yang,2 Rui-Ning Li3 1Weifang Medical College, Weifang, Shandong, People’s Republic of China; 2Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 3Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, People’s Republic of ChinaCorrespondence: Fu YangDepartment of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xi Chang Road, Kunming, Yunnan, 650032, People’s Republic of ChinaTel +86 13888428338Email dediracy@163.comPurpose: To identify the potential differential genes between primary and metastatic melanoma, screen out immune-related genes in core genes and analyze their immune correlation, thus searching for the early diagnostic biomarkers of cutaneous malignant melanoma (CMM) and the targets of curbing metastasis.Materials and Methods: We analyzed two microarray datasets (GSE8401 and GSE46517) derived from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between primary and metastatic melanoma were screened out using the GEO2R tool. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to identify the functions and pathways of DEGs. We analyzed protein–protein interaction of these DEGs based on the Search Tool for the Retrieval of Interacting Genes database and showed by Cytoscape software. In addition, the online Gene Expression Profiling Interactive Analysis tool (GEPIA) was used to analyze the prognostic value of hub genes expressed in metastatic melanoma patients. Immune-related genes in hub genes were screened and further analyzed.Results: A total of 178 upregulated DEGs and 4 downregulated DEGs were identified. 23 terms and 4 pathways were confirmed related to metastatic melanoma. Ten hub genes with a high degree of connectivity were found. Overexpression of three hub genes (DSG1, FLG, PKP1) (P< 0.01) was associated with metastasis and poor prognosis of CMM. Among them, the patients with overexpression of PKP1 suffered shorter survival. In addition, 2 immune-related genes (EGFR and CDH1) in hub genes were screened out and both of them were related to anti-tumor immunity, although their expression level did not affect the overall survival of CMM patients significantly.Conclusion: Our study suggests that DSG1, FLG and PKP1 were overexpressed in metastatic melanoma compared with primary melanoma, and overexpression of these three genes was an unfavorable prognostic factor ifor CMM patients, which may indicate that they are associated with promoting metastasis of malignant melanoma. EGFR and CDH1 play a crucial role in anti-tumor immunity for CMM. Further research is needed to explore the value of these genes in the inhibition of metastasis and treatment of CMM.Keywords: cutaneous malignant melanoma, metastasis, genes, PKP1, DSG1, FLG, CDH1, EGFR

BackgroundPemphigus vulgaris is an autoimmune intraepithelial bullous disease involving the skin and the mucous membranes. Imiquimod, a topical therapy for skin basal cell carcinoma, is an amine that induces the production of tumor necrosis factor alfa, interleukin-1 and other cytokines. Pemphigus induced by drugs has been frequently reported, mostly after systemic therapy.Case presentationWe present the case of a 50-year-old man who developed skin, intraoral, and genital mucosae lesions 3 days after a treatment with Imiquimod for multiple superficial basal cell carcinoma of the trunk. Direct and indirect immunofluorescence results were compatible with the diagnosis of pemphigus vulgaris. Enzyme-linked immunosorbent assay was negative for desmoglein 1 and 3, but interestingly, by immunoblotting on keratinocyte extracts a band of 170 kDa was obtained by IgG. The patient, after interrupting Imiquimod application, started a treatment with prednisolone and in 4 weeks showed a complete remission.ConclusionTopical Imiquimod therapy might induce atypical pemphigus vulgaris in some patients.

Abstract Background Inherited palmoplantar keratodermas (PPKs) are clinically and genetically heterogeneous and phenotypically diverse group of genodermatoses characterized by hyperkeratosis of the palms and soles. More than 20 genes have been reported to be associated with PPKs including desmoglein 1 (DSG1) a key molecular component for epidermal adhesion and differentiation. Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene. Methods This study describes clinical as well as genetic whole exome sequencing (WES) and di-deoxy sequencing investigations in two Pakistani families with a total of 12 individuals affected by PPK. Results WES identified a novel homozygous nonsense variant in SLURP1, and a novel heterozygous nonsense variant in DSG1, as likely causes of the conditions in each family. Conclusions This study expands knowledge regarding the molecular basis of PPK, providing important information to aid clinical management in families with PPK from Pakistan.

Clinically, the treatments against asthma like β2 agonist focus on controlling the symptoms rather than inhibiting recurrence radically. This study aims to evaluate the efficacy and mechanism of a potent Chinese prescription Yu-Ping-Feng-San (YPFS) against asthma recurrence. We here established an optimized house dust mite (HDM)-induced asthma recurrence mice model with typical asthmatic responses such as significantly augmented airway hyperresponsiveness (AHR), elevated serum IgE, pulmonary type 2 cytokines IL-5 and IL-13 levels, pathological changes including thickening bronchial wall, inflammatory infiltration of lung tissue, etc. Moreover, all typical asthmatic pathological features were prominently alleviated by YPFS applied during remission phase ahead of second elicitation, which was even more effective than three different types of medications dexamethasone, montelukast and salbutamol, which were commonly applied in clinical practice, administered during recurrence phase. Besides, we found that desmoglein 1 (DSG1) remained deficient when asthmatic responses regressed whereas tight junction (TJ) claudin 1 (CLDN1) or adherin junction (AJ) E-cadherin restored spontaneously. In vitro, DSG1 interference resulted in increased thymic stromal lymphopoietin (TSLP) secretion, and epithelial barrier compromise evidenced by significantly elevated transepithelial electrical resistance (TEER) and increased 4-kDa FITC-dextran influx. YPFS could downregulate TSLP production and restore HDM-induced DSG1 deficiency and barrier destruction, which was further reversed by shDSG1. Collectively, administration of YPFS in remission prominently alleviated HDM-induced asthma relapse by restoring DSG1 and decreasing TSLP overexpression, which might be the key factors contributing to chronic asthma relapse. Our data not only demonstrated the pivotal role of DSG1 in asthma pathogenesis, but also provided a novel and potent therapeutic strategy against chronic asthma.

Clinically, the treatments against asthma like β2 agonist focus on controlling the symptoms rather than inhibiting recurrence radically. This study aims to evaluate the efficacy and mechanism of a potent Chinese prescription Yu-Ping-Feng-San (YPFS) against asthma recurrence. We here established an optimized house dust mite (HDM)-induced asthma recurrence mice model with typical asthmatic responses such as significantly augmented airway hyperresponsiveness (AHR), elevated serum IgE, pulmonary type 2 cytokines IL-5 and IL-13 levels, pathological changes including thickening bronchial wall, inflammatory infiltration of lung tissue, etc. Moreover, all typical asthmatic pathological features were prominently alleviated by YPFS applied during remission phase ahead of second elicitation, which was even more effective than three different types of medications dexamethasone, montelukast and salbutamol, which were commonly applied in clinical practice, administered during recurrence phase. Besides, we found that desmoglein 1 (DSG1) remained deficient when asthmatic responses regressed whereas tight junction (TJ) claudin 1 (CLDN1) or adherin junction (AJ) E-cadherin restored spontaneously. In vitro , DSG1 interference resulted in increased thymic stromal lymphopoietin (TSLP) secretion, and epithelial barrier compromise evidenced by significantly elevated transepithelial electrical resistance (TEER) and increased 4-kDa FITC-dextran influx. YPFS could downregulate TSLP production and restore HDM-induced DSG1 deficiency and barrier destruction, which was further reversed by shDSG1. Collectively, administration of YPFS in remission prominently alleviated HDM-induced asthma relapse by restoring DSG1 and decreasing TSLP overexpression, which might be the key factors contributing to chronic asthma relapse. Our data not only demonstrated the pivotal role of DSG1 in asthma pathogenesis, but also provided a novel and potent therapeutic strategy against chronic asthma. [ABSTRACT FROM AUTHOR]

Congenital PAX6-aniridia is a rare panocular disease resulting from limbal stem cell deficiency. In PAX6-aniridia, the downregulation of the retinol-metabolizing enzymes ADH7 (All-trans-retinol dehydrogenase 7) and ALDH1A1/A3 (Retinal dehydrogenase 1, Aldehyde dehydrogenase family 1 member A3) have been described in limbal epithelial cells (LECs) and conjunctival epithelial cells. The aim of this study was to identify the role of retinol derivates in the differentiation of human LEC and its potential impact on aniridia-associated keratopathy development. Human LEC were isolated from healthy donor corneas and were cultured with retinol, retinoic acid, or pan-retinoic acid receptor antagonist (AGN 193109) acting on RARα, β, γ (NR1B1, NR1B2 NR1B3) or were cultured with pan-retinoid X receptor antagonist (UVI 3003) acting on RXR α, β, γ (retinoid X receptor, NR2B1, NR2B2, BR2B3). Using qPCR, differentiation marker and retinoid-/fatty acid metabolism-related mRNA expression was analysed. DSG1 (Desmoglein 1), KRT3 (Keratin 3), and SPINK7 (Serine Peptidase Inhibitor Kazal Type 7) mRNA expression was downregulated when retinoid derivates were used. AGN 193109 treatment led to the upregulation of ADH7, KRT3, and DSG1 mRNA expression and to the downregulation of KRT12 (Keratin 12) and KRT19 (Keratin 19) mRNA expression. Retinol and all-trans retinoic acid affect some transcripts of corneal LEC in a similar way to what has been observed in the LEC of PAX6-aniridia patients with the altered expression of differentiation markers. An elevated concentration of retinol derivatives in LEC or an altered response to retinoids may contribute to this pattern. These initial findings help to explain ocular surface epithelia differentiation disorders in PAX6-aniridia and should be investigated in patient cells or in cell models in the future in more detail.

Abstract: Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life‐threatening inherited condition caused by bi‐allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome‐causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasize the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits. [ABSTRACT FROM AUTHOR]

Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here, we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and, when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support human keratinocyte stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target. [Display omitted] • Desmosomal cadherin, desmoglein 1, requires the retromer for endosomal trafficking • The retromer is necessary for epidermal differentiation and stratification • Retromer chaperone enhances the function of Dsg1 and a disease-associated mutant • Retromer cargo GLUT1 is upregulated in Dsg1-deficient epidermis Hegazy et al. identify the endosomal trafficking complex, the retromer, as a regulator of epidermal development and homeostasis through its regulation of the important disease target, a desmosomal cadherin called desmoglein 1. Their work identifies the retromer as a possible therapeutic target for a systemic skin disorder. [ABSTRACT FROM AUTHOR]

Numerous studies have reported the presence of oxidized LDL (ox-LDL) and expression of its lectin-like receptor, LOX-1, have been shown in atherosclerotic regions. The present study aims to investigate the effects of ox-LDL on expression of desmoglein 1 (DSG1) and desmocollin 2 (DSC2) in endothelial cells, and to explore the role of LOX-1 mediated signal in the permeability injury associated with DSG1 and DSC2 disruption induced by oxidized lipoprotein. RT-PCR and Western blotting were applied to determine the mRNA and protein expression levels of DSG1 and DSC2 in human umbilical vein endothelial cells (HUVECs) respectively. Immunoreactivities of DSG1 and DSC2 were detected by laser scanning confocal microscope (LSCM). HUVEC monolayers permeability was evaluated by FITC-labeled LDL in transwell assay system. The possible signal was assessed using in vitro blocking LOX-1 or Ca 2+ channel or PKC. The DSG1 and DSC2 expression were decreased by ox-LDL in concentration- and time-dependent manner. The effects of ox-LDL were mediated by its endothelial receptor, LOX-1. In parallel experiments, ox-LDL increased the influx of extracellular calcium, activation of protein kinase C (PKC) and permeability to LDL, which was inhibited by the LOX-1blocking antibody (10 μg/ml), Ca 2+ channel blocker (Diltiazem, 50 μmol/L) and PKC-β inhibitor (hispidin, 4 μmol/L). These results suggested that ox-LDL-induced decrease in DSG1 and DSC2 expression and monolayer barrier injury via calcium uptake and PKC-β activation following up-regulation of LOX-1 is one of the mechanisms of inducing greater permeability in HUVECs. [ABSTRACT FROM AUTHOR]

Information processing is a cognitive trait forming the basis of complex abilities like executive function. The Trail Making Test (TMT) is a well-established test of information processing with moderate to high heritability. Age of the individual also plays an important role. A number of genetic association studies with the TMT have been performed, which, however, did not consider age as a moderating factor. We report the results of genome-wide association studies (GWASs) on age-independent and age-dependent TMT performance in two population-representative community samples (Munich Antidepressant Response Signature, MARS: N1 =540; Ludwig Maximilians University, LMU: N2 =350). Age-dependent genome-wide findings were then evaluated in a third sample of healthy elderly subjects (Sydney Memory and Ageing Study, Sydney MAS: N3 =448). While a meta-analysis on the GWAS findings did not reveal age-independent TMT associations withstanding correction for multiple testing, we found a genome-wide significant age-moderated effect between variants in the DSG1 gene region and TMT-A performance predominantly reflecting visual processing speed (rs2199301, Pmeta-analysis =1.3×10-7). The direction of the interaction suggests for the minor allele a beneficial effect in younger adults turning into a detrimental effect in older adults. The detrimental effect of the missense single nucleotide polymorphism rs1426310 within the same DSG1 gene region could be replicated in Sydney MAS participants aged 70-79, but not in those aged 80 years and older, presumably a result of survivor bias. Our findings demonstrate opposing effects of DSG1 variants on information processing speed depending on age, which might be related to the complex processes that DSG1 is involved with, including cell adhesion and apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Pemphigus foliaceus (PF) is the most common antibody-mediated autoimmune skin disease of dogs. Desmoglein-1 (DSG1), the major human PF antigen, represents only a minor autoantigen in canine PF (cPF). A recent immunomapping study proposed desmocollin-1 (DSC1) as a relevant candidate autoantigen for cPF. To investigate this hypothesis, 85 cPF sera were screened for the presence of anti-DSC1 IgG using indirect immunofluorescence (IIF) on live canine DSC1-transfected 293T cells. Seventy-five sera contained detectable antikeratinocyte IgG on IIF using footpad substrate (IIFpos cPF), while 10 did not (IIFneg cPF). Sera from 35 healthy dogs, eight from exfoliative superficial pyoderma (ESP)-affected dogs and 21 dogs with non-PF autoimmune blistering skin diseases served as controls. All sera were tested concurrently by IIF on canine DSG1-transfected as well as nontransfected cells. None of the healthy dog or ESP sera labelled any of the transfected or nontransfected cells. Fifty-seven of 75 IIFpos cPF (86%) and 7/10 of IIFneg cPF sera (70%) contained detectable anti-DSC1 IgG. None of these sera recognized nontransfected cells. Five cPF sera (6%) recognized DSG1 in addition to DSC1. Finally, 5/21 (24%) sera from dogs with non-PF autoimmune blistering diseases contained low anti-DSC1 IgG titers. In 7/10 dogs (70%), from whom serial serum samples were collected during treatment, anti-DSC1 IgG titers decreased in parallel with the reduction in disease clinical severity. Altogether, these findings suggest that DSC1 is a major autoantigen in cPF. [Copyright &y& Elsevier]

Background: Pemphigus foliaceus (PF) is a cutaneous autoimmune bullous disease characterized by the presence of anti-desmoglein 1 antibodies. The trigger for the formation of these antibodies is thought to consist of the vector insects of parasitic diseases found in endemic regions for PF, including leishmaniasis, as a non-pathogenic variant of these antibodies was found in patients with those parasitic diseases in endemic regions for PF. This hypothesis would be confirmed by the finding of the said non-pathogenic antibodies in patients with one of these parasitic diseases in regions non-endemic for pemphigus foliaceus. Therefore the aim of this study was the evaluation of Anti-DSG1 antibody in patients suffering to zoonotic cutaneous leishmaniasisin Isfahan city of Iran. Methods: Blood sera of 58 patients with zoonotic cutaneous leishmaniasis, confirmed by clinical signs and direct blood smear, were collected and enzyme-linked immunosorbent assay (ELISA) for anti-desmoglein 1 antibodies was performed on these sampl. Findings: 56 out of 58 serum samples of patients with cutaneous leishmaniasisin this study were negative for anti-Dsg1 antibodies using ELISA, with one sample having an indeterminate value and one sample being positive. Conclusion: Our results reject our initial hypothesis regarding the role of leishmaniasisin triggering the formation of anti-desmoglein 1 antibodies. Several alternate explanations are possible, including the role of the black fly Simuliumnigrimanum. [ABSTRACT FROM AUTHOR]

PAX6 haploinsufficiency related aniridia is characterized by disorder of limbal epithelial cells (LECs) and aniridia related keratopathy. In the limbal epithelial cells of aniridia patients, deregulated retinoic acid (RA) signaling components were identified. We aimed to visualize differentiation marker and RA signaling component expression in LECs, combining a differentiation triggering growth condition with a small interfering RNA (siRNA) based aniridia cell model (PAX6 knock down). Primary LECs were isolated from corneoscleral rims of healthy donors and cultured in serum free low Ca2+ medium (KSFM) and in KSFM supplemented with 0.9 mmol/L Ca2+. In addition, LECs were treated with siRNA against PAX6. DSG1, PAX6, KRT12, KRT 3, ADH7, RDH10, ALDH1A1, ALDH3A1, STRA6, CYP1B1, RBP1, CRABP2, FABP5, PPARG, VEGFA and ELOVL7 expression was determined using qPCR and western blot. DSG1, FABP5, ADH7, ALDH1A1, RBP1, CRABP2 and PAX6 mRNA and FABP5 protein expression increased (p ≤ 0.03), PPARG, CYP1B1 mRNA expression decreased (p ≤ 0.0003) and DSG1 protein expression was only visible after Ca2+ supplementation. After PAX6 knock down and Ca2+ supplementation, ADH7 and ALDH1A1 mRNA and DSG1 and FABP5 protein expression decreased (p ≤ 0.04), compared to Ca2+ supplementation alone. Using our cell model, with Ca2+ supplementation and PAX6 knockdown with siRNA treatment against PAX6, we provide evidence that haploinsufficiency of the master regulatory gene PAX6 contributes to differentiation defect in the corneal epithelium through alterations of RA signalling. Upon PAX6 knockdown, DSG1 differentiation marker and FABP5 RA signaling component mRNA expression decreases. A similar effect becomes apparent at protein level though differentiation triggering Ca2+ supplementation in the siRNA-based aniridia cell model. Expression data from this cell model and from our siRNA aniridia cell model strongly indicate that FABP5 expression is PAX6 dependent. These new findings may lead to a better understanding of differentiation processes in LECs and are able to explain the insufficient cell function in AAK. • PAX6 , DSG1 and RA signaling component FABP5 expression is significantly upregulated in presence of Ca2+ in LECs. • DSG1 protein expression is only visible under Ca2+ growth conditions, proving enhanced differentiation in LECs through Ca2+. • Ca2+ supplementation can be combined with PAX6 siRNA treatment to mimic aniridia cellular behavior observed in patients. • DSG1 and FABP5 seem to be PAX6 dependent or driven by PAX6 in LECs. [ABSTRACT FROM AUTHOR]

Abstract: Plucked (pk) is an autosomal recessive mouse mutation with a hair phenotype that arose spontaneously in the DBA/2J strain. Histological studies indicate that adult pk mutant mice lose truncal hair because of the scarring of follicles due to an apparent obstruction of the outward movement of the hair shaft within the follicular canal. We mapped the pk mutant phenotype to a 1.1cM region of chromosome 18 (between 6.6 and 7.7cM from the centromere) using 370 backcross progeny. Within this region, among others, are genes for desmosome cadherins. Desmosome cadherins are interesting candidates because of their critical roles for cell–cell adhesion in epidermal function. Northern Blot analysis of wild-type and pk mutant mice indicates that expression of both desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) is up-regulated in the skin of mutant pk mice. [Copyright &y& Elsevier]

Purpose: Palmoplantar keratodermas (PPKs) form a group of disorders characterized by thickening of palm and sole skin. Over the past 2 decades, many types of inherited PPKs have been found to result from abnormal expression, processing, or function of adhesion proteins., Methods: We used exome and direct sequencing to detect causative pathogenic variants. Functional analysis of these variants was conducted using reverse transcription quantitative polymerase chain reaction, immunofluorescence confocal microscopy, immunoblotting, a promoter reporter assay, and chromatin immunoprecipitation., Results: We identified 2 heterozygous variants (c.1226A>G and c.633&#95;634dupGT) in KLF4 in 3 individuals from 2 different unrelated families affected by a dominant form of PPK. Immunofluorescence staining for a number of functional markers revealed reduced epidermal DSG1 expression in patients harboring heterozygous KLF4 variants. Accordingly, human keratinocytes either transfected with constructs expressing these variants or downregulated for KLF4 displayed reduced DSG1 expression, which in turn has previously been found to be associated with PPK. A chromatin immunoprecipitation assay confirmed direct binding of KLF4 to the DSG1 promoter region. The ability of mutant KLF4 to transactivate the DSG1 promoter was significantly decreased when compared with wild-type KLF4., Conclusion: Loss-of-function variants in KLF4 cause a novel form of dominant PPK and show its importance in the regulation of epidermal differentiation., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Congenital PAX6-aniridia is a rare panocular disease resulting from limbal stem cell deficiency. In PAX6-aniridia, the downregulation of the retinol-metabolizing enzymes ADH7 (All-trans-retinol dehydrogenase 7) and ALDH1A1/A3 (Retinal dehydrogenase 1, Aldehyde dehydrogenase family 1 member A3) have been described in limbal epithelial cells (LECs) and conjunctival epithelial cells. The aim of this study was to identify the role of retinol derivates in the differentiation of human LEC and its potential impact on aniridia-associated keratopathy development. Human LEC were isolated from healthy donor corneas and were cultured with retinol, retinoic acid, or pan-retinoic acid receptor antagonist (AGN 193109) acting on RARα, β, γ (NR1B1, NR1B2 NR1B3) or were cultured with pan-retinoid X receptor antagonist (UVI 3003) acting on RXR α, β, γ (retinoid X receptor, NR2B1, NR2B2, BR2B3). Using qPCR, differentiation marker and retinoid-/fatty acid metabolism-related mRNA expression was analysed. DSG1 (Desmoglein 1), KRT3 (Keratin 3), and SPINK7 (Serine Peptidase Inhibitor Kazal Type 7) mRNA expression was downregulated when retinoid derivates were used. AGN 193109 treatment led to the upregulation of ADH7, KRT3, and DSG1 mRNA expression and to the downregulation of KRT12 (Keratin 12) and KRT19 (Keratin 19) mRNA expression. Retinol and all-trans retinoic acid affect some transcripts of corneal LEC in a similar way to what has been observed in the LEC of PAX6-aniridia patients with the altered expression of differentiation markers. An elevated concentration of retinol derivatives in LEC or an altered response to retinoids may contribute to this pattern. These initial findings help to explain ocular surface epithelia differentiation disorders in PAX6-aniridia and should be investigated in patient cells or in cell models in the future in more detail. [ABSTRACT FROM AUTHOR]

Background: Pemphigus is a potentially life-threatening auto-immune blistering disease and consequently it is important to monitor disease activity., Objectives: To assess the usefulness of serial antibody titers in the management of pemphigus and to predict disease activity in the clinical follow-up of pemphigus patients., Materials and Methods: In this prospective observational study, seven patients with pemphigus vulgaris and three patients with pemphigus foliaceus were examined on a monthly basis for 24 months, or two-weekly during active disease. Disease activity was registered according to a new score system., Results: A total of 158 samples were tested using commercial desmoglein (Dsg) 1 and Dsg3 enzyme-linked immunosorbent assay (ELISA) kits. The 20 U/mL cut-off for the anti-Dsg1 ELISA value was associated with a significantly higher risk of a skin activity score>0 (OR=7.91, 95% CI=1.71;36.65, p=0.01). A cut-off for disease activity at 5 gave an OR of 11.40 (95% CI=2.64;49.09, p=0.003). Dsg1 values of >15 had a sensitivity of 79.41% and specificity of 87.80% for predicting a relapse of skin disease in pemphigus patients. For Dsg3, no odds could be calculated for mucosal involvement, nor a predicting value for mucosal relapse., Conclusion: We conclude that only Anti-Dsg1 antibody ELISA values seem valuable in the follow-up of pemphigus patients and carry a predictive value. However, serial antibody titers cannot be seen as absolute indicators of disease activity and we believe that both Dsg1 and Dsg3 ELISA tests should be used with caution to monitor disease activity.