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Retinoids are a frequently used class of drugs in the treatment of inflammatory as well as malignant skin diseases. Retinoids have differential affinity for the retinoic acid receptor (RAR) and/or the retinoid X receptor (RXR). The endogenous dual RAR and RXR agonist alitretinoin (9-cis retinoic acid) demonstrated remarkable efficacy in the treatment of chronic hand eczema (CHE) patients; however, detailed information on the mechanisms of action remains elusive. Here, we used CHE as a model disease to unravel immunomodulatory pathways following retinoid receptor signaling. Transcriptome analyses of skin specimens from alitretinoin-responder CHE patients identified 231 significantly regulated genes. Bioinformatic analyses indicated keratinocytes as well as antigen presenting cells as cellular targets of alitretinoin. In keratinocytes, alitretinoin interfered with inflammation-associated barrier gene dysregulation as well as antimicrobial peptide induction while markedly inducing hyaluronan synthases without affecting hyaluronidase expression. In monocyte-derived dendritic cells, alitretinoin induced distinct morphological and phenotypic characteristics with low co-stimulatory molecule expression (CD80 and CD86), the increased secretion of IL-10 and the upregulation of the ecto-5′-nucleotidase CD73 mimicking immunomodulatory or tolerogenic dendritic cells. Indeed, alitretinoin-treated dendritic cells demonstrated a significantly reduced capacity to activate T cells in mixed leukocyte reactions. In a direct comparison, alitretinoin-mediated effects were significantly stronger than those observed for the RAR agonist acitretin. Moreover, longitudinal monitoring of alitretinoin-responder CHE patients could confirm in vitro findings. Taken together, we demonstrate that the dual RAR and RXR agonist alitretinoin targets epidermal dysregulation and demonstrates strong immunomodulatory effects on antigen presenting cell functions.

Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death among women. Despite its immunogenicity, effective antitumor responses are limited, due, in part, to the presence of forkhead box protein 3–positive (Foxp3+) T regulatory (Treg) cells in the tumor microenvironment. However, the mechanisms that regulate the accumulation and the suppressive function of these Foxp3+ Treg cells are poorly understood. Here, we found that the majority of Foxp3+ Treg cells accumulating in the tumor microenvironment of EOCs belong to the subset of Foxp3+ Treg cells expressing inducible costimulator (ICOS). The expansion and the suppressive function of these cells were strictly dependent on ICOS-L costimulation provided by tumor plasmacytoid dendritic cells (pDC). Accordingly, ICOS+ Foxp3+ Treg cells were found to localize in close vicinity of tumor pDCs, and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS+ Foxp3+ Treg cells were found to be strong predictors for disease progression in patients with ovarian cancer, with ICOS+ Treg cell subset being a stronger predictor than total Foxp3+ Treg cells. These findings suggest an essential role for pDCs and ICOS-L in immunosuppression mediated by ICOS+ Foxp3+ Treg cells, leading to tumor progression in ovarian cancer. Cancer Res; 72(20); 5240–9. ©2012 AACR.

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PDF file - 68K, Survival of ICOS+ but not ICOS- T regulatory cells are dependent on ICOS-L provided by plasmacytoid dendritic cells. ICOS+ and ICOS- T regulatory cells isolated from peripheral blood of healthy volunteers were co-cultured with or without autologous plasmacytoid dendritic cells in the presence or absence of neutralizing anti-ICOS-L antibodies as described. Data depicted represent numbers of viable cells after four days of culture. Representative experiment of at least three independent experiments is shown. pDC = plasmacytoid dendritic cells, Treg = T regulatory cells

PDF file - 54K, Plasmacytoid dendritic cells do not correlate with ICOS- Foxp3+ T regulatory cells in the tumor microenvironment. Percentages of plasmacytoid dendritic cells (pDC) and percentages of ICOS- Foxp3+ T regulatory cells as analyzed by FACS show no correlation within the tumor microenvironment of ovarian cancer

Rosacea is a common chronic inflammatory skin disease that is characterized by a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with high density of B. oleronius and increased activity of the serine protease kallikrein 5, which cleaves cathelicidin antimicrobial peptide, have been recognized as key pathogenic triggers in rosacea. However, how these events are linked to the hallmarks of the disease remains unknown. Here, we show that type I interferons produced by plasmacytoid dendritic cells represent the pivotal link between dysbiosis, an aberrant immune response, and neovascularization in rosacea. In fact, compared to other commensal bacteria, B. oleronius is highly susceptible and preferentially killed by cathelicidin antimicrobial peptides leading to enhanced generation of complexes with DNA. DNA from skin-associated microbiota but not from host cells is required for cathelicidin-induced activation of plasmacytoid dendritic cells and type I-interferon production, which is further amplified by B. oleronius. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA binding and type I interferon-inducing capacities, further facilitating type I interferon production within the skin. In turn, type I interferons induce IL22 whilst simultaneously rendering endothelial cells responsive through upregulation of the IL22-receptor, and thereby driving drive neoangiogenesis. These findings unravel novel pathomechanisms, which directly link several hallmarks of rosacea to the killing of dysbiotic commensal bacteria and the induction of a pathogenic type-I interferon-TH17/22 pathway.

Contains fulltext : 251811.pdf (Publisher’s version ) (Closed access) BACKGROUND: Loss-of-function mutations in the filaggrin (FLG) gene directly alter skin barrier function and critically influence atopic inflammation. While skin barrier dysfunction, Th2-associated inflammation and bacterial dysbiosis are well-known characteristics of atopic dermatitis (AD), the mechanisms interconnecting genotype, transcriptome and microbiome remain largely elusive. OBJECTIVE: In-depth analysis of FLG genotype-associated skin gene expression alterations and host-microbe interactions in AD. METHODS: Multi-omics characterization of a cohort of AD patients carrying heterozygous loss-of-function mutations in the FLG gene (AD(Mut)) (n = 15), along with matched wild-type (AD(Wt)) patients and healthy controls. Detailed clinical characterization, microarray gene expression and 16 S rRNA-based microbial marker gene data were generated and analyzed. RESULTS: In the context of filaggrin dysfunction, the transcriptome was characterized by dysregulation of barrier function and water homeostasis, while the lesional skin of AD(Wt) demonstrated the specific upregulation of pro-inflammatory cytokines and T-cell proliferation. S. aureus dominated the microbiome in both patient groups, however, shifting microbial communities could be observed when comparing healthy with non-lesional AD(Wt) or AD(Mut) skin, offering the opportunity to identify microbe-associated transcriptomic signatures. Moreover, an AD core signature with 28 genes, including CCL13, CCL18, BTC, SCIN, RAB31 and PCLO was identified. CONCLUSIONS: Our integrative approach provides molecular insights for the concept that FLG loss-of-function mutations are a genetic shortcut to atopic inflammation and unravels the complex interplay between genotype, transcriptome and microbiome in the human holobiont.

Ultraviolet (UV) B irradiation of keratinocytes results in the formation of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) which is a high-affinity ligand for the aryl hydrocarbon receptor (AHR). The resulting activation of AHR signaling induces the expression of cytochrome P450 (CYP) 1A1 which subsequently metabolizes FICZ. Importantly, FICZ is also a nanomolar photosensitizer for UVA radiation. Here, we assess whether a manipulation of the AHR-CYP1A1 axis in human epidermal keratinocytes affects FICZ/UVA-induced phototoxic effects and whether this interaction might be mechanistically relevant for the phototoxicity of the BRAF inhibitor vemurafenib. Treatment of keratinocytes with an AHR agonist enhanced the CYP1A1-catalyzed metabolism of FICZ and thus prevented UVA photosensitization, whereas an inhibition of either AHR signaling or CYP1A1 enzyme activity resulted in an accumulation of FICZ and a sensitization to UVA-induced oxidative stress and apoptosis. Exposure of keratinocytes to vemurafenib resulted in the same outcome. Specifically, CYP phenotyping revealed that vemurafenib is primarily metabolized by CYP1A1 and to a lesser degree by CYP2J2 and CYP3A4. Hence, vemurafenib sensitized keratinocytes to UVA-induced apoptosis by interfering with the CYP1A1-mediated oxidative metabolism of FICZ. In contrast to this pro-apoptotic effect, a treatment of UVB-damaged keratinocytes with vemurafenib suppressed apoptosis, a process which might contribute to the skin carcinogenicity of the drug. Our results provide insight into the mechanisms responsible for the photosensitizing properties of vemurafenib and deliver novel information about its metabolism which might be relevant regarding potential drug-drug interactions. The data emphasize that the AHR-CYP1A1 axis contributes to the pathogenesis of cutaneous adverse drug reactions., Graphical abstract Image 1

Background In recent years, the BRAF inhibitor vemurafenib has been successfully established in the therapy of advanced melanoma. Despite its superior efficacy, the use of vemurafenib is limited by frequent inflammatory cutaneous adverse events that affect patients' quality of life and may lead to dose reduction or even cessation of anti-tumor therapy. To date, the molecular and cellular mechanisms of vemurafenib-induced rashes have remained largely elusive. Methods In this study, we deployed immunohistochemistry, RT-qPCR, flow cytometry, lymphocyte activation tests, and different cell-free protein-interaction assays. Results We here demonstrate that vemurafenib inhibits the downstream signaling of the canonical pathway of aryl hydrocarbon receptor (AhR) in vitro, thereby inducing the expression of proinflammatory cytokines (eg, TNF) and chemokines (eg, CCL5). In line with these results, we observed an impaired expression of AhR-regulated genes (eg, CYP1A1) and an upregulation of the corresponding proinflammatory genes in vivo. Moreover, results of lymphocyte activation tests showed the absence of drug-specific T cells in respective patients. Conclusion Taken together, we obtained no hint of an underlying sensitization against vemurafenib but found evidence suggesting that vemurafenib enhances proinflammatory responses by inhibition of canonical AhR signaling. Our findings contribute to our understanding of the central role of the AhR in skin inflammation and may point toward a potential role for topical AhR agonists in supportive cancer care.

Die topische Behandlung der Psoriasis und ihrer Sonderformen hat einen hohen Stellenwert im Praxisalltag. Sie ist Therapiestandard bei leichter Psoriasis und wird unterstützend auch bei mittelschwerer bis schwerer Psoriasis eingesetzt. Bei der Optimierung der Behandlung der Psoriasis spielt neben den geeigneten Wirkstoffen auch die Wahl der Galenik eine entscheidende Rolle. Die Weiterentwicklungen in diesem Bereich wurden in der 2017 publizierten Aktualisierung der S3-Leitlinie nicht berücksichtigt. Der vorliegende Behandlungspfad wurde im Rahmen der PsoNet-­Sprecherkonferenz erarbeitet und durch die nationale Versorgungskonferenz Psoriasis bestätigt. Er stellt eine Illustration der aktuellen Optionen dar. Die Fachinformationen der genannten Präparate sind dabei stets zu berücksichtigen. Die Festlegung von Therapiezielen mit dem Patienten ist obligat und adhärenzsteigernd. Dabei sollten die persönlichen Präferenzen und Vorerfahrungen des Patienten berücksichtigt werden. Goldstandard in der Initialphase ist die Fixkombination aus Calcipotriol (Cal) 50 μg/g und Betamethason-Dipropionat (Bet) 0,5 mg/g 1x täglich über vier bis acht Wochen. Als Darreichungsform ist der Schaum am effektivsten, wobei die individuelle Wahl der Grundlage auch nach Patientenpräferenz erfolgen sollte. In der Erhaltungsphase hat sich die 1-2x wöchentliche (proaktive) Anwendung dieser Fixkombination bewährt. In zweiter Linie können auch Vitamin D3 Analoga (Calcipotriol, Tacalcitol) und topische Corticosteroide als Monotherapie zur Anwendung kommen. Eine begleitende wirkstofffreie topische Basistherapie sollte regelhaft empfohlen werden. Bei besonderen Therapiesituationen werden spezifische Empfehlungen gegeben. Reicht eine alleinige Lokaltherapie nicht aus, sollte eine Therapieeskalation analog der S3-Leitlinie zur Therapie der Psoriasis erfolgen.

The coronavirus disease 2019 (COVID‐19) is associated with a wide clinical spectrum of skin manifestations, including chilblain‐like, urticarial, vesicular and vasculitic lesions. Recently, delayed skin reactions following mRNA vaccination against SARS-CoV-2 have been reported. The exact pathomechanisms underlying these skin lesions remain unknown. Here, we describe eleven cases of delayed skin reactions after SARS-CoV-2 vaccination with the mRNA-1273 vaccine, discuss their transient and benign clinical courses and consider their potential pathomechanisms based on histopathological analyses. We conclude that further investigations to characterize the precise molecular and cellular mechanisms underlying this rare phenomenon are warranted.

Ultraviolet B (UVB) radiation induces mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPDs), in epidermal keratinocytes (KC). To prevent skin carcinogenesis, these DNA photoproducts must be removed by nucleotide excision repair (NER) or apoptosis. Here we report that the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of UVB-induced CPDs in human HaCaT KC and skin from SKH-1 hairless mice. Subsequent RNA interference and inhibitor studies in KC revealed that AHR specifically suppresses global genome but not transcription-coupled NER. In further experiments, we found that the accelerated repair of CPDs in AHR-compromised KC depended on a modulation of the p27 tumor suppressor protein. Accordingly, p27 protein levels were increased in AHR-silenced KC and skin biopsies from AHR−/− mice, and critical for the improvement of NER. Besides increasing NER activity, AHR inhibition was accompanied by an enhanced occurrence of DNA double-strand breaks triggering KC apoptosis at later time points after irradiation. The UVB-activated AHR thus acts as a negative regulator of both early defense systems against carcinogenesis, NER and apoptosis, implying that it exhibits tumorigenic functions in UVB-exposed skin. In fact, AHR−/− mice developed 50% less UVB-induced cutaneous squamous cell carcinomas in a chronic photocarcinogenesis study than their AHR+/+ littermates. Taken together, our data reveal that AHR influences DNA damage-dependent responses in UVB-irradiated KC and critically contributes to skin photocarcinogenesis in mice.

ObjectivesThis study aims to provide a comprehensive analysis of the age-dependent risk of psoriatic arthritis (PsA). For this purpose, it focuses on the varying incidences within the different age groups.MethodsThe data were collected as part of the morbidity-based risk adjustment of the statutory health insurance companies in Germany. This survey recorded the International Statistical Classification of Diseases and Related Health Problems (ICD)-coded diagnoses of 65 million German citizens. Our population-based study used these raw data to calculate the prevalence of PsA in the first step. Subsequently, we employed a new approach for the estimation of the age-specific and sex-specific incidence of PsA.ResultsThe age-specific and sex-specific incidence of PsA showed a continuous increase with rising age until it peaked slightly before the age of 60 and declined thereafter. The maximum value was higher in women (40 per 100 000 py) than in men (30 per 100 000 py). Furthermore, the incidence rate tends to climb over the survey period.ConclusionsThe data sets identified an unexpected high incidence. A meta-analysis by Scotti et al and other recent population-based studies served as a reference for the comparison. The pattern of the age-specific incidence illustrated that the risk for PsA disease shows considerable variations depending on age.

Despite recent advances in understanding microbial diversity in skin homeostasis, the relevance of microbial dysbiosis in inflammatory disease is poorly understood. Here we perform a comparative analysis of skin microbial communities coupled to global patterns of cutaneous gene expression in patients with atopic dermatitis or psoriasis. The skin microbiota is analysed by 16S amplicon or whole genome sequencing and the skin transcriptome by microarrays, followed by integration of the data layers. We find that atopic dermatitis and psoriasis can be classified by distinct microbes, which differ from healthy volunteers microbiome composition. Atopic dermatitis is dominated by a single microbe (Staphylococcus aureus), and associated with a disease relevant host transcriptomic signature enriched for skin barrier function, tryptophan metabolism and immune activation. In contrast, psoriasis is characterized by co-occurring communities of microbes with weak associations with disease related gene expression. Our work provides a basis for biomarker discovery and targeted therapies in skin dysbiosis., Atopic dermatitis (AD) and psoriasis (PSO) are associated with dysbiosis. Here, by analyses of skin microbiome and host transcriptome of AD and PSO patients, the authors find distinct microbial and disease-related gene transcriptomic signatures that differentiate both diseases.

Background Wound healing represents a dynamic process involving directional migration of different cell types. Chemokines, a family of chemoattractive proteins, have been suggested to be key players in cell-to-cell communication and essential for directed migration of structural cells. Today, the role of the chemokine network in cutaneous wound healing is not fully understood. Unraveling the chemokine-driven communication pathways in this complex process could possibly lead to new therapeutic strategies in wound healing disorders. Methods We performed a systematic, comprehensive time-course analysis of the expression and function of a broad variety of cytokines, growth factors, adhesion molecules, matrixmetalloproteinases and chemokines in a murine cutaneous wound healing model. Results Strikingly, chemokines were found to be among the most highly regulated genes and their expression was found to coincide with the expression of their matching receptors. Accordingly, we could show that resting and activated human primary keratinocytes (CCR3, CCR4, CCR6, CXCR1, CXCR3), dermal fibroblasts (CCR3, CCR4, CCR10) and dermal microvascular endothelial cells (CCR3, CCR4, CCR6, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3) express a distinct and functionally active repertoire of chemokine receptors. Furthermore, chemokine ligand–receptor interactions markedly improved the wound repair of structural skin cells in vitro. Conclusion Taken together, we here present the most comprehensive analysis of mediators critically involved in acute cutaneous wound healing. Our findings suggest therapeutic approaches for the management of wound closure by targeting the chemokine network. Electronic supplementary material The online version of this article (10.1186/s40001-017-0299-0) contains supplementary material, which is available to authorized users.

Interleukin 17-producing helper T cells (T(H)17 cells) have a major role in protection against infections and in mediating autoimmune diseases, yet the mechanisms involved are incompletely understood. We found that interleukin 26 (IL-26), a human T(H)17 cell-derived cytokine, is a cationic amphipathic protein that kills extracellular bacteria via membrane-pore formation. Furthermore, T(H)17 cell-derived IL-26 formed complexes with bacterial DNA and self-DNA released by dying bacteria and host cells. The resulting IL-26-DNA complexes triggered the production of type I interferon by plasmacytoid dendritic cells via activation of Toll-like receptor 9, but independently of the IL-26 receptor. These findings provide insights into the potent antimicrobial and proinflammatory function of T(H)17 cells by showing that IL-26 is a natural human antimicrobial that promotes immune sensing of bacterial and host cell death.

Objective: Follicular helper T (Tfh) cells play a critical role in germinal center formation and B cell activation, both of which are hallmarks of primary Sjögren's syndrome (SS). CCR9-expressing T helper cells have "Tfh-like" characteristics and their numbers are increased at mucosa-associated sites in several inflammatory conditions. Because the characteristics of these cells are unique and evaluation has been limited, this study was undertaken to investigate the local and systemic CCL25/CCR9 axis in patients with primary SS. Methods: Levels of CCL25 protein and messenger RNA (mRNA) and CCR9+ T helper cells were evaluated in the labial salivary glands (LSGs) of patients with primary SS and patients with sicca syndrome without a diagnosis of primary SS (non-SS sicca controls). CCL25 levels were assessed for correlation with parameters of inflammation and clinical features. Circulating CCR9+ and CXCR5+ T helper cells were compared on the basis of phenotypic and functional properties. Results: CCL25 protein and mRNA levels were elevated in the LSGs of patients with primary SS as compared to non-SS sicca controls. Increased levels of CCL25 were associated with B cell hyperactivity, autoimmunity, and levels of interleukin-21 (IL-21) and soluble IL-7 receptor α-chain (IL-7Rα). Furthermore, the frequency of CCR9-expressing cells in the LSGs was increased and levels of circulating CCR9+ T helper cells expressing programmed death 1 and inducible T cell costimulator were elevated in patients with primary SS. CCR9+ T helper cells displayed higher expression of IL-7Rα and secreted higher levels of interferon-γ, IL-17, IL-4, and IL-21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL-7. Both CCR9+ and CXCR5+ T helper cells induced IgG production by B cells more potently than that induced in the cultures with CCR9-CXCR5- T helper cells. Conclusion: Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL-7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease.

T follicular helper cells (Tfh) are implicated in various pathological conditions, but how they differentiate in Th2-skewed environments is unknown. Pattarini et al. delineate a pathway for human Tfh differentiation induced by TSLP through OX40L, relevant to atopic dermatitis., T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)–activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells. TSLP-induced T cells expressed CXCR5, CXCL13, ICOS, PD1, BCL6, BTLA, and SAP, among other Tfh markers. Functionally, TSLP-DC–polarized T cells induced IgE secretion by memory B cells, and this depended on IL-4Rα. TSLP-activated DCs stimulated circulating memory Tfh cells to produce IL-21 and CXCL13. Mechanistically, TSLP-induced Tfh differentiation depended on OX40-ligand, but not on ICOS-ligand. Our results delineate a pathway of human Tfh differentiation in Th2 environments.

As a rare antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) is characterized by asthma, severe peripheral eosinophilia and the presence of extravascular granulomas. Cutaneous involvement usually includes palpable purpura or cutaneous to subcutaneous nodes. We present the case of a 43-year-old woman with EPGA and the unusual cutaneous manifestation of livedo racemosa.

Zahlreiche dermatologische Krankheiten sind auf angeborene oder erworbene Fehlregulationen des Immunsystems zuruckzufuhren. Immunmodulierende sowie immunsupprimierende Agenzien spielen daher eine bedeutende Rolle in der dermatologischen Therapie. Andererseits haben verschiedene Studien eine Unterversorgung von systemischen Therapieansatzen bei Erkrankungen wie der atopischen Dermatitis oder der Psoriasis vulgaris festgestellt. Unter Beachtung der Nebenwirkungen und Medikamenteninteraktionen stellen diese Medikamente jedoch sichere und effektive Behandlungsoptionen dar. Im Folgenden mochten wir daher eine Ubersicht uber die wichtigsten oralen Immunsuppressiva bzw. Immunmodulatoren, ihrer Wirkmechanismen, Indikationen und unerwunschten Arzneimittelwirkungen sowie Neuerungen und therapeutische Perspektiven geben. Intravenos oder subkutan zu verabreichende Biologika werden in diesem Review nicht berucksichtigt.

Ultraviolet B (UVB) radiation induces mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPDs), in epidermal keratinocytes (KC). To prevent skin carcinogenesis, these DNA photoproducts must be removed by nucleotide excision repair (NER) or apoptosis. Here we report that the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of UVB-induced CPDs in human HaCaT KC and skin from SKH-1 hairless mice. Subsequent RNA interference and inhibitor studies in KC revealed that AHR specifically suppresses global genome but not transcription-coupled NER. In further experiments, we found that the accelerated repair of CPDs in AHR-compromised KC depended on a modulation of the p27 tumor suppressor protein. Accordingly, p27 protein levels were increased in AHR-silenced KC and skin biopsies from AHR

Systemic treatment options for moderate to severe pediatric psoriasis are limited. Due to uncertainties regarding severe adverse events the majority of established systemic therapeutic drugs for adult psoriasis are not administered to children. In 2011 the TNF-α-inhibitor etanercept (Enbrel(®)) was approved as the first biological agent for the treatment of plaque psoriasis in pediatric patients. It is available for children from the age of 6 years and constitutes an effective and safe treatment option during childhood. Our report is based on the successful treatment of three boys with etanercept each at the age of 11 years.

Juvenile systemic lupus erythematosus (JSLE) is a rare multisystem autoimmune disease with broad heterogeneity of clinical manifestations. Diagnosing JSLE is often very challenging. This life-threatening, unpredictable, and relapsing disease, which may affect various organ systems, requires interdisciplinary, lifelong care. Here, we report the case of a 13-year-old patient with JSLE suffering from recurrent arthralgia, lupus panniculitis, and rashes that were successfully treated with hydroxychloroquine and prednisolone.

Bei erworbenen Angioodemen mit C1-Esterase-Inhibitor-Defizienz spielt die Bildung von Autoantikorpern bzw. der erhohte Verbrauch des Komplementfaktors C1q eine bedeutende pathogenetische Rolle. Sie sind zudem haufig mit lymphoproliferativen Erkrankungen assoziiert. Das gleichzeitige Auftreten von Quaddeln ist jedoch untypisch fur diese Art von Angioodemen. Hier prasentieren wir den Fall eines Patienten mit einer chronisch lymphatischen B-Zell-Leukamie, der neben einer chronisch spontanen Urtikaria zusatzlich ein erworbenes Angioodem mit C1-Inhibitor-Mangel entwickelte. Eine Behandlung mit systemischen Glukokortikosteroiden, Antihistaminika und Omalizumab konnte nur eine diskrete Linderung der Urtikaria bewirken. Das humane C1-Inhibitor-Konzentrat Berinert® und der Bradykinin-B2-Rezeptor-Antagonist Icatibant wurden zur Therapie des erworbenen Angioodems verabreicht, erzielten jedoch nur eine vorubergehende Besserung, sodass eine auf Rituximab basierende Polychemotherapie zur Behandlung der Grunderkrankung eingeleitet wurde. Hierunter konnte eine Komplettremission sowohl der Urtikaria als auch der Angioodeme erzielt werden.

Der BRAF-Inhibitor Vemurafenib ist seit 2011 fur die Therapie des inoperablen oder metastasierten Melanoms bei Vorliegen einer BRAF-V600-Mutation zugelassen. Unter Behandlung mit Vemurafenib werden verschiedene unerwunschte Arzneimittelwirkungen wie beispielsweise Arthralgien oder sekundare Hauttumoren beobachtet. Insbesondere kutane Toxizitaten konnen die Lebensqualitat der Patienten stark beeintrachtigen und somit die Therapieadharenz gefahrden. Hier prasentieren wir den Fall einer Patientin mit Vemurafenib-induziertem Arzneimittelexanthem. Im Lymphozytenaktivierungstest allerdings ergab sich kein Anhalt fur eine Typ-IV-Sensibilisierung gegen Vemurafenib. Vor diesem Hintergrund einer wahrscheinlich nichtallergisch bedingten Hypersensitivitatsreaktion wurde erfolgreich eine Desensibilisierungstherapie mit Vemurafenib durchgefuhrt und daraufhin die unkomplizierte Fortfuhrung der antineoplastischen Behandlung in der effektiven, empfohlenen Dosierung ermoglicht.

The intracellular location of nucleic acid sensors prevents recognition of extracellular self-DNA released by dying cells. However, on forming a complex with the endogenous antimicrobial peptide LL37, extracellular DNA is transported into endosomal compartments of plasmacytoid dendritic cells, leading to activation of Toll-like receptor-9 and induction of type I IFNs. Whether LL37 also transports self-DNA into nonplasmacytoid dendritic cells, leading to type I IFN production via other intracellular DNA receptors is unknown. Here we found that LL37 very efficiently transports self-DNA into monocytes, leading the production of type I IFNs in a Toll-like receptor-independent manner. This type I IFN induction was mediated by double-stranded B form DNA, regardless of its sequence, CpG content, or methylation status, and required signaling through the adaptor protein STING and TBK1 kinase, indicating the involvement of cytosolic DNA sensors. Thus, our study identifies a novel link between the antimicrobial peptides and type I IFN responses involving DNA-dependent activation of cytosolic sensors in monocytes.

Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death among women. Despite its immunogenicity, effective antitumor responses are limited, due, in part, to the presence of forkhead box protein 3–positive (Foxp3+) T regulatory (Treg) cells in the tumor microenvironment. However, the mechanisms that regulate the accumulation and the suppressive function of these Foxp3+ Treg cells are poorly understood. Here, we found that the majority of Foxp3+ Treg cells accumulating in the tumor microenvironment of EOCs belong to the subset of Foxp3+ Treg cells expressing inducible costimulator (ICOS). The expansion and the suppressive function of these cells were strictly dependent on ICOS-L costimulation provided by tumor plasmacytoid dendritic cells (pDC). Accordingly, ICOS+ Foxp3+ Treg cells were found to localize in close vicinity of tumor pDCs, and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS+ Foxp3+ Treg cells were found to be strong predictors for disease progression in patients with ovarian cancer, with ICOS+ Treg cell subset being a stronger predictor than total Foxp3+ Treg cells. These findings suggest an essential role for pDCs and ICOS-L in immunosuppression mediated by ICOS+ Foxp3+ Treg cells, leading to tumor progression in ovarian cancer. Cancer Res; 72(20); 5240–9. ©2012 AACR.

Cutaneous injury in mice drives transient TLR7- and TLR9-mediated production of type I interferon by plasmacytoid dendritic cells, which is required for re-epithelialization of the skin., Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-α/β)–producing cells that express intracellular toll-like receptor (TLR) 7 and TLR9 and recognize viral nucleic acids in the context of infections. We show that pDCs also have the ability to sense host-derived nucleic acids released in common skin wounds. pDCs were found to rapidly infiltrate both murine and human skin wounds and to transiently produce type I IFNs via TLR7- and TLR9-dependent recognition of nucleic acids. This process was critical for the induction of early inflammatory responses and reepithelization of injured skin. Cathelicidin peptides, which facilitate immune recognition of released nucleic acids by promoting their access to intracellular TLR compartments, were rapidly induced in skin wounds and were sufficient but not necessary to stimulate pDC activation and type I IFN production. These data uncover a new role of pDCs in sensing tissue damage and promoting wound repair at skin surfaces.

Clinical manifestations of lichenoid tissue reactions are heterogenous and include the cutaneous lupus erythematosus and lichen planus. Lichenoid tissue reactions are characterized by epidermal basal-cell damage and a variable subepithelial inflammatory infiltrate including cytotoxic T(H)1 cells and plasmacytoid dendritic cells. Here, we summarize the current knowledge of the role of chemokines in the pathophysiology of lichenoid tissue reactions and propose mechanisms by which recruitment and local activation of cytotoxic T(H)1 cells and plasmacytoid dendritic cells may result in initiation and amplification of lichen planus and cutaneous lupus erythematosus.

In recent years, our knowledge of the immunopathogenesis of chronic inflammatory skin diseases has increased significantly. Accumulating evidence indicates that the complex interaction of structural cells, in particular keratinocytes and endothelial cells, with skin-infiltrating leukocytes is key to our understanding of psoriasis. The recruitment of pathogenic leukocyte subsets into the skin represents a prerequisite for the initiation and maintenance of psoriasis vulgaris and is mediated by a complex chemokine and cytokine network. Results of recent studies associating cytokines and chemokines with a psoriatic phenotype are outlined herein, and their role as therapeutic targets in psoriasis is discussed in detail.

Background As clinical and histological features of allergic and irritant contact dermatitis share common characteristics, the differentiation between them in the preclinical and clinical evaluations of chemicals remains difficult. Objective To identify the differences in the underlying immunological mechanisms of chemical-induced allergic or irritant skin responses. Methods We systematically studied the involvement of chemokines in both diseases by quantitative real-time polymerase chain reaction in mice and humans. The cellular origin of relevant chemokines and receptors was determined using immunohistochemistry; functional relevance was demonstrated in vitro by transwell chemotaxis and in vivo by adoptive transfer experiments using a model of hapten-induced murine contact hypersensitivity. Results Independent of overall skin inflammation, chemical-induced allergic and irritant skin responses showed distinct molecular expression profiles. In particular, chemokine genes predominantly regulated by T-cell effector cytokines demonstrated differential upregulation in hapten-specific skin inflammation. Notably, the expression of CXCR3 ligands, such as CXCL9 ( Mig ) and CXCL10 ( IP-10 ), was upregulated in chemical-induced allergic skin responses when compared with irritant skin responses. Furthermore, we showed that inflammatory chemokines such as CXCL10 prime leukocytes to respond to CXCL12 ( SDF-1 ), increasing their recruitment both in vitro and in vivo . Conclusion We provide important insights into the molecular basis of chemical-induced allergic and irritant contact dermatitis, identify novel markers suitable for their differentiation, and demonstrate the cooperation of inflammatory and homeostatic chemokines in the recruitment of pathogenic leukocyte subsets. Clinical implications Molecular differences between both diseases represent the basis for new approaches to diagnostics and therapy.

Background The introduction of pegylated interferon (PEG-IFN)-α in the treatment of chronic hepatitis C has led to an increase in sustained virological response. Despite reduced immunogenicity of the pegylated form in comparison with native interferon (IFN)-α, a high frequency of adverse cutaneous reactions has been reported with pegylated IFN-α. Here, we aimed to investigate the immunological mechanisms underlying pegylated IFN-α-induced drug eruptions. Methods Hepatitis C patients suffering from drug eruptions in association with administration of pegylated interferons were enrolled in the study (n = 22). Subjects were tested for sensitivity to pegylated IFN-α2a, pegylated IFN-α2b, or ribavirin using intradermal, scratch, and/or patch tests, as well as lymphocyte activation tests (LATs). Skin biopsies obtained from pegylated IFN-α-associated exanthemas, as well as from localized inflammatory skin reactions at pegylated IFN-α injection sites, were analyzed for the expression of relevant chemokines by quantitative real-time PCR and immunohistochemistry. Results A subset of patients suffering from pegylated IFN-α-associated exanthemas displayed positive intradermal tests to PEG-IFNs but not to conventional IFN (11/22). In selected patients, this observation correlated with the presence of pegylated IFN-specific T cells (3/11). Chemokine profiles of inflammatory skin reactions at the injection sites reflected an IFN-α-signature, whereas lesional skin of exanthemas showed induction of TH2-associated chemokines. Conclusions Our results indicate that specific sensitizations are one cause of exanthemas under therapy with PEG-IFNs. Clinical proof-of-concept analyses demonstrate that affected patients may benefit from a switch to conventional, nonpegylated drugs, enabling IFN-α therapy continuation without drug-associated skin eruptions.