Psoriasis (Pso) is a chronic inflammatory skin disease driven by T helper 17 (TH17) cells, with several clinical subtypes. While self-reactive immune responses have been observed, the role of autoantigens in Pso remains unclear. Using immunopeptidomics, we identified serpin family B member 3 (SERPINB3) and SERPINB4 as candidate autoantigens in Pso skin. In a mouse model, the SERPINB3 ortholog Serpinb3b enhanced inflammation, promoted tissue-resident memory T cells, and skewed immunity toward a TH2 phenotype. In humans, SERPINB3 reactivity was specifically associated with "eczematized psoriasis" (EczPso), a subtype marked by TH2/TH17 immune signatures. SERPINB3 protein was enriched in EczPso lesions and highly secreted by keratinocytes under combined TH2/TH17 stimulation. Lesional T cells from EczPso-but not from eczema or classical plaque Pso-proliferated in response to SERPINB3 and induced EczPso-like features in a skin model. Our findings identify SERPINB3 as an autoantigen driving a distinct Pso subtype, supporting more precise diagnosis and therapy.

Vitiligo, a chronic depigmenting disorder affecting 1–2

We appreciate the interest and reflections of Urbina and Benavides on our recent article published in Diagnostics and presentation of their two new patients [...]

BACKGROUND:Mastocytosis is characterized by an accumulation of clonal mast cells (MCs) in tissues such as the skin. Skin lesions in mastocytosis may be clinically subtle or heterogeneous, and giving the correct diagnosis can be difficult. METHODS:This study compiles personal experiences together with relevant literature, discussing possible obstacles encountered in diagnosing skin involvement in mastocytosis and cutaneous mastocytosis (CM). RESULTS:The nomenclature of the term "CM" is ambiguous. The WHO classification defines CM as mastocytosis solely present in the skin. However, the term is also used as a morphological description, e.g., in maculopapular cutaneous mastocytosis (MPCM). This is often seen in systemic, as well as cutaneous, mastocytosis. Typical CM manifestations (MPCM), including mastocytoma or diffuse cutaneous mastocytosis (DCM), all share a positive Darier's sign, and can thus be clinically recognized. Nevertheless, distinguishing monomorphic versus polymorphic MPCM may be challenging, even for experienced dermatologists. Less typical clinical presentations, such as MPCM with telangiectatic erythemas (formerly called telangiectasia macularis eruptiva perstans), confluent, nodular or xanthelasmoid variants may require a skin biopsy for histopathological confirmation. Because MC numbers in CM have a large overlap to those in healthy and inflamed skin, detailed histopathological criteria to diagnose mastocytosis in MPCM are needed and have been proposed. D816V KIT mutational analysis in tissue is helpful for confirming the diagnosis. Biomarkers allow the prediction of the course of CM into regression or evolution of the disease. Further diagnostic measures should screen for concomitant diseases, such as malignant melanoma, and for systemic involvement. CONCLUSIONS:Whereas in typical cases the diagnosis of CM may be uncomplicated, less typical manifestations may require specific investigations for making the diagnosis and predicting its course.

Immune checkpoint inhibitors (ICIs) enhance anticancer immunity by releasing repressive signals into tumor microenvironments (TMEs). To be effective, ICIs require preexisting immunologically "hot" niches for tumor antigen presentation and lymphocyte recruitment. How the mutational landscape of cancer cells shapes these immunological niches remains poorly defined. We found in human and murine colorectal cancer (CRC) models that the superior antitumor immune response of mismatch repair (MMR)-deficient CRC required tumor cell-intrinsic activation of cGAS-STING signaling triggered by genomic instability. Subsequently, we synthetically enforced STING signaling in CRC cells with intact MMR signaling using constitutively active STING variants. Even in MMR-proficient CRC, genetically encoded gain-of-function STING was sufficient to induce cancer cell-intrinsic interferon signaling, local activation of antigen-presenting cells, recruitment of effector lymphocytes, and sensitization of previously "cold" TMEs to ICI therapy in vivo. Thus, our results introduce a rational strategy for modulating cancer cell-intrinsic programs via engineered STING enforcement to sensitize resistant tumors to ICI responsiveness.

Psoriasis is a chronic inflammatory skin disease arising from poorly defined pathological cross-talk between keratinocytes and the immune system. BCL10 (B cell lymphoma/leukemia 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) are ubiquitously expressed inflammatory signaling proteins that can interact with the psoriasis susceptibility factor CARD14, but their functions in psoriasis are insufficiently understood. We report that although keratinocyte-intrinsic BCL10/MALT1 deletions completely rescue inflammatory skin pathology triggered by germline Card14 gain-of-function mutation in mice, the BCL10/MALT1 signalosome is unexpectedly not involved in the CARD14-dependent interleukin-17 receptor (IL-17R) proximal pathway. Instead, it plays a more pleiotropic role by amplifying keratinocyte responses to a series of inflammatory cytokines, including IL-17A, IL-1β, and TNF. Moreover, selective keratinocyte-intrinsic activation of BCL10/MALT1 signaling with an artificial engager molecule is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation, and aberrant BCL10/MALT1 activity is frequently detected in the skin of human sporadic psoriasis. Together, these results establish that BCL10/MALT1 signalosomes can act as initiators and crucial amplifiers of psoriatic skin inflammation and indicate a critical function for this complex in sporadic psoriasis.

Introduction The pathogenesis of atopic diseases is highly complex, and the exact mechanisms leading to atopic dermatitis (AD) onset in infants remain mostly enigmatic. In addition to an interdependent network of components of skin development in young age and skin barrier dysfunction underlying AD development that is only partially understood, a complex interplay between environmental factors and lifestyle habits with skin barrier and immune dysregulation is suspected to contribute to AD onset. This study aims to comprehensively evaluate individual microbiome and immune responses in the context of environmental determinants related the risk of developing AD in the first 4 years of a child's life. Methods and analyses The 'Munich Atopic Prediction Study' is a comprehensive clinical and biological investigation of a prospective birth cohort from Munich, Germany. Information on pregnancy, child development, environmental factors, parental exposures to potential allergens and acute or chronic diseases of children and parents are collected by questionnaires together with a meticulous clinical examination by trained dermatologists focusing on allergies, skin health, and in particular signs of AD at 2 months after birth and then every 6 months. In addition, skin barrier functions are assessed through cutometry, corneometry and transepidermal water loss at every visit. These measurements are completed with allergy diagnostics and extensive microbiome analyses from stool and skin swabs as well as transcriptome analyses using skin microbiopsies.The aim is to assess the relevance of different known and yet unknown risk factors of AD onset and exacerbations in infants and to identify possible accessible and robust biomarkers. Ethics and dissemination The study is approved by the Ethical Committee of the Medical Faculty of the Technical University of Munich (reference 334/16S). All relevant study results will be presented at national and international conferences and in peer-reviewed journals.

Contact DermatitisVolume 83, Issue 3 p. 241-242 CONTACT POINTOpen Access Severe photoallergy to systemic dronedarone (Multaq) Rand Al-Jarrah, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Contribution: Writing - original draftSearch for more papers by this authorAnnette Blasini, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Contribution: ​InvestigationSearch for more papers by this authorZsuzsanna Kurgyis, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Contribution: ​InvestigationSearch for more papers by this authorKnut Brockow, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Contribution: SupervisionSearch for more papers by this authorBernadette Eberlein, Corresponding Author bernadette.eberlein@tum.de orcid.org/0000-0003-4509-6491 Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Correspondence Bernadette Eberlein, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, Biedersteiner Str. 29, D-80802 München, Germany. Email: bernadette.eberlein@tum.de Contribution: Conceptualization, ​Investigation, Methodology, Writing - review & editingSearch for more papers by this author Rand Al-Jarrah, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Contribution: Writing - original draftSearch for more papers by this authorAnnette Blasini, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Contribution: ​InvestigationSearch for more papers by this authorZsuzsanna Kurgyis, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Contribution: ​InvestigationSearch for more papers by this authorKnut Brockow, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Contribution: SupervisionSearch for more papers by this authorBernadette Eberlein, Corresponding Author bernadette.eberlein@tum.de orcid.org/0000-0003-4509-6491 Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, München, Germany Correspondence Bernadette Eberlein, Department of Dermatology and Allergy Biederstein, School of Medicine, Technische Universität München, Biedersteiner Str. 29, D-80802 München, Germany. Email: bernadette.eberlein@tum.de Contribution: Conceptualization, ​Investigation, Methodology, Writing - review & editingSearch for more papers by this author First published: 27 April 2020 https://doi.org/10.1111/cod.13577Citations: 2AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Dronedarone, a non-iodinated congener of amiodarone, is a class III antiarrhythmic agent, approved by the U.S. Food and Drug Administration (FDA) in 2009. The most common side effects of dronedarone are diarrhea, nausea, and abnormality of liver function.1 Compared to amiodarone, photosensitivity is a rare adverse reaction and only a few case reports exist.2-4 Here we describe the first case of a severe photoallergic drug reaction with dronedarone use. CASE REPORT In February 2019, cardiologists started a therapy with dronedarone 400 mg (Multaq) twice daily orally for rhythm control along with apixaban (Eliquis) in a 64-year-old woman. Four weeks later she noticed redness on her cheeks after sitting in the sun for 1.5 hours. The next day she took a long walk in the sun; overnight she developed redness and swelling of her face, neck, and backs of her hands with itching, worsening during the following day. Dronedarone was discontinued and she was treated with a steroid ointment and antihistamines. Two days later, pronounced edema in the previously affected areas developed. On laboratory investigations, liver enzyme levels were four times higher than the normal limit. She was given oral steroids. Because healing was prolonged, Eliquis was additionally discontinued. The skin lesions remained for another 3 to 4 weeks and spread to the upper arms, neck, and décolleté (Figure S1). Complete healing was achieved after 6 weeks, with an increased sensitivity to sunlight remaining throughout the summer. Photopatch testing with Multaq (crushed film-coated tablets in pet., Sanovi-Aventis, Frankfurt, Germany) "as is" was positive (++) 2 and 3days after irradiation with 5J/cm2 UVA (FigureS2). Eliquis (crushed film-coated tablets in pet., Bristol Myers Squibb, New York City, New York) "as is" was negative. Patch tests with the two drugs and photopatch tests using the German and European baseline series were negative except for fragrance mix 8.0% in the non-irradiated area. DISCUSSION Phototoxicity is a common side effect of amiodarone, but with dronedarone, a structural analogue of amiodarone, photosensitivity and skin discoloration has occurred in only 0.7% patients compared to 0.3% in the placebo group.1 Experimental photosensitization studies using THP-1 cells and interleukin 8 (IL-8) as biomarkers showed that dronedarone is likely to cause skin photosensitization,5 but only three clinical cases of phototoxicity to dronedarone have been reported. Complete healing after discontinuation or photoprotective measures occurred within a few weeks.2-4 In contrast, our patient experienced a prolonged period of illness with spreading over the primarily affected areas. A skin biopsy was not obtained, but together with the positive photopatch test we diagnosed a photoallergic drug reaction to Multaq. To our knowledge this is the first reported case of dronedarone-induced photoallergy in the literature. AUTHOR CONTRIBUTIONS Bernadette Eberlein: Conceptualization; investigation; methodology; writing-review and editing. Rand Al-Jarrah:Writing-original draft. Annette Blasini: Investigation. Zsuzsanna Kurgyis: Investigation. Knut Brockow: Supervision. Supporting Information Filename Description cod13577-sup-0001-FigureS1.docxWord 2007 document , 4 MB Figure S1: Clinical appearance of photoallergic drug reaction caused by Multaq. (The photos were kindly provided by the patient.) cod13577-sup-0002-FigureS2.docxWord 2007 document , 26.2 MB Figure S2: Positive result of photopatch test with Multaq 3 days after irradiation with 5 J/cm2 UVA Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007; 357(10): 987- 999. CrossrefCASPubMedWeb of Science®Google Scholar 2Ladizinski B, Elpern DJ. Dronaderone-induced phototoxicity. J Drugs Dermatol. 2013; 12(8): 946- 947. PubMedWeb of Science®Google Scholar 3Kuo S, Menon K, Kundu RV. Photosensitivity reaction from dronedarone for atrial fibrillation. Cutis. 2014; 94(5): E10- E11. PubMedGoogle Scholar 4Datar P, Kafle P, Schmidt FM, Bhattarai B, Mukhtar O. Dronedarone-induced phototoxicity in a patient with atrial fibrillation. Cureus. 2019; 11:e5731(9). https://doi.org/10.7759/cureus.5731PubMedWeb of Science®Google Scholar 5Marcolino AIP, Macedo LB, Nogueira-Librelotto DR, Vinardell MP, Rolim CMB, Mitjansc M. Comparative evaluation of the hepatotoxicity, phototoxicity and photosensitizing potential of dronedarone hydrochloride and its cyclodextrin-based inclusion complexes. Photochem Photobiol Sci. 2019; 18(6): 1565- 1575. CrossrefCASPubMedWeb of Science®Google Scholar Citing Literature Volume83, Issue3September 2020Pages 241-242 ReferencesRelatedInformation

The detection of microbes and damaged host cells by the innate immune system is essential for host defense against infection and tissue homeostasis. However, how distinct positive and negative regulatory signals from immune receptors are integrated to tailor specific responses in complex scenarios remains largely undefined. Clec12A is a myeloid cell-expressed inhibitory C-type lectin receptor that can sense cell death under sterile conditions. Clec12A detects uric acid crystals and limits proinflammatory pathways by counteracting the cell-activating spleen tyrosine kinase (Syk). Here, we surprisingly find that Clec12A additionally amplifies type I IFN (IFN-I) responses in vivo and in vitro. Using retinoic acid-inducible gene I (RIG-I) signaling as a model, we demonstrate that monosodium urate (MSU) crystal sensing by Clec12A enhances cytosolic RNA-induced IFN-I production and the subsequent induction of IFN-I-stimulated genes. Mechanistically, Clec12A engages Src kinase to positively regulate the TBK1-IRF3 signaling module. Consistently, Clec12A-deficient mice exhibit reduced IFN-I responses upon lymphocytic choriomeningitis virus (LCMV) infection, which affects the outcomes of these animals in acute and chronic virus infection models. Thus, our results uncover a previously unrecognized connection between an MSU crystal-sensing receptor and the IFN-I response, and they illustrate how the sensing of extracellular damage-associated molecular patterns (DAMPs) can shape the immune response.

Nature doi:10.1038/nature24649 (2017) Owing to a typesetter error, Extended Data Fig. 5 of this Letter was corrupted, with part of the histology image from panel c obscuring the flow cytometry data plots in panel a. This has been corrected online. The original Extended Data Fig. 5 is provided as Supplementary Information to this Erratum.

Melanoma often recurs in patients after the removal of the primary tumor, suggesting the presence of recurrent tumor-initiating cells that are undetectable using standard diagnostic methods. As cell fusion has been implicated to facilitate the alteration of a cell’s phenotype, we hypothesized that cells in the peritumoral stroma having a stromal phenotype that initiate recurrent tumors might originate from the fusion of tumor and stromal cells. Here, we show that in patients with BRAFV600E melanoma, melanoma antigen recognized by T-cells (MART1)-negative peritumoral stromal cells express BRAFV600E protein. To confirm the presence of the oncogene at the genetic level, peritumoral stromal cells were microdissected and screened for the presence of BRAFV600E with a mutation-specific polymerase chain reaction. Interestingly, cells carrying the BRAFV600E mutation were not only found among cells surrounding the primary tumor but were also present in the stroma of melanoma metastases as well as in a histologically tumor-free re-excision sample from a patient who subsequently developed a local recurrence. We did not detect any BRAFV600E mutation or protein in the peritumoral stroma of BRAFWT melanoma. Therefore, our results suggest that peritumoral stromal cells contain melanoma-derived oncogenic information, potentially as a result of cell fusion. These hybrid cells display the phenotype of stromal cells and are therefore undetectable using routine histological assessments. Our results highlight the importance of genetic analyses and the application of mutation-specific antibodies in the identification of potentially recurrent-tumor-initiating cells, which may help better predict patient survival and disease outcome.

After the removal of primary cutaneous melanoma some patients develop local recurrences, even after having histologically tumor-free re-excision. A potential explanation behind this phenomenon is that tumor cells switch their phenotype, making their recognition via standard histopathological assessments extremely difficult. Tumor-stromal cell fusion has been proposed as a potential mechanism for tumor cells to acquire mesenchymal traits; therefore, we hypothesized that melanoma cells could acquire fibroblast- and macrophage-like phenotypes via cell fusion. We show that melanoma cells spontaneously fuse with human dermal fibroblasts and human peripheral blood monocytes in vitro. The hybrid cells’ nuclei contain chromosomes from both parental cells and are indistinguishable from the parental fibroblasts or macrophages based on their morphology and immunophenotype, as they could lose the melanoma specific MART1 marker, but express the fibroblast marker smooth muscle actin or the macrophage marker CD68. Our results suggest that, by spontaneous cell fusion in vitro, tumor cells can adopt the morphology and immunophenotype of stromal cells while still carrying oncogenic, tumor-derived genetic information. Therefore, melanoma–stromal cell fusion might play a role in missing tumor cells by routine histopathological assessments.

Mitochondrial apoptosis is controlled by proteins of the B-cell lymphoma 2 (Bcl-2) family. Pro-apoptotic members of this family, known as BH3-only proteins, initiate activation of the effectors Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), which is counteracted by anti-apoptotic family members. How the interactions of Bcl-2 proteins regulate cell death is still not entirely clear. Here, we show that in the absence of extrinsic apoptotic stimuli Bak activates without detectable contribution from BH3-only proteins, and cell survival depends on anti-apoptotic Bcl-2 molecules. All anti-apoptotic Bcl-2 proteins were targeted via RNA interference alone or in combinations of two in primary human fibroblasts. Simultaneous targeting of B-cell lymphoma-extra large and myeloid cell leukemia sequence 1 led to apoptosis in several cell types. Apoptosis depended on Bak whereas Bax was dispensable. Activator BH3-only proteins were not required for apoptosis induction as apoptosis was unaltered in the absence of all BH3-only proteins known to activate Bax or Bak directly, Bcl-2-interacting mediator of cell death, BH3-interacting domain death agonist and p53-upregulated modulator of apoptosis. These findings argue for auto-activation of Bak in the absence of anti-apoptotic Bcl-2 proteins and provide evidence of profound differences in the activation of Bax and Bak.

Dermal or transdermal medication may lead to irritant contact dermatitis. However, little information is available on the irritant effect of surfactants which are applied in topical formulations. Our aim was to examine the irritant effect of the most frequent compounds in topical products. A murine model was applied. The following compounds were examined: sodium lauryl sulphate (SLS), polyethoxylated (40EO) hydrogenated castor oil and sucrose laurate. SLS led to severe erythema, increase in transepidermal water loss (TEWL) and induced necrosis and accumulation of neutrophylic granulocytes and lymphocytes. Exposure to sucrose laurate resulted in an elevation of TEWL, but histology did not reveal impairment of the skin structure. Application of polyethoxylated (40EO) hydrogenated castor oil was not accompanied by tissue damage. Special attention should be paid to the irritant effect of SLS. Polyethoxylated (40EO) hydrogenated castor oil seems to be a non-irritant agent and sucrose laurate is also a promising candidate for application in topical preparations.