NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency.

Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.

Trial of Spesolimab for Generalized Pustular Psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares. METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity. RESULTS: A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab. CONCLUSIONS: In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).

Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses.

Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4(+) T cell effector function.

Device-based physical therapies in chronic pruritus: A narrative review.

Chronic pruritus is a highly prevalent disease associated with high psychosocial and economic burdens. In addition to pharmacological treatments, device-based physical therapies also offer antipruritic effects. Phototherapy, laser, electrical neurostimulation technologies, acupuncture, cryotherapy, and cold atmospheric plasma are, in part, still experimental but emerging treatment options that augment our repertoire to treat patients with chronic pruritus. In this narrative review, we provided an overview of these physical modalities and their role in itch management.

Artificial intelligence-driven skin aging simulation as a novel skin cancer prevention.

INTRODUCTION: Skin cancer, a prevalent cancer type among fair-skinned patients globally, poses a relevant public health concern due to rising incidence rates. Ultraviolet (UV) radiation poses a major risk factor for skin cancer. However intentional tanning associated with sunburns remains a common practice, notably among female adults Appropriate prevention campaigns targeting children and adolescents are needed to improve sun-protection behavior particularly in these age groups. The aim of our study is to investigate if an AI-based simulation of facial skin aging can enhance sun-protection behavior in female adults. METHODS: In this single-center prospective observational pilot study at Department of Dermatology at the University Hospital of Basel, we took photographs of healthy young females' faces with a VISIA-CR camera (Canfield Scientific Inc., Parsippany, New Jersey, Version 8.2) between February to March 2021. Digital images were performed in three angles (straight, left 45°, right 45°). All participants received an AI-based simulation of their facial skin with continuous aging to 80 years. A newly created anonymous questionnaire capturing participants' sociodemographic data and also tanning and sun-protection behavior was completed in pre- and post-aging simulation. To observe long-term effects, a 2-year follow-up was conducted between March to April 2023. RESULTS: The 60 participants (mean age 23.6±2.5 years) evaluated the importance of sun-protection significantly higher after skin aging simulation with VISIA-CR camera (p<0.0001; 95%-CI:8.2-8.8). Post-intervention, 91.7% (55/60) of the females were motivated to reduce UV exposure and to intensify UV protection in the future since the individual UV-dependent risk was perceived significantly higher (p<0.001; 95%-CI: 5.9-6.7). At two-year follow-up, 96% (24/25) indicated persistent effort reducing UV exposure. The preference for SPF50+ sunscreen increased to 46.7% (28/65) directly after the skin-aging simulation and continued to rise up to 60.0% (15/25) after two years. CONCLUSIONS: Our data emphasize the potential of AI-assisted photo-aging interventions to enhance motivation for UV protection in the short and the long term We encourage that different age and gender groups are addressed in a personalized, generation-specific manner with the appropriate media and by considering the Hawthorne effect. Campaigns with visual AI support can improve the intent of cancer-preventative behavior.

The impact of phototherapy on itch intensity and itch-related quality of life amongst different skin diseases, skin phototypes and genders - A prospective study with 102 patients.

BACKGROUND: Phototherapy is a mainstay to treat itchy conditions. However, only little is known about differences in the antipruritic effect of phototherapy amongst different skin conditions, phototypes and genders. METHODS: In this prospective, single-center study, we analyzed the effect of phototherapy on itch intensity and itch-related quality of life amongst these subgroups after a treatment duration of 4 weeks, while on-demand treatment with topical corticosteroids, topical calcineurin inhibitors and/or antihistamines was allowed. RESULTS: Of 102 patients (age 53.0 ± 18.7, 56 females [54.9%]), 72 (78.3%) reported a significant reduction of itch intensity by Δ -2.76 on a 0-10 Numerical Rating Scale (NRS), p = <.001, 95% CI [2.2; 3.3] paralleled by a significant improvement of itch-related quality of life as measured by the German version of the ItchyQoL by Δ 7.3, p = <.001, 95% CI [4.4; 11.6]. The best improvement of itch intensity and itch-related QoL was reported by patients with pruritus on non-diseased skin (ΔNRS -3.5; Δ 9.7 Ger-ItchyQoL points), followed by patients with atopic dermatitis and psoriasis. We found no statistical differences in the response to phototherapy amongst Fitzpatrick phototypes I-VI. Women had higher itch intensities at baseline but itch-related quality of life impairment at baseline and phototherapy treatment response did not significantly differ between genders. CONCLUSION: Phototherapy appears to induce a meaningful itch reduction in various itchy skin conditions, all phototypes and both genders within 4 weeks that directly translates into improvement of itch-related quality of life.

Variations of skin thermal diffusivity on different skin regions.

BACKGROUND AND OBJECTIVE: Skin thermal diffusivity plays a crucial role in various applications, including laser therapy and cryogenic skin cooling.This study investigates the correlation between skin thermal diffusivity and two important skin parameters, melanin content and erythema, in a cohort of 102 participants. METHODS: An in-house developed device based on transient temperature measurement was used to assess thermal diffusivity at different body locations. Melanin content and erythema were measured using a colorimeter. Statistical analysis was performed to examine potential correlations. RESULTS: The results showed that the measured thermal diffusivity values were consistent with previous reports, with variations observed among subjects. No significant correlation was found between thermal diffusivity and melanin content or erythema. This suggests that other factors, such as skin hydration or epidermis thickness, may have a more dominant influence on skin thermal properties. CONLCUSION: This research provides valuable insights into the complex interplay between skin thermal properties and physiological parameters, with potential implications for cosmetic and clinical dermatology applications.

AI-powered visual diagnosis of vulvar lichen sclerosus: A pilot study.

BACKGROUND: Vulvar lichen sclerosus (VLS) is a chronic inflammatory skin condition associated with significant impairment of quality of life and potential risk of malignant transformation. However, diagnosis of VLS is often delayed due to its variable clinical presentation and shame-related late consultation. Machine learning (ML)-trained image recognition software could potentially facilitate early diagnosis of VLS. OBJECTIVE: To develop a ML-trained image-based model for the detection of VLS. METHODS: Images of both VLS and non-VLS anogenital skin were collected, anonymized, and selected. In the VLS images, 10 typical skin signs (whitening, hyperkeratosis, purpura/ecchymosis, erosion/ulcers/excoriation, erythema, labial fusion, narrowing of the introitus, labia minora resorption, posterior commissure (fourchette) band formation and atrophic shiny skin) were manually labelled. A deep convolutional neural network was built using the training set as input data and then evaluated using the test set, where the developed algorithm was run three times and the results were then averaged. RESULTS: A total of 684 VLS images and 403 non-VLS images (70% healthy vulva and 30% with other vulvar diseases) were included after the selection process. A deep learning algorithm was developed by training on 775 images (469 VLS and 306 non-VLS) and testing on 312 images (215 VLS and 97 non-VLS). This algorithm performed accurately in discriminating between VLS and non-VLS cases (including healthy individuals and non-VLS dermatoses), with mean values of 0.94, 0.99 and 0.95 for recall, precision and accuracy, respectively. CONCLUSION: This pilot project demonstrated that our image-based deep learning model can effectively discriminate between VLS and non-VLS skin, representing a promising tool for future use by clinicians and possibly patients. However, prospective studies are needed to validate the applicability and accuracy of our model in a real-world setting.

Patient and dermatologists' perspectives on augmented intelligence for melanoma screening: A prospective study.

BACKGROUND: Artificial intelligence (AI) shows promising potential to enhance human decision-making as synergistic augmented intelligence (AuI), but requires critical evaluation for skin cancer screening in a real-world setting. OBJECTIVES: To investigate the perspectives of patients and dermatologists after skin cancer screening by human, artificial and augmented intelligence. METHODS: A prospective comparative cohort study conducted at the University Hospital Basel included 205 patients (at high-risk of developing melanoma, with resected or advanced disease) and 8 dermatologists. Patients underwent skin cancer screening by a dermatologist with subsequent 2D and 3D total-body photography (TBP). Any suspicious and all melanocytic skin lesions ≥3 mm were imaged with digital dermoscopes and classified by corresponding convolutional neural networks (CNNs). Excisions were performed based on dermatologist's melanoma suspicion, study-defined elevated CNN risk-scores and/or melanoma suspicion by AuI. Subsequently, all patients and dermatologists were surveyed about their experience using questionnaires, including quantification of patient's safety sense following different examinations (subjective safety score (SSS): 0-10). RESULTS: Most patients believed AI could improve diagnostic performance (95.5%, n = 192/201). In total, 83.4% preferred AuI-based skin cancer screening compared to examination by AI or dermatologist alone (3D-TBP: 61.3%; 2D-TBP: 22.1%, n = 199). Regarding SSS, AuI induced a significantly higher feeling of safety than AI (mean-SSS (mSSS): 9.5 vs. 7.7, p < 0.0001) or dermatologist screening alone (mSSS: 9.5 vs. 9.1, p = 0.001). Most dermatologists expressed high trust in AI examination results (3D-TBP: 90.2%; 2D-TBP: 96.1%, n = 205). In 68.3% of the examinations, dermatologists felt that diagnostic accuracy improved through additional AI-assessment (n = 140/205). Especially beginners (<2 years' dermoscopic experience; 61.8%, n = 94/152) felt AI facilitated their clinical work compared to experts (>5 years' dermoscopic experience; 20.9%, n = 9/43). Contrarily, in divergent risk assessments, only 1.5% of dermatologists trusted a benign CNN-classification more than personal malignancy suspicion (n = 3/205). CONCLUSIONS: While patients already prefer AuI with 3D-TBP for melanoma recognition, dermatologists continue to rely largely on their own decision-making despite high confidence in AI-results. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04605822).

Position statement of the EADV Artificial Intelligence (AI) Task Force on AI-assisted smartphone apps and web-based services for skin disease.

BACKGROUND: As the use of smartphones continues to surge globally, mobile applications (apps) have become a powerful tool for healthcare engagement. Prominent among these are dermatology apps powered by Artificial Intelligence (AI), which provide immediate diagnostic guidance and educational resources for skin diseases, including skin cancer. OBJECTIVE: This article, authored by the EADV AI Task Force, seeks to offer insights and recommendations for the present and future deployment of AI-assisted smartphone applications (apps) and web-based services for skin diseases with emphasis on skin cancer detection. METHODS: An initial position statement was drafted on a comprehensive literature review, which was subsequently refined through two rounds of digital discussions and meticulous feedback by the EADV AI Task Force, ensuring its accuracy, clarity and relevance. RESULTS: Eight key considerations were identified, including risks associated with inaccuracy and improper user education, a decline in professional skills, the influence of non-medical commercial interests, data security, direct and indirect costs, regulatory approval and the necessity of multidisciplinary implementation. Following these considerations, three main recommendations were formulated: (1) to ensure user trust, app developers should prioritize transparency in data quality, accuracy, intended use, privacy and costs; (2) Apps and web-based services should ensure a uniform user experience for diverse groups of patients; (3) European authorities should adopt a rigorous and consistent regulatory framework for dermatology apps to ensure their safety and accuracy for users. CONCLUSIONS: The utilisation of AI-assisted smartphone apps and web-based services in diagnosing and treating skin diseases has the potential to greatly benefit patients in their dermatology journeys. By prioritising innovation, fostering collaboration and implementing effective regulations, we can ensure the successful integration of these apps into clinical practice.

Sex differences in adverse events from systemic treatments for psoriasis: A decade of insights from the Swiss Psoriasis Registry (SDNTT).

BACKGROUND: Psoriasis is a disease that often requires prolonged systemic treatment. It is important to determine the safety of available therapies. There is currently little insight into sex-specific differences in the safety of systemic psoriasis therapies. OBJECTIVES: To examine the real-world, long-term safety of systemic psoriasis therapies with sex stratification in drug-related adverse events (ADRs). METHODS: Ten-year data from adults with moderate-to-severe psoriasis requiring systemic treatment (conventional systemic therapies [CST], biologics) were obtained from the Swiss psoriasis registry (SDNTT). ADRs were categorized according to the international terminology Medical Dictionary for Regulatory Activities (MedDRA). Safety was assessed by calculating event rates per 100 patient-years (PY). We used descriptive statistics for patient and disease characteristics, and binomial and t-tests to compare treatment groups and sex. RESULTS: In total, 791 patients (290 females) were included with a mean age of 46 years. 358 (45%) received CSTs and 433 (55%) biologics; both groups had similar baseline characteristics except for more joint involvement in patients using biologics (26.86% vs. 14.8%, p < 0.0001). CSTs were associated with a 2.2-fold higher ADR rate (40.43/100 PY vs. 18.22/100 PY, p < 0.0001) and an 8.0-fold higher drug-related discontinuation rate than biologics (0.16/PY vs. 0.02/PY, p < 0.0001). Trends showed non-significant higher serious adverse event rates per 100 PY for biologics (8.19, CI 6.87-9.68) compared to CSTs (7.08, CI 5.39-9.13) (p = 0.3922). Sex stratification revealed a significantly higher overall ADR rate for all treatments in females (1.8-fold for CSTs [57.30/100 PY vs. 31.69/100 PY] and 2.0-fold for biologics [27.36/100 PY vs. 13.9/100 PY], p < 0.0001), and drug-related discontinuation rates for most CSTs in females. CONCLUSION: Females were associated with a significantly higher rate of ADRs and drug-related discontinuation rates. Sex stratification should be taken into consideration when designing studies in the patient-tailored management of psoriasis.

Dermatology teaching for undergraduate medical students in clinical routine - a structured four-week curriculum.

BACKGROUND: Dermatology teaching is fundamental for the promotion of young colleagues in our specialty. However, traditional teaching methods are being scrutinized by students of the 'Generation Y and Z', which can pose new challenges for teaching institutions. We therefore aimed to assess the motivational impact and reception of a newly created four-week curriculum containing modernized teaching methods integrated into clinical routine. METHODS: In this single-center study, 67 medical students completed this curriculum composed of weekly learning objectives including knowledge of morphological terms, 10 common dermatoses, communication and presentation skills. The participants provided information on their level of interest in dermatology each week as well as positive and negative aspects of the curriculum. RESULTS: During the curriculum a significant median increase in interest in dermatology was reported with no differences between the genders. Low initial interest could be improved, high initial interest maintained. Participants with an interest in scientific work (20.9%) were more motivated during the curriculum. The variety, quality of teaching and structure were the main aspects rated positively. Suggestions for improvement included the need for more teaching by senior doctors, transfer of responsibility, and a working environment updated to the latest technology standards. CONCLUSION: The presented curriculum was well received by the participants and allowed to better define learning preferences of new generations which can be helpful to modernize traditional teaching methods. Interest in scientific work could be a factor to identify students with a particularly strong interest in dermatology.

Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.

BACKGROUND: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVES: This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed. RESULTS: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4+ T cells and low TCR-Vα7.2+ T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSIONS: This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

Immunologic and Genetic Contributors to CD46-Dependent Immune Dysregulation.

Mutations in CD46 predispose to atypical hemolytic uremic syndrome (aHUS) with low penetrance. Factors driving immune-dysregulatory disease in individual mutation carriers have remained ill-understood. In addition to its role as a negative regulator of the complement system, CD46 modifies T cell-intrinsic metabolic adaptation and cytokine production. Comparative immunologic analysis of diseased vs. healthy CD46 mutation carriers has not been performed in detail yet. In this study, we comprehensively analyzed clinical, molecular, immune-phenotypic, cytokine secretion, immune-metabolic, and genetic profiles in healthy vs. diseased individuals carrying a rare, heterozygous CD46 mutation identified within a large single family. Five out of six studied individuals carried a CD46 gene splice-site mutation causing an in-frame deletion of 21 base pairs. One child suffered from aHUS and his paternal uncle manifested with adult-onset systemic lupus erythematosus (SLE). Three mutation carriers had no clinical evidence of CD46-related disease to date. CD4+ T cell-intrinsic CD46 expression was uniformly 50%-reduced but was comparable in diseased vs. healthy mutation carriers. Reconstitution experiments defined the 21-base pair-deleted CD46 variant as intracellularly-but not surface-expressed and haploinsufficient. Both healthy and diseased mutation carriers displayed reduced CD46-dependent T cell mitochondrial adaptation. Diseased mutation carriers had lower peripheral regulatory T cell (Treg) frequencies and carried potentially epistatic, private rare variants in other inborn errors of immunity (IEI)-associated proinflammatory genes, not found in healthy mutation carriers. In conclusion, low Treg and rare non-CD46 immune-gene variants may contribute to clinically manifest CD46 haploinsufficiency-associated immune-dysregulation.

A platelet-mediated system for shuttling blood-borne bacteria to CD8α+ dendritic cells depends on glycoprotein GPIb and complement C3.

The acquisition of pathogen-derived antigen by dendritic cells (DCs) is a key event in the generation of cytotoxic CD8(+) T cell responses. In mice, the intracellular bacterium Listeria monocytogenes is directed from the blood to splenic CD8α(+) DCs. We report that L. monocytogenes rapidly associated with platelets in the bloodstream in a manner dependent on GPIb and complement C3. Platelet association targeted a small but immunologically important portion of L. monocytogenes to splenic CD8α(+) DCs, diverting bacteria from swift clearance by other, less immunogenic phagocytes. Thus, an effective balance is established between maintaining sterility of the circulation and induction of antibacterial immunity by DCs. Other gram-positive bacteria also were rapidly tagged by platelets, revealing a broadly active shuttling mechanism for systemic bacteria.

Objective hand eczema severity assessment with automated lesion anatomical stratification.

Hand eczema (HE) is one of the most frequent dermatoses, known to be both relapsing and remitting. Regular and precise evaluation of the disease severity is key for treatment management. Current scoring systems such as the hand eczema severity index (HECSI) suffer from intra- and inter-observer variance. We propose an automated system based on deep learning models (DLM) to quantify HE lesions' surface and determine their anatomical stratification. In this retrospective study, a team of 11 experienced dermatologists annotated eczema lesions in 312 HE pictures, and a medical student created anatomical maps of 215 hands pictures based on 37 anatomical subregions. Each data set was split into training and test pictures and used to train and evaluate two DLMs, one for anatomical mapping, the other for HE lesions segmentation. On the respective test sets, the anatomy DLM achieved average precision and sensitivity of 83% (95% confidence interval [CI] 80-85) and 85% (CI 82-88), while the HE DLM achieved precision and sensitivity of 75% (CI 64-82) and 69% (CI 55-81). The intraclass correlation of the predicted HE surface with dermatologists' estimated surface was 0.94 (CI 0.90-0.96). The proposed method automatically predicts the anatomical stratification of HE lesions' surface and can serve as support to evaluate hand eczema severity, improving reliability, precision and efficiency over manual assessment. Furthermore, the anatomical DLM is not limited to HE and can be applied to any other skin disease occurring on the hands such as lentigo or psoriasis.

Human epidermis organotypic cultures, a reproducible system recapitulating the epidermis in vitro.

The translatability of research is highly dependent on models that recapitulate human tissues and organs. Here, we describe a procedure for the generation of human epidermis organotypic cultures (HEOCs) from primary keratinocytes isolated from foreskin and adult skin as well as from an immortalized keratinocyte cell line (KerTr). We tested several media conditions to develop a defined HEOC growing and expansion media. We characterized the HEOCs and show that in optimal culture conditions they express the proliferation marker Ki67, the basement membrane protein collagen 17 (col17) and the epidermal differentiation markers keratin 15 (K15), keratin 14 (K14), keratin 5 (K5), keratin 10 (K10), keratin 1 (K1), transglutaminase 1 (TGM1), transglutaminase 3 (TGM3) and filaggrin (FLG). Thus, they recapitulate the human epidermis and are stratified from the basal layer to the stratum corneum. These HEOC can be generated reproducibly on a large scale, making it an invaluable model for screening therapeutic compounds and also for the study of pathologies affecting the epidermis.

Intravenous immunoglobulins, cyclosporine, and best supportive care in epidermal necrolysis: Diverse effects on systemic inflammation.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but potentially life-threatening cutaneous adverse reactions. There is still no consensus on adjuvant treatments, and little is known about their effects on systemic inflammation in SJS/TEN. Our aim was to characterize the systemic and cutaneous immune profiles of SJS/TEN patients and to investigate whether/how intravenous immunoglobulins (IVIG), cyclosporine A (CSA), and best supportive care only (BSCO) affected the systemic immune signature and clinical outcome (6 week-mortality, complications, hospitalization stay). METHODS: We included 16 patients with SJS/TEN, treated with high-dose IVIG (n = 8), CSA (n = 4) or BSCO (n = 4). Serial serum samples were obtained prior-, 5-7 days, and 21 days after treatment onset. Serum levels of inflammation-/immune response-associated proteins were measured by high-throughput proteomics assay (OLINK) and cytotoxic molecules by ELISA. RNA extracted from skin biopsies collected prior treatment was analyzed by Nanostring. RESULTS: Serum inflammatory profiles in SJS/TEN patients were notably characterized by massive upregulation of type 1 immune response and proinflammatory markers. Surprisingly, there was limited overlap between cutaneous and serum immune profiles. Serial serological measurements of immune response markers showed very diverse dynamics between the different treatment groups. IVIG-treated patients showed completely different dynamics and most significant proteomic changes in an early phase (Day 5-7). In all treatment groups, type 1-/inflammatory response markers were dampened at day 21. Clinically, there were no outcome differences. CONCLUSION: Our study demonstrates that BSCO, CSA, and IVIG have very diverse biological effects on the systemic inflammatory response in SJS/TEN, which may not correlate with clinical outcome differences.