Allergy

To the editorO_ST_ABSBackgroundC_ST_ABSAnaphylaxis is an acute and potentially life-threatening hypersensitivity reaction often involving the cardiovascular system. Circulating microRNAs (miRNAs/miR), including those carried by extracellular vesicles (EVs), are emerging biomarkers that display regulatory functions in allergy. This study aims to investigate the role of miR-29a in anaphylaxis. MethodsMiR-29a (3p and 5p) levels were assessed by qPCR from acute and baseline samples of serum and EVs from 70 patients with food- and drug-mediated anaphylaxis. EVs purification was confirmed by Western blot, electron microscopy, and NanoSight. MiR-29a-3p target genes were studied in silico using systems biology analysis (SBA). Moreover, miR-29a levels were evaluated in vitro in endothelial cells (ECs) exposed to anaphylactic mediators. Additionally, a panel of endothelial glycocalyx (eGCX)-associated mRNA was analyzed after transfection with a miR-29a-3p inhibitor. ResultsPatients with food-induced anaphylaxis exhibited reduced miR-29a-3p levels in both serum and EVs during the acute reaction. In contrast, miR-29a-5p levels were decreased in serum but not in EVs. No significant modulation of either miRNA was observed in drug-induced anaphylaxis. SBA of miR-29a-3p identified molecular pathways, biological processes and functional networks associated with eGCX remodelling. Intracellular levels of miR-29a-3p were modulated in vitro in ECs following exposure to anaphylactic mediators. Inhibition of miR-29a-3p significantly reduced ESM1 expression. ConclusionsThe miR-29a-3p levels are decreased in serum and EVs from patients with acute food-induced anaphylaxis, suggesting its potential as a promising biomarker. Moreover, a role for miR-29a-3p in eGCX integrity under anaphylactic conditions was demonstrated, potentially regulating ESM1. Key MessageMiR-29a-3p is selectively reduced in serum and extracellular vesicles during acute food-induced anaphylaxis and may regulate endothelial glycocalyx-related pathways, which supports its potential as a novel biomarker and molecular mediator of vascular involvement in anaphylactic reactions.

Background: The determinants of immunoglobulin E (IgE) remain poorly understood in older adults, a population with an increasing burden of chronic diseases. Identifying IgE's determinants may improve its clinical interpretation in the evaluation of allergic and IgE-related conditions. Objective: To investigate age, sex, smoking, alcohol, body mass index (BMI), corticosteroid use, and season as potential determinants of total IgE (tIgE) and inhaled allergen-specific IgE (sIgE). Methods: Using Rotterdam Study data, we investigated the determinants of tIgE and sIgE using multivariable linear regression. Longitudinal changes and the effects of corticosteroids were assessed with linear mixed models. Results: We included 8769 participants, of which 478 had repeated IgE measurements. Age showed a U-shaped relationship with tIgE and L-shaped relationship with sIgE (both p<0.001). Women had lower tIgE (OR [95%CI]: 0.69 [0.65-0.74]), whereas current smokers (1.34 [1.23-1.46]), higher BMI (1.01 [1.01-1.02]), topical corticosteroid users (1.27 [1.07-1.50]) and inhaled corticosteroid users (1.93 [1.64-2.26]) showed higher tIgE. Women (0.96 [0.92-1.00]), former smokers (0.87 [0.83-0.91]) and current smokers (0.72 [0.68-0.76]) had lower sIgE, whereas topical corticosteroid users (1.20 [1.07-1.35]) and inhaled corticosteroid users (1.20 [1.07-1.35]) showed higher sIgE. Over time, tIgE and sIgE decreased (p<0.001) but did not significantly change after corticosteroid use. Conclusion: We identified age, sex, smoking, BMI, season and topical and inhaled corticosteroids as determinants of tIgE and sIgE. Incorporating these determinants may improve IgE's clinical interpretation for the diagnosis and management of allergic and IgE-related conditions. Future research should investigate how these determinants shape IgE's relationship with chronic diseases in aging populations.

BackgroundT helper 2 (Th2) lymphocytes orchestrate type-2 immunity and drive allergic diseases that disproportionately affect females. Sexual dimorphism in Th2 responses is well-documented, yet current models attribute sex differences exclusively to circulating gonadal hormones and sex chromosomes. Whether cell-intrinsic steroidogenesis, mediated by the enzyme Cyp11a1, contributes to female-biased Th2 differentiation and function remains unknown. MethodsTranscriptomes of in vitro generated Th2 cells from male and female T cell-specific Cyp11a1-knockout (Cyp11a1fl/fl;Cd4Cre) and control (Cyp11a1fl/fl) mice were compared. Differential expression, hallmark pathway analysis, transcription factor activity scoring, and functional assays were performed across sexes and genotypes. Cyp11a1-dependent differentially expressed genes were integrated with sex-stratified human Th2 transcriptomes obtained from the type-2 inflammatory skin disease atopic dermatitis. ResultsCyp11a1 deletion markedly reduced the transcriptional signature distinguishing female from male Th2 cells. Female Cyp11a1-knockout Th2 cells underwent extensive transcriptomic reprogramming converging toward the male profile, while male cells were largely unaffected. Female-specific pathway changes included reduced inflammatory signatures and enhanced cell-cycle programmes. Functionally, female Cyp11a1-deficient Th2 cells exhibited significantly increased proliferation and elevated IL-13 production; male knockout cells showed no comparable changes. These effects were developmentally stage-specific, emerging during Th2 differentiation but not in naive precursors. Cross-species analysis identified a conserved gene module shared between Cyp11a1-deficient female mouse Th2 cells and female-biased human Th2 cells in atopic dermatitis. ConclusionsCyp11a1-mediated steroidogenesis is a cell-intrinsic regulator of the female-biased Th2 transcriptional and functional state, identifying de novo steroidogenesis as a mechanism of immunological sexual dimorphism with direct relevance for female-predominant allergic disease.

BackgroundImmunoglobulin E (IgE) plays a fundamental role in the pathogenesis of allergic disease, including asthma. The IgE-producing plasma cells (PCs) are thought to persist indefinitely, providing a sustained source of allergen-specific IgE. Although these cells can accumulate in the bone marrow (BM), after prolonged allergen exposure, their frequency remains remarkably low, and the mechanisms that regulate their migration are poorly understood. ObjectiveTo investigate the chemokine receptor profile and the migration potential of the human IgE-producing cells. MethodsTonsil B cells were stimulated with IL-4 and anti-CD40 to induce class switching to IgE and IgG1. The chemokine receptor profile of IgE+ and IgG1+ switched cells was determined using flow cytometry and migration towards relevant chemokines was quantified using transwell chemotaxis assays. Chemokine expression was also validated by re-analysis of a published single cell RNA sequencing (scRNAseq) dataset of PCs isolated from nasal polyps (NP) of patients with allergic fungal rhinosinusitis. ResultsIgE PCs exhibit significantly reduced expression of the BM-homing chemokine receptor CXCR4 and impaired migration towards its ligand, CXCL12. While IgE+ PCs can upregulate CCR10 and respond to its ligand, CCL28, this behaviour is similar to IgG1+ PCs. Strikingly, however, IgE PCs selectively upregulate CCR2 and migrate robustly towards its ligand CCL2. Re-analysis of NP scRNAseq data confirmed that IgE PCs express significantly higher levels of CCR2 compared with PCs of all other isotypes. ConclusionsThese findings identify CCR2 as a key regulator of IgE PC migration and provide insights into their homing preferences that may shape the nature of the IgE responses.

BackgroundEpidemiological studies have consistently documented an inverse association between atopic dermatitis (AD) and glioblastoma (GBM), yet the immunogenetic mechanisms underlying this paradox remain elusive. We hypothesized that distinct immune subsets driven by shared genetic variants exhibiting antagonistic pleiotropy may explain this relationship. ObjectiveTo dissect the immunogenetic basis underlying the inverse association between AD and GBM by integrating single-cell transcriptomics and clustered Mendelian randomization, and to identify shared immune subsets and genetic variants exhibiting antagonistic pleiotropy that may explain this epidemiological paradox. MethodsWe integrated single-cell RNA sequencing (scRNA-seq) of publicly available datasets from AD skin (GSE153760) and GBM tumors (GSE256490) with genome-wide association study (GWAS) summary statistics. Disease-specific immune cell subsets were identified, and pathway enrichment was conducted on marker genes. Clustered Mendelian randomization (MR-Clust) was applied to detect heterogeneous causal effects, followed by drug target enrichment analysis using the DGIdb database. ResultsscRNA-seq revealed that Th2A cells were the predominant pathogenic subset in AD lesions, whereas S100A9+HLA-low suppressive monocytes were enriched in the GBM microenvironment. Both subsets shared enrichment in the NF-{kappa}B and Fc{varepsilon}RI signaling pathways, revealing a common immunological framework linking peripheral Type 2 inflammation to central nervous system immunosuppression. MR-Clust identified a distinct genetic cluster (Cluster 2) comprising 32 genes (e.g., IL4R, JAK1, SYK, FCER1G) significantly overexpressed in these cell types. This cluster exhibited antagonistic pleiotropy: it was directionally associated with reduced AD risk (OR = 0.930, 95% CI 0.846-1.023, p = 0.137) but a non-significant risk trend for GBM (OR = 1.447, 95% CI 0.737-2.841, p = 0.283). Drug target analysis indicated that Cluster 2 genes are primary targets of approved AD therapies, including dupilumab (IL4R) and JAK inhibitors (JAK1). ConclusionOur integrative analysis uncovers an immune-genetic axis linking Th2A cells in AD to suppressive monocytes in GBM, providing a mechanistic basis for their inverse comorbidity. These findings highlight a potential therapeutic paradox, underscoring the need for pharmacovigilance regarding long-term cancer risk in AD patients receiving targeted immunomodulators.

The primary route of SARS-CoV-2 entry is via respiratory epithelium. However, many COVID-19 patients developed dermatological lesions, and SARS-CoV-2 RNA has been detected in the patients skin. Inflammatory skin diseases, psoriasis and atopic dermatitis (AD), significantly increased the risk of COVID-19. To evaluate the potential role of skin in SARS-CoV-2 host interactions, we utilized 3D human skin organoids (HSO) generated from human epidermal keratinocytes, as well as neonatal skin explants. HSO were treated with cytokines involved in acute and chronic skin inflammation and cytokine storm in severe COVID-19 disease, TNF-, IL-6, IL-1{beta}, and IFN-{gamma}, individually and in combination. HSO were also treated with Th1 (TNF- + IL-17) and Th2 (IL-4 + IL-13) cocktails inducing pro-psoriasis and pro-AD HSO changes, respectively. All individual cytokines, and especially their combinations, elevated the expression of ACE2 and TMPRSS2 at mRNA/protein levels. The Th2 induced only TMPRSS2, the Th1 predominantly induced ACE2. Topically applied Spike-pseudotyped lentiviral Tomato reporter, which binds ACE2 similarly to SARS-CoV-2, successfully infected control and cytokine-treated HSO as well as neonatal skin explants. Cytokine treatment, especially TNF- + IL-6 + IL-1{beta} + IFN-{gamma} and the Th1, significantly increased viral entry. Transcriptomic analysis further revealed partial overlap between gene expression signatures induced by Spike-mediated entry in inflamed HSO and those observed in lung tissue from COVID-19 patients, supporting the biological relevance of skin models. Together, these findings demonstrate that inflammation enhances the permissiveness of human skin to SARS-CoV-2 entry, suggesting that the skin may represent a previously underappreciated interface in viral host interactions.

miR-378a-3p has been reported to be upregulated in the lesional skin of patients with atopic dermatitis (AD); however, its function in AD remains unclear. Here, we demonstrate that miR-378a-3p expression is induced by IL-4 and live Staphylococcus aureus (S. aureus) in normal human epidermal keratinocytes (NHEKs) cultured in proliferative conditions or in a 3D epidermal culture model. Transcriptomic profiling and gene set enrichment analysis of miR-378a-3p-transfected NHEKs revealed positive enrichment of inflammatory response pathways alongside downregulation of genes associated with epidermal development. More specifically, miR-378a-3p enhanced expression of multiple NF-{kappa}B-dependent inflammatory mediators, accompanied by increased phosphorylation of p65, indicating activation of canonical NF-{kappa}B pathway. Notably, miR-378a-3p concomitantly reduced the expression of several NF-{kappa}B family members and upstream adaptor molecules, supporting a model in which miR-378a-3p promotes canonical NF-{kappa}B activity through coordinated modulation of multiple components within the NF-{kappa}B regulatory network. In NHEKs exposed to live S. aureus, miR-378a-3p significantly increased the secretion of IL-1{beta}, IL-1Ra, and IL-8, indicating that miR-378a-3p may amplify innate immune responses triggered by S. aureus colonization in AD. Collectively, these findings identify miR-378a-3p as a positive regulator of keratinocyte inflammatory responses that may contribute to AD exacerbation, particularly in the context of S. aureus colonization.

To explore the mechanism of Hsa_circ_0000629 adsorbing miR-212-5p/ nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) through sponge in bronchial asthma. Twenty BALB/C mice were randomly divided into a normal control group and an asthma group. Pathological changes in lung tissue were observed via HE staining. Human bronchial epithelial cells (16HBE) were transfected with Hsa_circ_0000629 overexpression group (Hsa_circ_0000629-over), Hsa_circ_0000629 siRNA (Hsa_circ_0000629-si), mimic NC, miR-212-5p mimic, inhibitor NC, miR-212-5p inhibitor, and LPS+Hsa_circ_0000629 si. LPS-induced asthmatic cell models (LPS group) and untransfected 16HBE cells (NC group) served as controls. qRT-PCR was used to measure Hsa_circ_0000629, miR-212-5p and NLRP3 expression. ELISA assessed interleukin 18 (IL-18), interleukin 1{beta} (IL-1{beta}), interleukin 6 (IL-6) and tumor necrosis factor - (TNF-) levels. Cell proliferation and the apoptosis were evaluated by EDU assay and flow cytometry, respectively. Western blot analyzed Cleaved-caspase 1, 3 and 9 proteins expression. Dual-luciferase assay verified the binding sites of Hsa_circ_0000629 to miR-212-5p and NLRP3 to miR-212-5p. HE staining revealed inflammatory cell infiltration, bronchial wall thickening, smooth muscle hyperplasia, and alveolar destruction in asthmatic mice. Compared with the controls, Hsa_circ_0000629 and NLRP3 expression were significantly increased, while miR-212-5p expression was decreased in asthmatic lung tissues. In 16HBE cells, Hsa_circ_0000629-over and LPS groups showed elevated Hsa_circ_0000629 and NLRP3 expression but reduced miR-212-5p levels. Silencing Hsa_circ_0000629 in LPS-treated cells (LPS+Hsa_circ_0000629-si) reversed these effects. Overexpression of miR-212-5p counteracted Hsa_circ_0000629-induced NLRP3 upregulation, while miR-212-5p inhibition enhanced NLRP3 expression. LPS exposure increased TNF-, IL-18, IL-6, and IL-1{beta} levels, reduced cell proliferation, and promoted apoptosis. These changes were attenuated by Hsa_circ_0000629 silencing or miR-212-5p overexpression. Western blot confirmed that Hsa_circ_0000629 overexpression upregulated Cleaved-Caspase 1, 3, and 9, whereas miR-212-5p mimic or Hsa_circ_0000629-si reversed this trend. Dual-luciferase assays demonstrated targeted interactions among Hsa_circ_0000629, miR-212-5p, and NLRP3. Interference with Hsa_circ_0000629 expression can alleviate LPS induced apoptosis in 16HBE cells and inhibit the expression of inflammatory factors by targeting the miR-212-5p/NLRP pathway, which may be a new target for the treatment of asthma.

Autophagy has been implicated in several lung diseases, either protecting tissues or driving pathology. Hypersensitivity pneumonitis (HP) is a complex inflammatory lung disease, and autophagy is heavily involved in regulating inflammation. The role of autophagy in HP remains unclear. The aim of our study was to understand the role of autophagy in HP pathogenesis. GFP-LC3 transgenic mice were exposed intranasally to Saccharopolyspora rectivirgula (SR) to induce HP and follow autophagy activation in the lung. Then, we take advantage of our Atg4b-deficient mouse model to assess how autophagy disruption impacts lung inflammation in response to SR antigen challenge. Increased autophagy activation was observed in epithelial and inflammatory cells after SR antigen exposure in GFP-LC3 transgenic lungs. GFP-LC3 puncta colocalized with ATG4B and ATG5 in epithelial and inflammatory cells after antigen exposure. Autophagy impairment limits the inflammatory response after SR antigen exposure in the lungs from the Atg4b-deficient mice when compared to WT mice. To evaluate whether lipopolysaccharide (LPS) exacerbates the inflammatory response in the Atg4b-deficient, a SR+LPS combined treatment was developed and we discovered that LPS aggravates the SR-induced HP in WT but not in Atg4b-deficient mice. Reduced HP severity in Atg4b-deficient mice was associated with decreased expression of NFkB, CCL1, CCL25, CXCL1, TNFR1, IL-13, and IL-17A, diminished CD4+ T cell recruitment and expansion, reduced M2-like macrophages, and decreased granuloma and iBALT development. Our findings highlight autophagy as a critical driver in HP pathogenesis and as a potetial target for novel theraphy development.

Methods: Using Global Burden of Disease (GBD) data, we analyzed prevalence, incidence, mortality, and disability-adjusted life years (DALYs) rates across global and 21 GBD regions from 1990-2023. Joinpoint regression identified temporal trends, age-period-cohort models analyzed effect contributions, Das Gupta decomposition quantified demographic and epidemiological impacts, inequality indices assessed health equity, and Bayesian models projected 2024-2038 trends. Results: In 2023, the global number of children and adolescents with asthma reached 131 million, with an age-standardized prevalence rate (ASPR) of 1,789.9 per 100,000. From 1990 to 2023, the global ASPR and age-standardized incidence rate (ASIR) of asthma in children and adolescents showed an upward trend, while the age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life years (DALYs) rate (ASDR) exhibited a downward trend. Among the 0-14 age group, the disease burden was greater in males than in females, whereas in the 15-19 age group, males had a lower disease burden than females. Projections indicate that over the next 15 years, the overall disease burden will continue to decline; however, female mortality rates and DALYs rates are projected to show an upward trend. Conclusions: The increasing prevalence and incidence rates, coupled with declining mortality and DALYs rates of asthma among children and adolescents globally, underscore the necessity for targeted public health interventions. These findings provide crucial insights for early diagnosis, treatment optimization, and global health policy formulation.

BackgroundClinical and genetic evidence on the association between atopic dermatitis (AD) and subsequent psoriasis remains conflicting, and it is unclear whether this risk is modified by systemic treatments. Recent reports suggest type 2-targeted biologics may unmask psoriasis in AD patients, but data are limited. We thus aimed to assess whether AD is associated with incident psoriasis and whether this risk differs by systemic treatment, particularly biologics versus conventional systemic immunosuppressants (cvIS). MethodsScoping analyses informed a locked analytic design, preregistration at OSF, and confirmatory execution. Propensity score-matched analyses compared AD with non-AD controls and biologics with cvIS. Sensitivity analyses, Cox model triangulation, and control outcomes assessed robustness. FindingsAmong [~]300,000 matched pairs, AD was associated with increased psoriasis risk (primary HR 3.81, 95% CI 3.35-4.34), consistent across all 8 sensitivity analyses and model triangulation. Biologic treatment was associated with reduced psoriasis risk versus cvIS (primary HR 0.20, 95% CI 0.11-0.35), consistent across 6 of 7 evaluable sensitivity analyses and Cox triangulation. Positive and negative control outcomes showed expected directional patterns. InterpretationAcknowledging limitations including residual confounding and coding misclassification, AD was associated with increased psoriasis risk and biologics with lower psoriasis risk than cvIS. FundingDFG (EXC2167, SFB1526, LU877/25-1), Schleswig-Holstein Excellence-Chair Program, Swedish Society for Dermatology and Venereology, and the Tore Nilson Foundation. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAtopic dermatitis (eczema) and psoriasis are the two most common chronic inflammatory skin diseases worldwide. For a long time, doctors and researchers assumed these two conditions could not occur in the same person, as they were thought to involve opposing immune responses. However, this view has been challenged over the past decade. Some large studies, including population-based cohorts from Taiwan and the United Kingdom, have found that people with eczema may be at higher risk of developing psoriasis over time, while other studies, including genetic analyses, have suggested the opposite: that the two diseases may actually protect against each other. This conflicting picture has left clinicians uncertain about the true relationship between the two diseases in everyday clinical practice. A separate but related concern has emerged with the introduction of a new class of highly effective treatments for eczema, biologics, particularly dupilumab. Case reports and observational studies, including a large study published in JAMA Dermatology in 2025, have raised the possibility that these medications might trigger psoriasis in some patients, potentially by shifting the immune system from one inflammatory pattern to another. However, prior studies on this question had important methodological limitations: they were not pre-planned and registered before data collection, they did not always tightly link treatment use to an eczema diagnosis, and critically, none compared biologic treatment directly against conventional immunosuppressant medications, the most relevant clinical comparator. Added value of this studyThis study is a large and methodologically rigorous investigation of both questions: whether eczema itself increases the risk of developing psoriasis, and whether the type of systemic treatment used for eczema influences that risk. Using a database of over 110 million electronic health records from across the United States, we matched approximately 300,000 patients with eczema to 300,000 patients without eczema and followed them for up to seven years. We also compared nearly 5,500 patients treated with biologics to an equal number treated with conventional immunosuppressants. Crucially, our study was pre-registered before any data were analyzed, meaning the research questions, methods, and analyses were locked in advance and could not be adjusted based on what the data showed. We also used a range of additional analyses to test whether our findings were robust, including checks using outcomes that should not be affected by eczema or its treatment (such as appendectomy and hearing loss), which confirmed that our results were not likely explained by bias alone. We found that eczema was associated with an increased risk of developing psoriasis, but that this risk was substantially influenced by the choice of comparison group, ranging from approximately 1.4-fold to nearly 4-fold depending on the analytical approach. More strikingly, we found that patients treated with biologics had a markedly lower risk of developing psoriasis compared with those treated with conventional immunosuppressants, the opposite of what prior reports had suggested. This finding was consistent across nearly all additional analyses performed. Implications of all the available evidenceTaken together with existing evidence, these findings suggest two important conclusions. First, clinicians should be aware that eczema, particularly moderate-to-severe eczema requiring systemic treatment, may carry an elevated risk of developing psoriasis over time. This does not mean that all patients with eczema need to be screened for psoriasis routinely, but it does support clinical awareness and monitoring in higher-risk patients. Second, and perhaps most importantly for treatment decisions, biologics do not appear to increase the risk of psoriasis compared with conventional immunosuppressants and may in fact be associated with a lower risk. This provides reassurance for patients and clinicians considering biologic therapy and challenges the narrative that these medications trigger psoriasis. Future research should aim to confirm these findings in other populations, investigate the biological mechanisms underlying the relationship between eczema and psoriasis, and examine whether specific biologic agents differ from one another in their effects on psoriasis risk.

BackgroundExtreme-phenotype comparisons allowed the discovery of novel asthma genetic risk loci. However, this approach remains unexplored in epigenome-wide association studies (EWAS). We aimed to identify bulk and cell-specific methylation markers of asthma with severe exacerbations across diverse ancestry groups. MethodsWe conducted a meta-EWAS of 739,543 CpGs in whole blood among 1,192 African American and Latino pediatric populations, comparing non-asthmatics and asthma exacerbators. Genome-wide CpGs were followed up for replication in a meta-analysis across 1,516 ethnically diverse participants and in a cross-tissue evaluation of 393 nasal samples. We conducted differentially methylated region (DMRs), cell-type-deconvoluted, and quantitative trait loci analyses (whole-genome sequencing n=1,668; RNA-seq n=1,209). We examined enrichment in traits, pathways, and druggable genes, and analyzed DNAm predictors of plasma proteins and aging. ResultsDNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (p<9x10-8, {lambda}=1.05). We replicated 25 CpGs in blood cells, cross-validated 7 in nasal samples, and detected 42 cell-specific DNAm markers mainly driven by T cells. DNAm at 134 CpGs was associated with gene expression in whole blood, including 118 associations with T-cell receptor genes, and 446 CpGs were regulated by [&ge;]1 genetic variant. We found enrichment for previous associations with environmental exposures, immune disorders, immune and inflammatory pathways, and druggable genes by developmental drugs. 21 methylation-predicted plasma proteins, involved in host defense, and one lung aging clock were associated with asthma exacerbations. ConclusionsThe first meta-EWAS of extreme asthma phenotypes identified hundreds of novel DNAm markers, suggesting novel methylation biomarkers and candidate drugs for asthma and supporting the role of T cells.

Sarcoidosis is a multisystem disorder that primarily affects the lungs and is characterizedby granulomatous inflammation. However, much of the underlying disease mechanisms remain poorly understood. Extracellular vesicles (EVs) are small membrane-bound particles released by all cells and carry various cargos including metabolites. They are involved in intercellular communication that can be dysregulated in diseases.This study characterizes the metabolic cargo of EVs isolated from bronchoalveolar lavage fluid (BALF), using liquid chromatography-mass spectrometry (LC-MS)-based metabolomic analysis, in patients with sarcoidosis (n=37), compared to healthy controls (n=10). Additionally, the sarcoidosis signature was compared to another pulmonary disorder, anti-synthetase syndrome (ASyS, n=10). Arachidonic acid (AA) results were verified by ELISA. A total of 1202 metabolites were detected, with 111 annotated ones further analyzed. EVs from sarcoidosis patients showed distinct metabolomic profiles compared to both ASyS patients and healthy controls, with 38 annotated metabolites differentially expressed in any of the groups. In both annotated and non-annotated data, sarcoidosis patients clustered separately from ASyS patients and healthy individuals. Furthermore, sarcoidosis patients clustered in 3 subgroups, whereof one was similar to ASyS patients and one stood out as showing higher cell counts in BALF. Higher AA levels were found in sarcoidosis patient EVs by LC-MS, and AA results were verified by ELISA. Our data show that BALF EV metabolites are disease-dependent and support the notion thatsarcoidosis patients should be further subgrouped for better diagnosis and treatment.

Interleukin-33 (IL-33) is a key cytokine in mast cell mediated immunity, promoting inflammatory cytokine production without inducing degranulation. Here, we compared IL-33 induced proteomic responses across three mast cell culture systems, Foetal Liver derived Mast Cells (FLMCs), Bone Marrow derived Mast Cells (BMMCs), and Peritoneal Mast Cells (PMCs), using quantitative data-independent acquisition mass spectrometry. Although baseline proteomes were largely conserved across all mast cell types, clear differences were observed between culture systems. PMCs exhibited a more mature phenotype, characterised by higher abundance of granule-associated proteins and lower levels of proteins involved in metabolism and translation. In contrast, FLMCs and BMMCs displayed higher levels of biosynthetic and metabolic machinery, consistent with a less differentiated state. IL-33 stimulation induced a conserved proteomic programme across all mast cell types, enriched for inflammatory signalling pathways, cytokine production, and enzymes involved in prostaglandin and biogenic amine biosynthesis. Pathway analysis demonstrated robust activation of nuclear factor {kappa}B (NF{kappa}B) associated signalling, with a relative enrichment of components linked to non-canonical NF{kappa}B signalling and tumour necrosis factor (TNF) receptor associated pathways. Mechanistically, IL-33 driven proteomic remodelling was strongly regulated by mitogen-activated protein kinase (MAPK) signalling. p38 MAPK emerged as the dominant regulator of the IL-33 response, with ERK1/2 contributing to a subset of induced proteins. These pathways differentially regulated key effector outputs, including IL-6, IL-9, IL-1 family cytokines, and enzymes required for prostaglandin, serotonin, and histamine biosynthesis. Together, these data define conserved IL-33 dependent inflammatory programmes across mast cell differentiation states and demonstrate how MAPK signalling pathways shape the composition of mast cell effector responses.

Hidradenitis suppurativa (HS) is a chronic, debilitating, inflammatory skin disorder. Medications have been reported in association with cases of new-onset HS or exacerbation of existing disease; however, the extent of this risk is unclear. We queried the FDA adverse event reporting system (FAERS) from 2003-2023 to identify drug-specific reporting signals for HS. We stratified reports by whether HS was listed as an indication (Drug-Worsened, DW) or not (Drug-Induced, DI) to distinguish disease flares from de novo disease. Primary suspect drugs with > 3 HS reports were included. Disproportionality was quantified using reporting odds ratio (ROR) with Wald 95% confidence intervals (CI). Time-to-onset was also evaluated. We identified 5,529 HS reports: 3,725 DW and 1,804 DI. Females comprised 63% (mean age 41) and the US was the top reporting country (81.8% DW; 53.66% DI). In the DI group, statistically significant signals were observed for immunomodulators also used to treat HS including adalimumab (n=506, ROR= 12.6 [11.3-14.0]) infliximab (n=108, ROR=8.2 [6.7-10.0]), and secukinumab (n=79, ROR=6.6 [5.2-8.2]), consistent with paradoxical reactions. Median time-to-onset was 22 days for secukinumab, compared to 312 and 319 days for adalimumab and infliximab. Signals were also identified for isotretinoin (n=28, ROR= 6.2 [4.2-8.9]), and for antineoplastic agents including cytarabine (n=25, ROR= 24.7 [16.6-36.6]) and omacetaxine (n=8; ROR= 7416 [CI 2923-18816]), which may reflect reported eccrine hidradenitis. In the DW group, adalimumab (n=2967), secukinumab (n=67), and infliximab (n=57) predominated but displayed lower RORs (0.72-1.4), likely reflecting indication bias. While mechanisms of drug-associated HS require further clarification, our findings demonstrate significant associations and highlight the importance of dermatologic monitoring when initiating certain agents.

Alpha-gal Syndrome (AGS) is a potentially life-threatening allergy caused by an IgE-mediated immune response to galactose--1,3-galactose (alpha-gal), a carbohydrate epitope present in most mammalian meats. Currently, strict avoidance of mammalian meat remains the primary management strategy for affected individuals, and alpha-gal-free beef is not commercially available. Here, we leverage cultivated meat as a biotechnology plat-form to address this unmet clinical need by engineering alpha-gal-free bovine muscle cells. Using CRISPR/Cas9 genome editing, we disrupted GGTA1, the gene encoding 1,3-galactosyltransferase, in immortalized bovine satellite cells (iBSCs). High-efficiency editing produced clonal GGTA1 knockout iBSCs harboring a homozygous frameshift mutation. Flow cytometry and immunofluorescence confirmed loss of the alpha-gal epitope, while bulk RNA-seq indicated minimal disruption of global gene expression and preserved myogenic differentiation capacity. Importantly, lysates from GGTA1 knockout iBSCs elicited substantially reduced basophil activation in assays using plasma from a patient with AGS, indicating reduced basophil activation consistent with reduced allergenic potential. Together, these findings establish a proof of concept for engineering AGS-compatible cultivated meat and demonstrate the potential of cultivated meat technologies to address human health challenges. HIGHLIGHTS{circ} CRISPR/Cas9-mediated disruption of GGTA1 eliminated alpha-gal from bovine satellite cells {circ}GGTA1 knockout cells retained myogenic identity and differentiation capacity {circ}GGTA1 knockout reduced basophil activation in an alpha-gal syndrome immune assay {circ}Genome-edited bovine cells provide a proof of concept for AGS-compatible cultivated meat

Inflammatory skin diseases (ISDs) affect up to 25% of the global population. Yet, large-scale comparative single-cell RNA-sequencing (scRNA-seq) analyses between ISDs are still missing. Here, we integrated scRNA-seq datasets spanning 27 skin diseases from 50 studies, comprising over 2 million cells from 441 samples. Using the healthy skin cell atlas as reference, we could build a robust ISD atlas that enabled us to differentiate universal inflammatory signatures and disease-specific ones. This highlighted, for example, a shared gene program between keratinocytes in atopic dermatitis and parapsoriasis, not present in cutaneous T-cell lymphoma, confirms the plasticity of Th17 cells throughout ISDs, defines specific macrophage signatures in acne, and reveals a yet undescribed role of mural cells in ISDs. This demonstrates the power of the ISD atlas as a resource to resolve disease-specific immune mechanisms. The complete atlas is available through an interactive online portal at https://isd-atlas.derma.meduniwien.ac.at.

BackgroundPsoriasis is a chronic immune-mediated inflammatory disease (IMID) with systemic involvement. In mild-to-moderate disease, circulating cytokines may inadequately capture systemic inflammatory burden. Composite haematological indices derived from complete blood counts, such as the systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI), have emerged as sensitive prognostic markers of systemic inflammation, including in psoriasis. This exploratory post hoc analysis investigated the effects of orally administered herring roe oil (HRO), a phospholipid-rich marine oil, on systemic inflammation in patients with mild-to-moderate psoriasis utilizing these biomarkers. MethodsData were analysed from a randomized, double-blind, placebo-controlled 26-week clinical study which investigated HRO supplementation in patients (N = 64) with mild-to-moderate psoriasis (NCT03359577). SII, SIRI, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were calculated at baseline, week 12, and week 26 for patients where baseline complete blood counts (CBCs) were available (n = 60). Patients missing baseline CBCs were excluded from the analysis. Continuous changes were assessed using ANCOVA with baseline adjustment. Categorical responder analyses were performed with 25% and 30% reduction thresholds and stratification by baseline biomarker medians were performed to evaluate treatment responses and impact of baseline inflammation. ResultsCompared with placebo, HRO treatment resulted in significant mean reductions in SII, SIRI, and PLR at week 26, with supportive trends and responder effects observed as early as week 12 compared to placebo. Patients with elevated baseline inflammatory indices showed the greatest reductions in systemic inflammation. Stratification by baseline SII further revealed enhanced clinical benefit, with statistically significant PASI50 response rates in the HRO arm at week 26 among patients with lower baseline SII. ConclusionHRO supplementation was associated with a time{square}dependent reduction in systemic inflammatory biomarkers in mild{square}to{square}moderate psoriasis patients. These findings support the utility of composite inflammatory indices for monitoring systemic inflammation and suggest that baseline SII may have utility in predicting treatment response and may be a useful tool for stratification in clinical trials in mild to moderate psoriasis patients. These results could also suggest platform-potential of HRO for resolution{square}oriented interventions across several inflammatory conditions.

BackgroundTrained immunity is a durable functional reprogramming of innate immune cells characterized by enhanced responsiveness upon secondary challenge. While metabolic rewiring and epigenetic remodeling are well-established features of this process, the contribution of ubiquitin-mediated post-translational regulation remains poorly defined. MethodsWe performed an integrative analysis of publicly available human transcriptomic datasets derived from monocytes, macrophages, and PBMCs exposed to established training stimuli ({beta}-glucan, Bacillus Calmette-Guerin [BCG], and hemin-{beta}-glucan) followed by secondary stimulation. A curated panel of deubiquitinating enzymes (DUBs) and E3 ubiquitin ligases with established immune functions was analyzed for differential expression. Gene Ontology (GO) and KEGG pathway enrichment analyses were conducted to evaluate higher-order convergence across independent datasets. ResultsAcross multiple trained immunity models, we identified reproducible transcriptional remodeling of ubiquitin-modifying enzymes. USP25, OTUB1, and TRIM25 were consistently upregulated following restimulation, whereas several chromatin- and cytokine-regulatory DUBs--including USP3, USP4, USP7, USP16, MYSM1, and USP38--were downregulated. Normalization to RPMI-restimulated controls reduced many activation-associated signals; however, USP25 remained persistently elevated, suggesting a stable training-associated signature. Pathway enrichment analysis independently demonstrated significant engagement of ubiquitin-related functional categories across datasets, supporting coordinated reorganization of ubiquitin regulatory networks. ConclusionThese findings identify selective transcriptional remodeling of the ubiquitin- proteasome system as a recurring feature of trained immunity. Integrating ubiquitin signaling into the established metabolic-epigenetic framework expands the conceptual model of innate immune memory and suggests that ubiquitin-modifying enzymes function as modulatory rheostats shaping immune amplitude and stability. Future functional and proteomic studies are required to determine whether these transcriptional signatures directly mediate trained immunity phenotypes.

Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by excessive keratinocyte proliferation, immune cell infiltration and dysregulated inflammatory signaling. Despite the availability of biologic therapies targeting inflammatory cytokines, many patients experience incomplete responses or relapse, highlighting the need to better understand molecular regulators of cutaneous inflammation. CD109 is a glycosylphosphatidylinositol (GPI)-anchored protein previously identified by our lab as a co-receptor and negative regulator of Transforming Growth Factor-{beta} (TGF-{beta}) signaling that inhibits fibrotic responses. Emerging evidence suggests that CD109 also modulates immune and inflammatory pathways. In this study, we investigated whether epidermal CD109 overexpression influences cutaneous inflammatory responses. Transgenic (TG) mice overexpressing CD109 under the keratin-14 (K14) promoter were used to restrict transgene expression to the epidermis. TG and wild-type (WT) littermates were subjected to lipopolysaccharide (LPS)-induced skin inflammation. CD109 TG mice exhibited significantly reduced immune cell recruitment, including macrophages and neutrophils, along with decreased expression of the pro-inflammatory mediators IL-1 and MCP-1/CCL2 compared with WT mice. Transcriptomic analysis of primary keratinocytes revealed downregulation of multiple inflammatory signaling pathways in CD109-overexpressing cells, including TNF-/NF-{kappa}B, IL-2/STAT5, IFN-{gamma}, IFN-, and IL-6/JAK/STAT3 pathways. Together, these findings demonstrate that epidermal CD109 overexpression attenuates cutaneous inflammatory responses by suppressing key inflammatory signaling networks and limiting immune cell recruitment, suggesting that CD109 may represent an important regulator of inflammatory signaling in the skin and a potential target for inflammatory skin diseases such as psoriasis.