Allergy

BackgroundPeanut allergies continuously present urging public health challenges. Oral immunotherapy (OIT) is an important treatment option for peanut allergies, but its effectiveness varies, in terms of inducing desensitization (DS) or achieving long-term sustained unresponsiveness (SU). Identifying biomarkers to predict OIT outcomes is thus of great translational interests. MethodsWe thoroughly analyzed data from the POISED trial and our in-house OPIA trial, with a particular focus on the peanut-reactive T cells, in an attempt to identify potential biomarkers at baseline before OIT to distinguish DS and SU outcomes. ResultsIn both the POISED trial and OPIA trial, we found that functional profiles of peanut-reactive T cells at baseline before OIT, such as their type II T helper (Th2) cell cytokine productions, including IL-4, were associated with the DS versus SU outcomes after OIT cessation. ConclusionsBaseline peanut-reactive T cell functional profiles might provide new possibilities for biomarker discovery to predict peanut allergy OIT outcomes.

ObjectiveThis study aimed to evaluate the efficacy, safety, and optimal strains of probiotics for pediatric allergic rhinitis (AR) using meta-analysis and network meta-analysis. MethodsA systematic search was conducted in databases including PubMed, Web of Science, Cochrane Library, and China National Knowledge Infrastructure up to July 31, 2025, to identify randomized controlled trials (RCTs). Inclusion criteria were pediatric patients with AR, probiotic interventions, control groups receiving placebo or standard treatment, and reported outcomes such as Total Nasal Symptom Score (TNSS), Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ), serum IgE levels, clinical efficacy, or adverse events. Study quality was assessed using the JADAD scale, with meta-analysis and network meta-analysis (NMA) performed via RevMan and R software, calculating standardized mean differences (SMD), relative risks (RR), and surface under the cumulative ranking curve (SUCRA) values. ResultsTwenty-six RCTs were included, involving 3,014 patients (1,565 in the probiotic group and 1,404 in the control group). Meta-analysis showed that probiotics significantly reduced TNSS (SMD = -0.85, 95% CI [-1.25, -0.44], P < 0.05), improved PRQLQ scores (SMD = -3.94, 95% CI [-4.55, -3.33], P < 0.05), enhanced clinical efficacy (RR = 1.16, 95% CI [1.07, 1.25], P < 0.05), and decreased adverse events (RR = 0.22, 95% CI [0.06, 0.82], P < 0.05), but exerted no overall effect on serum IgE (SMD = -0.39, 95% CI [-0.99, 0.09], P = 0.11). Subgroup and NMA analyses indicated that mixed strains performed superiorly across multiple outcomes. ConclusionsProbiotics, particularly mixed strains, are a safe and effective adjunctive therapy for pediatric AR, improving symptoms and quality of life. Large-scale RCTs are required to validate optimal regimens.

BackgroundAtopic dermatitis (AD) is a chronic skin disease that typically occurs in early childhood. In this cross-sectional case-control study, our objective was to employ machine learning approaches to identify novel clusters of protective or susceptibility features associated with AD. Methods and FindingsWe utilised an integrated dataset comprising previously established environmental, cytokine, antibody, and gene expression data from AmaXhosa children, both healthy and with AD, living in either rural or urban settings of South Africa, aged 12-36 months. The applied machine learning methods included the GeneSelectR workflow to identify a subset of relevant genes, the calculation of SHAP values to explain the machine learning output, and the use of DIABLO to integrate the datasets for a comprehensive analysis. Key findings included the identification of a protective cluster of environmental features primarily found in the rural setting, which were correlated with plasma cytokine levels and with expression of autophagy-related genes. Additionally, we identified AD susceptibility clusters where levels of allergen-specific and total IgE antibodies correlated with the cytokines MCP-4 and TARC. Lastly, we identified an RNA-Seq feature signature specific to the disease endotype. ConclusionsThe application of various machine learning methods enabled the identification of significant factors associated with AD in a complex, multi-modular dataset, making the output explainable and potentially informing targeted interventions and improved diagnostic criteria.

BackgroundAtopic diseases are estimated to affect 30-40% of the global population. However, the potential protective effect of hypoallergenic infant formula against conditions such as atopic dermatitis (AD), cows milk protein allergy (CMPA), and asthma remains uncertain. ObjectiveTo conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating hypoallergenic formula for atopic disease prevention in high-risk infants. The primary outcome was AD and secondary outcomes were CMPA and asthma. MethodsA systematic review and meta-analysis was conducted according to PRISMA 2020. RCTs involving high-risk infants were identified through PubMed, Cochrane Library, and Web of Science. Exclusion criteria included interventions not initiated at birth, enrolment of sick infants, and non-RCTs. Pooled Relative Risks (RR) with 95% confidence intervals (CI) were calculated using a random-effects model. ResultsWe included 9 RCTs that enrolled high-risk infants. The meta-analysis found a borderline significant protective effects of AD (RR=0.78 [0.59-1.03], p=0.059; I2=46.5%), a significant protective effect of hypoallergenic formula in prevention of CMPA (RR=0.51 [0.27-0.97], p=0.0228; I2=37.3%), and no significant risk reduction for asthma (RR=0.78 [0.51-1.20], p=0.059; I2=37.5%). ConclusionThis systematic review and meta-analysis found no statistically significant protective effect of hypoallergenic formula for AD or asthma, though a non-significant trend toward risk reduction was observed. A significant risk reduction was seen for CMPA (RR{approx}0.5), although not all diagnoses were confirmed by oral food challenge. These findings suggest potential patient-specific benefits, but larger, well-designed RCTs are needed to confirm them.

BackgroundGastroenteric tract requires robust tolerogenic mechanisms to tolerize foreign antigens like foods and microbiota. This is critical to establish the immune homeostasis, which upon disruption, might contribute to a plethora of atopic disorders, including food allergy and eosinophilic esophagitis (EOE). Recently, there was a new subset of tolerizing dendritic cells (tolDCs), PRDM16 tolDC, discovered in the gut of mice and humans, which confers protection against food allergy. Whether an analogous population of it exist in the esophagus is unknown, especially in the context of EOE, another atopic disease associated with dietary antigens. MethodsWe thoroughly analyzed the human esophagus cell atlas single cell RNA-seq dataset and the myeloid DC-VERSE dataset, in an attempt to identify and characterize the esophageal counterpart of the intestinal PRDM16 tolDC. ResultsWe identified the esophageal counterpart of intestinal PRDM16 tolDC as a conventional type II DC subtype expressing PRDM16, termed as cDC2C (PRDM16). We demonstrated the similarities between PRDM16 tolDC and cDC2C (PRDM16) regarding their transcriptomic and functional profiles. Importantly, we found that cDC2C (PRDM16) were expanded during EOE and exhibited an anti-inflammatory phenotype, suggesting their protective role in EOE. Notably, these tolerogenic DCs were not found in other atopic diseases beyond the gastroenteric tract. ConclusionsWe here defined a novel tolerogenic DC population in human esophagus and demonstrated their implications in the pathophysiology of EOE. These findings would provide novel insights towards the tolerogenic mechanisms along the gastroenteric tract and possess translational relevance for EOE diagnosis and interventions.

BackgroundAn adverse female sex-bias exists across many autoimmune disorders, yet its underlying mechanisms, particularly the role of sex hormones, remains poorly understood. Furthermore, the physiological influence of sex hormones in regulating T cell function remains undefined. We examined for the critical role of estrogen and progesterone, in regulating CD4+ T cell responses, specifically with respect to inflammation and their bone erosion potential in RA. MethodsInflammatory markers, circulating antibodies, sex hormone receptors, ER and PR levels were investigated in both RA patients and controls. Further, RA CD4+ T cells were stimulated in varying concentrations of estradiol and progesterone and assessed for modulation in cytokines, transcription factors, RANKL, and FasL expression. Subsequent ex-vivo studies were performed to examine the role of sex hormones in modulating T cell responses. ResultsRA patients displayed systemic inflammation and high circulating antibodies, with significantly higher expression in synovial fluid. Higher expression of ER and PR was evinced on RA CD4+ T cells. Upon hormone stimulation, two cohorts of patients namely responders and non-responders were observed with respect to modulation in cytokines, transcription factors, RANKL, and FasL expression. Our ex-vivo Th1 and Th17 cells demonstrated that sex hormones play a physiological role in modulating inflammation and have bone erosion potential. ConclusionOur findings demonstrate the pivotal significance of sex hormones in modulating TCR responses, thereby regulating inflammation and bone erosion in RA pathology. Further dissection of TCR signaling pathways with respect to sex hormone stimulation may provide promising targets for therapeutic implications. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/25342530v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@b74525org.highwire.dtl.DTLVardef@1cc01aorg.highwire.dtl.DTLVardef@1881e4forg.highwire.dtl.DTLVardef@17de2a8_HPS_FORMAT_FIGEXP M_FIG C_FIG

AimsGestational diabetes mellitus (GDM) is the most common pregnancy-related medical complication. GDM is linked to aberrant immune responses in both mothers and offsprings, specifically, the subsequent development of inflammatory diseases. Whereas prior research has focused on specific immune cell subsets, a comprehensive overview of the impacts of GDM on maternal and fetal immune landscape is lacking. Here, we aim to comprehensively decipher how GDM modulates various immune cell populations in mothers and offsprings. MethodsA prospective, longitudinal case-control study was carried out. Maternal blood from GDM-affected (GDM, n=18) and non-GDM-affected (Ctrl, n=21) mothers were collected at ante-(36-38 weeks of gestation) and post-partum (6-8 weeks post-partum) timepoints. Cord blood from GDM (n=7) and Ctrl (n=11) pregnancies were collected upon C-section. They were analyzed with the state-of-the-art cytometry by time of flight (CyTOF) with a 40-marker panel. Additionally, a publicly available RNA-seq dataset for cord blood mononuclear cells was re-analyzed to confirm results from CyTOF experiments. ResultsCompared to Ctrl, GDM was associated with more activated maternal T cell subsets ante-partum, including increased CD45RO+ and Ki67+ CD4+ T cell populations, which reverted post-partum. GDM-affected maternal innate lymphoid cell (ILC) also exhibited increased granzyme B production ante-partum. On the other hand, in GDM-impacted cord blood, fetal T and B cells were more activated, displaying less naive and more effector phenotypes, further supported by RNA-seq analyses. ConclusionsOur comprehensive analyses revealed that GDM is linked to profound changes in the immune landscapes of the mothers (ante-/post-partum) and foetuses (at birth), casting novel insights towards GDM pathophysiology. Longitudinal immune profiling might be warranted for early detection and stratification of risk, and development of targeted interventions to prevent inflammatory disorders in GDM mothers and their offspring. Research in contextO_LIWhat is already known about this subject? O_LIThe maternal and intrauterine environments are important contributors to long-term health outcomes of mothers and offsprings. C_LIO_LISome maternal and fetal immunity changes have been observed in gestational diabetes mellitus (GDM)-affected pregnancies. C_LIO_LIGDM is associated with increased risk of later-life metabolic and inflammatory diseases in mothers as well as offsprings. C_LI C_LIO_LIWhat is the key question? O_LIWhat are the longitudinal alterations in maternal and fetal immune landscapes in GDM-affected pregnancies? C_LI C_LIO_LIWhat are the new findings? O_LIHigh-dimensional immune profiling provided the most comprehensive overview of alterations in maternal and fetal immune landscapes associated with GDM. C_LIO_LIGDM is associated with skewing of maternal CD4+ T cell and ILC towards activated phenotypes ante-partum. C_LIO_LIGDM is linked to more activated fetal T and B cell profiles. C_LI C_LIO_LIHow might this impact on clinical practice in the foreseeable future? O_LIUnderstanding the complex alterations in the maternal and fetal immune landscape in GDM-affected pregnancy provides insights into the long-term impacts of GDM on the mother and offspring. C_LI C_LI

Sjogrens disease (SjD) is a chronic autoimmune disorder characterized by inflammation of the exocrine glands, leading to dry mouth and dry eyes. This study investigates the role of interleukin-9 (IL-9) and T helper 9 (Th9) cells in the pathogenesis of SjD. We found that serum IL-9 levels were significantly elevated in SjD patients and correlated with clinical laboratory parameters, including autoantibody production. In a mouse model of SjD, IL-9 and Th9-associated cytokines were also elevated, and Th9 cells were enriched in the salivary glands. Our results suggest that IL-9 is produced by multiple cell types, including macrophages, CD4+ T cells, and NK cells, and that Th9 cells contribute to the development of SjD by promoting inflammation and autoantibody production. We also found that Th9 and Th17 polarization conditions increased Th2 and Th17 cells in SjD mice, indicating a shared epigenetic program that renders T cells permissive to multiple differentiation pathways. Anti-IL-9 treatment had a sex-dependent effect, reducing autoantibody production in male mice but worsening focal glandular infiltration in female mice. Our findings suggest that IL-9 plays a complex role in SjD pathobiology, contributing to both local immunoregulation and systemic autoantibody response. Overall, this study offers new insights into the role of IL-9 and Th9 cells in SjD, highlighting the potential for therapeutic targeting of the IL-9/Th9 axis in the treatment of this disease.

BackgroundImpulse oscillometry is a noninvasive pulmonary function test performed during quiet breathing and requires minimal patient cooperation. It is useful for detecting small airway disease and provides increased sensitivity for diagnosing asthma in younger children who may have difficulty completing standard spirometry. Bronchodilator testing, a standard assessment of airflow obstruction reversibility, is recommended in patients with suspected asthma who present obstructive airflow patterns. ObjectiveTo evaluate impulse oscillometry parameters before and after bronchodilator administration across different age groups and to examine the relationship between age and airway resistance in patients with clinician-diagnosed asthma. MethodsThis retrospective study included patients with clinician-diagnosed asthma who demonstrated obstructive airflow patterns and a positive bronchodilator response. Participants were grouped by age: younger than 6 years, 6 to 20 years, and older than 20 years. Key impulse oscillometry parameters--airway resistance at 5 Hz, airway resistance at 20 Hz, the difference between these values, and resonance frequency--were collected and compared across groups. A positive bronchodilator response was defined as a reduction in airway resistance of more than 30% in individuals younger than 18 years and more than 40% in adults. ResultsA total of 225 patients (123 males and 102 females) were included, with a median age of 6 years. At baseline, the median airway resistance at 5 Hz was 175.34% of the reference value (95% CI, 171.66-178.62), and airway resistance at 20 Hz was 121.68% (95% CI, 118.73-127.12). The median difference between these values was 52.32% (95% CI, 49.89-57.14), and the median resonance frequency was 5.11 Hz (95% CI, 4.62-5.35). After bronchodilator administration, airway resistance at 5 Hz decreased to 123.56% (95% CI, 119.07-126.77), corresponding to a median reduction of 52.8% (95% CI, 49.48-56.08; P < 0.0001). Age demonstrated a moderate positive correlation with airway resistance at 20 Hz (r = 0.51, P < 0.001). ConclusionsProximal airway resistance increases with age among patients with asthma, suggesting age-related differences in airway inflammation. Impulse oscillometry combined with bronchodilator assessment provides a practical approach for evaluating airflow reversibility and enhances diagnostic accuracy in suspected asthma.

BackgroundCervical cancer is one of the most common malignant tumors of the female reproductive system. Existing treatments provide limited benefit for patients with advanced, recurrent or metastatic disease, and reliable prognostic markers are lacking. In this study we integrated multi-omic data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. Protein-coding genes meeting the criteria of an adjusted P value < 0.05 and |log2 fold-change| > 5 were screened; 693 genes were identified. We further focused on three genes related to the tumor microenvironment--interleukin 21 (IL21), C-X-C motif chemokine ligand 9 (CXCL9) and cluster of differentiation 1A (CD1A)--and performed differential expression analysis, survival analysis, clinical stage analysis and immune infiltration correlation analysis to clarify their prognostic value and potential mechanisms in cervical cancer. Results(1) CXCL9 and CD1A were highly expressed in cervical cancer tissues, and all three genes showed high expression across different pathological stages without stage-dependent differences; (2) high expression of IL21, CXCL9 and CD1A improved patient prognosis and was positively associated with overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI); (3) expression of IL21, CXCL9 and CD1A was closely correlated with infiltration of multiple immune cells: IL21 correlated with total T cells, helper T cells and B cells, CXCL9 correlated with T cells and activated dendritic cells, and CD1A correlated with immature dendritic cells. ConclusionIL21, CXCL9 and CD1A are potential prognostic biomarkers and key immunomodulatory factors in cervical cancer. This study provides a new direction for immunotherapy and individualized precision treatment of cervical cancer.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but commonly cause immune-related adverse events (irAEs), whether administered as monotherapy or in combination with other oncological agents. We present the first reported case of ICI-induced granulomatous sialadenitis in a male patient in his mid-fifties with BRAF-V600E-mutated papillary thyroid carcinoma who received sequential treatment with BRAF/MEK inhibitors followed by pembrolizumab. The patient experienced acute-onset severe xerostomia and salivary hypofunction, prompting ICI cessation and salivary gland biopsy. Integrative analysis using histology, single-cell RNA sequencing, and spatial transcriptomics revealed macrophage- and T-cell-mediated epithelial damage driven by epithelial senescence and Th1-polarized inflammation. Corticosteroid therapy reduced granuloma burden and improved salivary flow rates and tissue architecture; however, extensive fibrosis persisted despite treatment. These findings underscore the critical importance of early irAE recognition and intervention to preserve glandular function and enable continuation of cancer therapy.

The Endoplasmic Reticulum AminoPeptidase 2 (ERAP2) gene encodes an aminopeptidase involved in antigenic peptide processing for the MHC-I pathway. Genetic variants in the ERAP2 gene are associated with autoimmune conditions and infectious diseases. The linkage between genetic variants in the ERAP2 gene has given rise to the prevailing assumption that a single ERAP2 allotype with invariant amino acid sequence accounts for all immunological functions of ERAP2. Here, we show by analyzing exon-sequencing data from 160,000 individuals that 15 missense amino acid variants across the ERAP2 gene result in an array of different protein allotypes that are maintained in the European population. These allotypes can be divided into three haplotype groups, defined by the genotypes of two common splice-altering variants. We found novel associations between newly identified protein allotypes and immune-mediated diseases, suggesting that ERAP2 functional variation modifies disease susceptibility at the population level. An MHC class I antigen presentation assay revealed that disease-associated ERAP2 allotypes differ in their capacity to generate antigenic peptides for MHC-I presentation, resulting in differential activation of an antigen-specific T-cell receptor compared to non-disease-associated allotypes. These findings provide strong evidence that ERAP2 function is allotype-dependent and demonstrate that ERAP2 diversity shapes MHC-I antigen presentation and T-cell immunity. Significance statementThe ERAP2 enzyme modulates adaptive immunity and plays a role in autoimmunity, infection, and cancer. The authors discovered that a variety of protein allotypes of ERAP2 are maintained in the human population. Allotypes that increase disease risk for autoimmune and cardiovascular conditions are functionally distinct in their capacity to activate T-cells. The results of this study demonstrate that ERAP2 is a functionally diverse immune modulator that contributes to immune variation and influences susceptibility to immune-mediated diseases.

Staphylococcus aureus plays a central role in the exacerbation of atopic dermatitis (AD), but the population structure and pathogenic determinants of strains colonizing AD patients remain poorly understood. It is unclear whether these strains mirror those circulating in the general community or whether specific clonal lineages are selectively adapted to the AD skin microenvironment. Data addressing this question are scarce, particularly in Portugal. In this study, we investigated the molecular epidemiology and pathogenic traits of S. aureus colonizing skin lesions in adult patients with AD in Portugal. We found that lesion-associated isolates belonged predominantly to the methicillin-susceptible S. aureus MSSA-ST398 clonal type, a lineage that is widely circulating in the Portuguese community, particularly among vulnerable populations, and that has also been implicated in severe human infections. Notably, isolates from this clonal type in AD harboured specific pathogenicity traits associated with skin barrier disruption, including hemolysin and urease production, which may contribute to their success as colonizers in AD. Our findings highlight that S. aureus colonization in AD arises from a dynamic interplay between community-level molecular epidemiology and disease-specific selective pressures. While circulating lineages provide the genetic background diversity, the AD skin microenvironment appears to shape which clones ultimately become dominant. Such an integrated perspective may help to inform future geographically tailored strategies aimed at limiting bacterial burden and preventing disease exacerbation in AD.

Identification of early interventions to reduce/eliminate asthma - the most common chronic disease among children - could significantly reduce burden on the healthcare system. Large-scale asthma Exposome-Wide Association Studies (ExWAS) could identify potential interventions, however integration of diverse data is required to address association confounders. The CHILD Cohort Study has followed 3,454 healthy Canadian children and their families from early pregnancy, collecting exceptionally diverse data including 24,852 variables from participant questionnaires, clinical data, household and neighbourhood-level exposures, and sample-derived chemical analytic/omic datasets. Here, we report integration of these datasets into the CHILDdb database platform, and use these data to perform ExWAS and machine learning analyses, identifying and further characterizing associations between childhood asthma and 2,954 diverse early exposures (pregnancy to age 5). Significant asthma associations include antibiotic use, human milk components, DEHP phthalate, and mothers prenatal cleaning product/disinfectant exposure. Subsequent analysis revealed epigenetic changes in the cord blood at birth, after prenatal cleaner exposure, and different microbiome and/or inflammatory cytokine changes associated with different asthma-associated exposures in the child. Collective results support asthma as a heterogeneous condition involving multiple etiologies, with associated endotypes, including prenatal exposures with potential transgenerational effects, and suggest targets for early interventions.

Multiple sclerosis (MS) therapies primarily rely on lymphocyte depletion or trafficking blockade, carrying risks of systemic immunosuppression; however, such treatments have limited efficacy in secondary progressive multiple sclerosis (SPMS). Thus, drugs that target stage-specific inflammation without broad immunosuppression are an unmet clinical need. In this double-blind, placebo-controlled phase II trial, 30 patients with relapsing MS received weekly oral OCH or placebo for 24 weeks. In the pre-specified SPMS subgroup (n=12), OCH achieved complete relapse prevention (p=0.0003), prolonged relapse-free survival (p=0.0079), no new lesions (0/6), with no evidence of disease activity (NEDA-3) in 5/6 patients. In comparison, for the placebo-treated group, 5/6 patients suffered relapses, 2/6 patients developed new lesions, and no placebo-treated SPMS achieved NEDA-3. Invariant natural killer T (iNKT) cells, a regulatory lymphocyte population that is numerically and functionally impaired in MS, are a potential target for MS therapy. Glycolipid OCH is a selective iNKT cell stimulator, skewing the cytokine environment towards Th2. OCH treatment resulted in increased IL-4-producing Th cells in patient peripheral blood while decreasing pathogenic GM-CSF-producing Th cells. Parallel studies in mouse models of MS (EAE) corroborated this mechanism and further revealed that OCH activated gut iNKT cells. Disease amelioration by OCH depended on IL-4 and its efficacy was further enhanced by depletion of B cells. These data revealed the gut-brain axis mediation of progressive-stage pathology distinct from relapsing-remitting MS. Findings from this bidirectional translational study uncover mechanistic differences between SPMS and other types of MS and highlight divergent roles for B cells and Th cells. Furthermore, OCH exerts its therapeutic benefit via targeting mechanisms that are distinct from currently available drugs; exploiting iNKT cell regulatory potential to reprogram pathogenic T helper responses without lymphocyte depletion. The unique yet effective nature of OCH treatment positions it as an attractive future oral therapy for SPMS. One Sentence SummaryThe iNKT cell activating ligand OCH suppresses disease activity selectively in secondary progressive MS in a phase II clinical trial, revealing stage-specific IL-4-mediated immune cell interactions in MS pathology.

Vaccination frequently elicits suboptimal immunogenicity in organ transplant recipients, particularly those on long-term immunosuppressive therapy, highlighting the need for improved understanding of immunosuppression mechanisms and optimized vaccination strategies. This study enrolled a cohort of 132 individuals and observed significantly lower antibody levels in kidney transplant recipients (KTRs) compared to non-transplant controls (non-KTRs). Antibody levels were inversely associated with both the dosage and duration of immunosuppressive therapy. Complementary small animal studies demonstrated that immunosuppressive treatment dosage-dependently and reversibly impaired antibody production, primarily by depleting immune cells, notably B cells. A single shot of adenoviral vector-based vaccines demonstrated enhanced immunogenicity relative to two shots of alum-adjuvanted protein vaccines, inducing potent neutralizing antibodies (NAbs) and a Th1-biased T-cell response even under continuous immunosuppression. The enhanced response was driven by reduced interference from pre-existing antibodies, sustained transgene expression, and the reprogramming of lipid metabolism to activate T and B cells. Our findings advocate for tailored vaccination strategies, positioning adenoviral vectors as a candidate modality for this vulnerable population.

BackgroundHuge neutrophilic infiltrates within lesional and perilesional tissue in hidradenitis suppurativa (HS) give rise to the hypothesis that neutrophil extracellular trap (NET) formation may further drive systemic immune activation in HS. As intrinsic constituents of NETs, nucleosomes-particularly circulating nucleosome containing Histone H3.1 (H3.1-nucleosomes)-serve as reliable indicators of NETosis in the blood. ObjectivesTo investigate whether plasma H3.1-nucleosomes, fluctuate with HS activity. MethodsParticipants were adults with moderate to severe HS. Peripheral blood samples were collected at each visit, EDTA plasma was prepared under standardized conditions and stored at -80{degrees}C. They were subsequently analyzed for circulating H3.1-nucleosomes with a proprietary assay. Baseline and longitudinal data were evaluated in relation to HS severity, clinical characteristics and clinical response using both the HS clinical response score (HiSCR) and the at least 55% decrease of the international HS4 score (IHS4-55). Results93 patients were enrolled; in serial measurements were available for 54. Patients were classified into two clusters; hyper-H3.1 and hypo-H3.1 based on the over-time kinetics of H3.1-nucleosomes. The hyper-H3.1 cluster is characterized by more severe disease. H3.1-nucleosomes 24 ng/ml or more suggest higher total count of inflammatory lesions and of draining tunnels. More than 45% decrease of H3.1-nucleosomes between visits is associated with higher chances for attainment of HiSCR and IHS4-55 responses with biologicals targeting TNF, IL-1 and IL-17. ConclusionsCirculating H3.1-nucleosome levels reflect HS disease activity and surrogate response to treatment. What is already know about this topic?Biomarkers to provide precision approach in hidradenitis suppurativa remain an unmet need. What does this study add?For the first time an easy-to-measure blood test is presented to classify patients and to surrogate treatment. H3.1-nucleosomes distinguish patients into high- and low-level of neutrophil activation. Over-time decreases by 45% or more indicate response to biological treatment. What is the translational message?The new blood test may be used to initiate trials where treatment guidance of both initiation and early stop of treatment will be studied.

Antiphospholipid syndrome (APS) and systemic sclerosis (SSc) are immune-mediated multisystem autoimmune diseases with distinct clinical phenotypes but overlapping pathogenic themes, including immune dysregulation, chronic inflammation, and endothelial injury. Using peripheral blood transcriptome datasets from the Gene Expression Omnibus (GSE102215: 9 APS/9 controls; GSE231691: 49 SSc/18 controls), we performed differential expression analysis within each cohort (limma; |log2FC|>1, P<0.05) and identified 281 genes dysregulated in the same direction in both diseases (100 upregulated and 181 downregulated). Enrichment analyses highlighted interferon-related and cytokine/inflammatory signaling programs in APS and SSc. To derive a compact diagnostic signature, we combined random forest feature ranking with a single-hidden-layer artificial neural network, prioritizing five shared candidate biomarkers (S100A8, IER5L-AS1, LTK, PRR5-ARHGAP8, and PCDH1). Each gene showed consistent case-control differences in both cohorts (P<0.001) and achieved good discrimination (AUC>0.75), with S100A8 performing most consistently (AUC=0.98 in APS; AUC=0.88 in SSc). CIBERSORT deconvolution indicated a myeloid-skewed blood profile in both diseases, characterized by higher neutrophil and monocyte/macrophage signals; SSc additionally showed stronger inferred CD4+ T cell and NK cell signals. S100A8 expression correlated with inferred neutrophil abundance in both cohorts (APS r=0.62; SSc r=0.58; P<0.05). Finally, miRNA-target prediction and DSigDB drug-signature enrichment generated regulatory and pharmacologic hypotheses, including immune-regulatory miRNAs (e.g., miR-155 and miR-146a) and candidate compounds (celecoxib, tamibarotene, HMN-176, and XMD14-99). Overall, these results nominate shared blood transcriptional markers and immune correlates across APS and SSc for follow-up validation.

RIG-I is a cytosolic immune receptor that provides the first line of defense by detecting viral RNA and triggering antiviral responses. Its physiological role in humans remains unclear, as no patients with complete RIG-I deficiency have yet been reported. We identified a critically ill COVID-19 patient with severe RIG-I deficiency caused by heterozygous RIG-I G731R, a novel dominant loss-of-function variant. The G731R mutation in helicase motif VI disrupts the arginine finger, impairing the ATPase activity of RIG-I, but not its RNA-binding ability. However, viral RNA binding fails to expose the signaling domains, thereby impairing the IFN-{beta} response of G731R. Instead, G731R competes with wild-type RIG-I, exerting a dominant negative effect. The loss-of-function is caused by bulky-charged substitutions at G731, as alanine or leucine substitution results in an unexpected gain-of-function phenotype. These findings highlight the importance of uncompromised RIG-I function for human antiviral immunity and the pleiotropic effects of single mutations.

Vitiligo is an autoimmune disorder characterized by melanocyte destruction. We performed a rank-based meta-analysis of six independent transcriptomic studies (115 samples) spanning microarray, bulk and single-cell RNA-seq platforms to identify consensus signatures of lesional skin. Robust Rank Aggregation identified 114 differentially expressed genes (FDR < 0.05) with striking asymmetry: 108 downregulated versus 6 upregulated. Downregulated genes were dominated by melanocyte markers (MLANA, TYRP1, DCT, PMEL, KIT). Upregulated genes included interferon-stimulated genes (OAS1, OAS2, EPSTI1). Pathway-level meta-analysis confirmed uniform suppression of melanogenesis, while immune activation was heterogeneous across datasets. Single-cell data from three included studies confirmed melanocyte depletion. The 108 downregulated genes showed exclusive expression in melanocytes. These include neural genes (PLP1, GPM6B, NRXN3), consistent with melanocytes neural crest origin. We also identified candidate melanocyte markers such as CYB561A3 and QPCT with high melanocyte specificity and consistent downregulation in vitiligo. These findings reveal a robust melanocyte loss signature in vitiligo detectable across all platforms, and study-dependent immune activation possibly influenced by sampling method and disease characteristics.