Journal of Allergy and Clinical Immunology

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.

Introduction: Although temporal variation is the hallmark of asthma, recommended diagnostic approaches largely rely on single clinic-based measurements. Ambulatory monitoring captures diurnal and day-to-day variability and may therefore enhance diagnostic accuracy. We evaluated the clinical feasibility and potential utility of home spirometry and fractional exhaled nitric oxide (FeNO) monitoring in asthma diagnosis. Methods: Symptomatic, untreated adults with GP-suspected asthma underwent diagnostic tests including bronchodilator reversibility, in-clinic FeNO, blood eosinophil counts and bronchial challenge. Participants measured spirometry and FeNO four times daily over one week; during the second week spirometry were measured twice daily. The reference standard was provided (asthma/not-asthma) by an expert panel of at least two asthma specialists based on clinical history and the results of all in-clinic testing; home spirometry (except for peak expiratory flow) and FeNO measurements were blinded to the panel. Results: Of 67 eligible participants, 51(76%) were recruited, and 38 had asthma confirmed or excluded by the panel. 1058 home spirometry measurements were obtained from 37(73%) participants; 848 home FeNO readings were obtained from 39(76%) participants. Among those completing at least one home measurement, median (IQR) adherence was 66.7(58.6-97.6)% for spirometry and 78.5(51.8-103.6)% for FeNO. Collection of health impact data for economic evaluation was feasible. In participants with a confirmed diagnostic outcome who completed home measurements (FeNO: n=32; spirometry: n=28), the putative home-testing metrics demonstrated high sensitivities at [≥]90% specificity, and outperformed peak expiratory flow diurnal variability. Incorporating home testing into the BTS/NICE/SIGN 2024 diagnostic pathway had the potential to reduce reliance on bronchial challenge testing by 57%. Conclusions: Home spirometry and FeNO testing and the prospective collection of health-economic data in the diagnostic setting were feasible. Home-based testing strategy showed early potential to improve asthma diagnosis and pathway efficiency. These findings support further evaluation through an adequately powered diagnostic accuracy study and health-economic assessment.

Background: Extreme-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. Methods: We 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. Results: DNAm 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. Conclusions: The 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.

Background Recent guidelines differ in how fractional exhaled nitric oxide (FeNO) is used to diagnose school-age asthma, either as one of several tests with a cut-off at 25 ppb or as a single rule-in test at 35 ppb. Evidence on its diagnostic performance and clinical utility in subgroups remain limited. Methods We analysed data from 1,979 school-age children in the Swiss Paediatric Airway Cohort referred for suspected asthma. We investigated FeNO performance with diagnosis by paediatric pulmonologists as reference standard using receiver operating characteristics curves, selected cut-offs and simulated predictive values across different prevalence. Subgroup analyses considered allergic sensitisation with allergic rhinitis and current inhaled corticosteroid (ICS) use. Results In the overall cohort (asthma diagnosis 70%), FeNO showed poor discrimination for asthma (AUC 0.66; 95% CI 0.64-0.68) with an optimal cut-off at 22 ppb. At 25 and 35 ppb, sensitivity was low (43%, 95% CI 40-46; 31%, 95% CI 29-34) and specificity moderate to high (84%, 95% CI 77-84; 90%, 95% CI 87-92). Positive predictive value at 35 ppb was 88% and was 57% when simulated at a prevalence of 30%. FeNO had no diagnostic value in non-sensitised children and lower performance in sensitised children with allergic rhinitis than in those without (AUC 0.59 vs 0.68). Current ICS use did not influence performance. Conclusion FeNO has limited diagnostic performance as a stand-alone test for school-age asthma, and underlying asthma prevalence and allergic characteristics should be considered in the interpretation.

BackgroundGastroesophageal reflux disease (GERD) is highly prevalent in systemic sclerosis (SSc) and frequently persists despite proton pump inhibitor (PPI) therapy. However, the mechanisms underlying PPI-refractory GERD in SSc remain incompletely understood. MethodsWe conducted a singlel7lcentre, retrospective study of adults with SSc who underwent ambulatory pH-multichannel intraluminal impedance (pH/MII) monitoring while receiving twicel7ldaily PPI therapy (2021-2025). Esophageal motility (highl7lresolution manometry, HREM) and gastric emptying scintigraphy were integrated to examine associations between gastro-esophageal dysmotility and reflux phenotypes. ResultsThirty patients were included, of whom 67% had PPI-refractory reflux symptoms and 33% were undergoing pre-lung transplantation evaluation. Refractory GERD was present in 29/30 patients (97%) based on Lyon 2.0 classification, with conclusive evidence in 53% and borderline evidence in 43%. Esophageal dysmotility was identified in 80%, most commonly absent contractility (67%), and was associated with impaired reflux clearance, reflected by longer acid clearance times (2.20 [1.15-3.75] vs 1.15 [0.43-1.90] min) and prolonged reflux episode duration (16.60 [4.38-40.63] vs 1.95 [0.53-20.43] min). Gastric dysmotility was identified in 60.7% and was associated with an increased reflux episode burden (51.00 [30.00-81.50] vs 25.00 [21.00-54.00] episodes/24h). ConclusionsPPIl7lrefractory GERD is nearly universal in this SSc cohort and reflects heterogeneous, quantifiable abnormalities across the foregut, including impaired esophageal clearance and increased reflux burden related to gastric retention. These findings support integrated physiologic evaluation to define reflux mechanisms, inform risk stratification (including lung transplantation), and guide targeted, mechanism-based therapies beyond acid suppression.

Background: Itch in systemic sclerosis (SSc) is thought to be most significant in early disease, but no longitudinal studies have examined itch course. We estimated itch presence and severity from SSc disease onset, accounting for participant age and time since onset at each assessment. Methods: People with SSc from the multinational Scleroderma Patient-centred Intervention Network Cohort completed past-week itch severity assessments (0 to 10 numerical rating scale) at enrolment and longitudinally at 3-month intervals. To estimate itch probability (score > 0) and, if present, itch severity, we used two-stage mixed effects models with basis splines to address non-linearity. The primary predictor was age at each assessment, partitioned into age at non-Raynaud phenomenon symptom onset and time since onset. We estimated prevalence and severity for onset ages of 20, 30, 40, 50 and 60 years and, for each onset age, at 2 years, 3 years, 4 years, 5 years, 7 years, and 5-year intervals 10 years to 35 years post-onset. Findings: We included 2173 participants with 19 733 itch assessments (mean [standard deviation] 9.1 [6.9] assessments). 1896 of 2173 (87.3%) participants were women. Mean age at enrolment was 54.7 (SD 12.7) years. 873 (40.2%) participants had diffuse cutaneous SSc. Predicted itch probability was between 35.0% (95% CI 31.8% to 38.5%) and 36.8% (95% CI 33.3% to 40.4%) at all onset age and disease duration combinations. Mean itch severity, when present, was moderate, between 4.1 (95% CI 4.1 to 4.1) and 4.4 (95% CI 4.3 to 4.4), for all age and duration combinations. Interpretation: Itch prevalence and mean severity were stable across onset ages and over time within onset ages. Findings suggest that itch is common in SSc and not as closely related to disease duration as previously thought. Research is needed to elucidate itch pathophysiology and identify effective management strategies.

BackgroundThyroid Eye Disease (TED) is an autoimmune orbital disorder driven by pathogenic T-cell subsets, including T-helper 1 (Th1) and follicular helper T (Tfh) cells, which sustain orbital inflammation and thyroid-stimulating immunoglobulin (TSI) production. Selenium supplementation has demonstrated clinical benefit in mild TED, yet its immunological mechanisms remain poorly defined. MethodsA murine TED model was established in female BALB/c mice via TSHR plasmid immunisation. Animals maintained on a low-selenium diet (0.07 ppm) received sodium selenite supplementation at 0.2 mg/kg/day. Orbital pathology was assessed by immunohistochemistry, H&E and Massons Trichrome staining. T-cell subset abundance was quantified by flow cytometry, and serum T4, TRAb, and IL-21 levels were measured by ELISA. In vitro dose-response experiments examined the effects of selenium on Tfh cell viability, IL-21 production, apoptosis, and ferroptosis. ResultsSelenium supplementation reduced CD3 T-cell orbital infiltration, collagen fibrosis, and serum T4 and TRAb levels in TSHR-immunised mice. Flow cytometry revealed significant reductions in Tfh and Th1 cell abundance, with Th17 cells unaffected. Serum IL-21 and B-cell abundance were also markedly reduced in vivo. In vitro, selenium exhibited a biphasic, dose-dependent effect on Tfh cells: low concentrations maintained viability and IL-21 production, while higher concentrations induced ferroptosis and apoptosis. ConclusionsSelenium modulates pathogenic T-cell responses in TED, most prominently suppressing the Tfh compartment and attenuating the Tfh-B cell-autoantibody axis via ferroptosis and apoptosis. These findings suggest a mechanistic framework for the clinical benefit of selenium in mild TED and highlight the importance of dose selection within its narrow therapeutic window.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T-cell subsets. A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted ANCOVA, correlation network analysis, and principal component analysis (PCA). Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion. In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired CCR7-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions. These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches.

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.

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.

Background: immune dysregulation underlies cardiovascular risk excess in systemic autoimmune diseases, such as rheumatoid arthritis (RA) and Sjogren disease (SjD). However, exact mediators are unknown. Regulatory autoantibodies targeting G protein coupled receptors, including CXCR3, have emerged as modulators of immune and vascular homeostasis, but their role in autoimmunity remains ill defined. Our aim was to evaluate antiCXCR3 levels in systemic autoimmunity and their potential value as biomarkers. Methods: antiCXCR3 IgG serum levels were quantified in early RA (n=84), clinically suspect arthralgia (n=12), and controls (n=65). Established RA (n=103) and SjD (n=44) were recruited for validation. Atherosclerosis was assessed by carotid ultrasound. Cytokines were measured by multiplex immunoassays. Cardiometabolic related proteins were evaluated using high-throughput targeted proteomics. Publicly available datasets were used for validation. Results: antiCXCR3 antibodies were significantly reduced in early RA and arthralgia compared with controls, independently of disease activity, autoantibodies, or systemic inflammation. This finding was confirmed in validation cohorts. AntiCXCR3 were negatively associated with good therapeutic outcomes upon csDMARD at 6 and 12 months. Lower anti-CXCR3 levels were independently associated with atherosclerosis occurrence and extent across conditions. Incorporating antiCXCR3 into mSCORE improved risk stratification. AntiCXCR3 were related to proteomic signatures linked to immune activation and to apoptosis, chemotaxis, and cell adhesion in an atherosclerosis dependent manner. Transcriptomic analyses indicated compartment specific CXCR3 dysregulation. Conclusion: reduced antiCXCR3 antibodies represent a shared hallmark bridging systemic autoimmunity and atherosclerosis burden, shaping our understanding on the regulatory role of antibodies at the vascular immune interface. Clinical translation of anti-CXCR3 antibodies hold promise to improve risk stratification.

BackgroundMalnutrition compromises mucosal immunity, especially in the respiratory tract, increasing susceptibility to pathogens like Streptococcus pneumoniae. This study assessed whether nasal administration of Lacticaseibacillus rhamnosus CRL1505 or its peptidoglycan could promote the recovery of nasopharynx-associated lymphoid tissue (NALT) structure and functionality, thereby enhancing resistance to S. pneumoniae infection in protein-malnourished mice. MethodsMale Swiss albino mice were fed to a protein-free diet to induce malnutrition, followed by nutritional repletion with or without nasal supplementation of CRL1505 or its peptidoglycan. Resistance to S. pneumoniae infection, NALT architecture, immune cell composition in NALT and regional lymph nodes, and nasal cytokine production were evaluated. ResultsProtein deficiency caused marked NALT atrophy, immune cell depletion, and heightened susceptibility to S. pneumoniae. Nutritional repletion alone partially reversed these effects. In contrast, nasal supplementation with CRL1505 or its postbiotic fully restored NALT structure and cellularity, normalized lymphoid and myeloid populations, and reduced pathogen burden. Both treatments increased B and T lymphocytes, immature B cells, dendritic cells, and macrophages. The postbiotic also enhanced MHCII expression and balanced neutrophil-like Gr-1 cells. Notably, immune enhancement was evident even before infection, indicating a mucosal priming effect. Cytokine levels in nasal fluids remained largely unchanged. ConclusionsNasal delivery of L. rhamnosus CRL1505 or its postbiotic effectively reestablished NALT integrity and mucosal immunity in malnourished mice, providing significant protection against respiratory pathogens. These findings support the development of nasal immunobiotic formulations as non-invasive interventions to bolster respiratory defenses in immunocompromised hosts.

ImportanceEmerging data show that B-cell depleting chemotherapies, which are increasingly used to treat autoimmune disorders and multiple sclerosis, can be associated with mucosal side effects such as inflammatory vaginitis. ObjectiveEvaluate the impact of rituximab treatment on vaginal mucosal immune markers, endocervical immune cell populations and vaginal microbiome. DesignCross-sectional observational study conducted between 2022 - 2024. SettingAcademic medical center, Boston Massachusetts. ParticipantsWe enrolled women aged >18 years who were either 1) receiving rituximab for autoimmune renal disease or were 2) healthy controls ExposureTreatment with rituximab, an anti CD20 monoclonal antibody. Main outcome and measureWe compared endocervical immune cell populations, vaginal fluid immune markers, vaginal fluid immunoglobulins and vaginal microbiome composition between individuals being treated with rituximab and healthy controls. ResultsWe enrolled 26 women treated with rituximab for autoimmune renal disease and 26 healthy controls. Median circulating and endocervical B-cell and plasma cell proportions were significantly lower in treated participants compared to controls. Median vaginal fluid IgA concentrations were significantly lower in participants treated with rituximab, while ILE, IgM, IgG1, IgG2, IgG3 and IgG4 were not different between groups. Total T cell frequencies were similar between groups, but the proportion of activated T cells (CD4+CD38+HLADR+) was significantly lower in people treated with rituximab. Concentrations of IL10, IL13, IL17, IL21, IL23, IL4, ITAC and TNFa were elevated in vaginal fluid from the rituximab group, while IL-8 was lower. A CST-IV-C, low-Lactobacillus pattern of vaginal microbiota was more common in the rituximab group. Conclusions and RelevanceSystemic B-cell depletion is associated with reduced vaginal fluid IgA, a more diverse microbiome composition, and increases in many vaginal fluid immune markers compared to healthy controls. The reduction in vaginal fluid IgA may provide opportunities for vaginal bacteria to induce inflammation. Key pointsO_ST_ABSQuestionC_ST_ABSHow does circulating B-cell depletion impact the vaginal microenvironment? FindingsIn this cross-sectional study of 52 women, B cell and plasma cell proportions were significantly lower in both blood and vaginal mucosa among rituximab-treated participants compared to healthy controls. Vaginal IgA concentrations, but not other immunoglobulins, were significantly lower in rituximab treated participants. In treated participants, vaginal cytokine concentrations were elevated, and microbiome composition shifted toward non-Lactobacillus-dominant communities. In six people with inflammatory vaginitis, both circulating and endocervical B cells were lowest in people with the most severe symptoms. MeaningSystemic B cell depletion is associated with alterations in vaginal mucosal immune markers and microbiome composition which increase local inflammation.

Purpose: Aicardi-Goutieres syndrome (AGS) is a type I interferonopathy presently associated with nine genes. PTPN1 is a negative regulator of the interferon pathway previously associated with chronic inflammation and recently type 1 IFN autoinflammation. Methods: Genomic data from undiagnosed individuals with suspected AGS were interrogated for PTPN1 variants, and predicted loss-of-function (pLOF) and damaging missense variants in PTPN1 were sought in two additional academic databases as well as the All of Us database. Results: We identified 13 cases with ultra-rare heterozygous pLOF or highly damaging missense variants in PTPN1. Nine cases were identified in a cohort of 53 individuals (~ 17%) with clinical, imaging and persistent biochemical features of AGS. Median age of onset is 1.75 years (IQR 0.67), significantly later (p< 0.0001) than other AGS genotypes. Four additional cases were identified in academic datasets with variable clinical features suggestive of autoinflammation. Additionally, 49 individuals with ultra-rare, damaging PTPN1 variants were identified in the All of Us database, none had features suggestive of AGS, but autoimmunity was highly prevalent (~21.6%). Conclusion: Our data implicate PTPN1 as a cause of later-onset presentations of AGS within a broader spectrum of autoinflammatory phenotypes. Segregation and biobank data demonstrate reduced penetrance, with carriers being enriched for autoimmune disorders.

BackgroundThis study aims to examine the independent relationships between individual components of metabolic syndrome (MetS) and two key clinical outcomes in patients with Crohns disease (CD): disease activity, as quantified by the Crohns Disease Activity Index (CDAI), and the occurrence of complications. MethodsThis retrospective cross-sectional study included 376 adults with newly diagnosed Crohns disease. Multiple linear regression was used to examine associations between metabolic parameters and CDAI scores, while multivariate logistic regression assessed links to complications. Analyses were also based on clinical CDAI cut-offs. Predictive nomograms were developed and internally validated via bootstrap resampling. ResultsMultiple linear regression indicated that higher CDAI scores were independently associated with lower BMI (B = -5.866, P < 0.001), lower HDL-C levels (B = -81.770, P < 0.001), higher triglycerides (B = 15.618, P = 0.001), and lower ESR (B = -0.375, P = 0.03). Multivariate logistic regression established low HDL-C (OR = 0.042, P < 0.001), low BMI (OR = 0.915, P = 0.034), and high triglycerides (OR = 1.792, P = 0.007) as significant independent risk factors for complications. The developed nomograms demonstrated strong predictive performance, with an adjusted R2 of 0.207 for the CDAI model and an AUC of 0.765 for the complication model. For both predictive tasks, the model incorporating separate TG and HDL-C measurements significantly outperformed the TG/HDL-C ratio model. ConclusionMetabolic disturbances demonstrate a significant association with increased disease severity and a higher risk of complication development in Crohns disease. Core tipO_LIDual-outcome study reveals HDL-C and TG differentially link to CD inflammation and complications, pointing to distinct mechanisms. C_LIO_LILow HDL-C is the strongest independent predictor for CD complications, underscoring its protective role beyond cholesterol transport. C_LIO_LIIndividual TG and HDL-C metrics outperform their ratio in prediction, challenging its use and suggesting independent pathways in CD. C_LIO_LILow BMI independently associates with both adverse outcomes, refining the "obesity paradox" and highlighting malnutritions key role. C_LIO_LIA practical, validated nomogram (AUC=0.765) integrates HDL-C, TG, and BMI to stratify complication risk, aiding clinical decision-making. C_LI

Background Plasma gelsolin (pGSN) is a non-immunosuppressive anti-inflammatory immunomodulator with demonstrated efficacy in animal models of acute lung injury. Its potential role in moderate-to-severe acute respiratory distress syndrome (ARDS) is currently under investigation. Methods We conducted a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of recombinant human pGSN (rhu-pGSN) following intravenous (IV) administration to healthy volunteers. Thirty-two participants were assigned to 4 sequentially ascending dose cohorts (6, 12, 18, 24 mg/kg of body weight) to receive five IV infusions of rhu-pGSN or saline placebo. Each cohort includes 8 subjects randomized 3:1 with rhu-pGSN or placebo. Doses were administered at 0 hours, 12 hours, 36 hours, 60 hours, and 84 hours. The primary outcome is the incidence and severity of clinical and laboratory AEs regardless of causality. Secondary outcomes include the pharmacokinetics of IV rhu-pGSN and the presence of anti-rhu-pGSN antibodies at Day 28. Results Overall, 10 subjects (41.7%) who received rhu-pGSN reported a total of 13 adverse events (AEs), and 1 subject (12.5%) who received placebo reported an AE. All AEs were mild or moderate. AEs in system organ classes that were reported by 2 or more subjects in either arm were skin and subcutaneous tissue disorders (12.5% rhu-pGSN; 0% placebo), gastrointestinal disorders (8.3% rhu-pGSN; 0% placebo), and nervous system disorders (12.5% rhu-pGSN; 12.5% placebo). No AEs by preferred term were reported by more than 1 subject in either arm. Three subjects (12.5%) experienced an AE assessed as related to study drug. No serious AEs occurred, and no AEs led to study discontinuation, dose interruption/reduction, or death. There were no apparent between-treatment differences in laboratory abnormalities, vital signs, or electrocardiogram findings. Conclusions Overall, in this study, IV rhu-pGSN (up to 24 mg/kg daily) appeared safe and well tolerated compared to placebo. The median half-life of rhu-pGSN exceeded 14 h across all dosing regimens, supporting once daily IV dosing in healthy subjects. Trial registration This study was registered with ClinicalTrials.gov on 2023-03-29 under the registration identifier NCT05789745.

Autoimmunity is emerging as a new etiology for early-onset gastric cancer (GC). However, it remains unclear what molecular pathways drive the initiation and progression of autoimmune tumorigenesis. Given that Major Histocompatibility Complex Class II (MHCII) is the strongest genetic risk factor for many autoimmune diseases, we hypothesized that MHCII-mediated autoantigen presentation drives tumorigenic differentiation of epithelial cells. Here we show that epithelial MHCII, rather than MHCII from immune cells, plays an essential role in the initiation of autoimmunity-driven tumorigenic differentiation of gastric epithelial cells, which was characterized by increased expression of cancer-associated markers with immune-evasive and stem-like features that potentiate premalignant progression. In addition, we show that early gastric premalignancy is reversible upon the removal of epithelial MHCII. This study reveals that epithelial MHCII antigen presentation is essential in the early stages of autoimmune-driven gastric tumorigenesis and highlight epithelial MHCII as a potential biomarker or therapeutic target in early interventions of autoimmunity-driven cancer development.

Equine asthma (EA) is a highly prevalent, chronic, inflammatory disease of the lower airways ranging from mild-to-moderate to severe clinical presentations. Diagnosis currently relies on bronchoalveolar lavage fluid (BALF) cytology, an invasive method associated with interobserver variability, which highlights the need for more reproducible approaches. MicroRNAs (miRNAs) are small noncoding RNAs involved in post-transcriptional gene regulation. They are stable and readily detectable in body fluids and have shown promising results as biomarkers in human asthma. The aim of this study was to characterize miRNA abundance profiles in BALF and serum from horses with distinct EA endotypes to evaluate their biomarker potential and explore their involvement in disease pathogenesis. A total of 43 horses were included and classified as either EA (n=32) or controls (n=11), based on clinical examination and BALF cytology. The EA horses were further divided into three endotypes based on BALF inflammatory cell composition: neutrophilic asthma (n=10), mastocytic asthma (n=15), and mixed asthma (n=7). RNA was isolated from both serum and BALF samples and analyzed by quantitative real-time PCR (qPCR) targeting 103 miRNAs linked to asthma and pulmonary inflammation in humans. Differential miRNA abundance was analyzed across EA endotypes. The most significantly differentially abundant miRNAs were used for in silico target prediction and pathway enrichment analyses. Horses with mixed EA had significantly lower levels of eca-miR-125a-3p and eca-miR-125b-5p in BALF compared to controls. Additionally, eca-miR-146a-5p abundance was significantly increased in BALF from horses with neutrophilic EA compared to mastocytic EA. Target and pathway enrichment analyses for eca-miR-146a-5p identified immune-relevant pathways, such as MAPK and T-cell receptor signaling, supporting its involvement in inflammatory processes associated with asthma. This study identified three promising candidates, eca-miR-125a-3p, eca-miR-125b-5p, and eca-miR-146a-5p, as potential biomarkers associated with different EA endotypes. These miRNAs are interesting candidates for further investigation in an independent cohort.

Rheumatoid arthritis is a prototypical autoimmune disease, characterised by prolonged systemic autoimmunity prior to organ-specific tissue inflammation. To achieve the contemporary goal of autoimmune disease prevention, a nuanced understanding of the transition from systemic autoimmunity to tissue-specific inflammation is critical. Here, we sought to identify immune signatures associated with the transition to subclinical joint inflammation detected by multi-joint ultrasound in anti-citrullinated protein antibodies (ACPA+)-positive individuals who imminently progress to RA. To achieve this, we performed single-cell transcriptomic and proteomic profiling on prospectively collected blood samples from high-risk ACPA+ imminent progressors, who were further stratified by the presence or absence of ultrasound (US)-detectable subclinical synovitis and compared them with ACPA+ non-progressors. We found type-1 interferon (IFN-I) activation in circulating CD14+ classical monocyte and GZMK+ CD8+ T cells preceding subclinical joint inflammation in ultrasound-negative (USneg) future progressors. In contrast, US-positive (USpos) future progressors exhibited a phenotypic shift in CD14+ classical monocytes towards IL1B+ expression and clonal expansion of GZMB+ cytotoxic CD8+ T cells at the onset of subclinical synovitis. Plasma proteomics also revealed a shift from Toll-like receptor-associated innate pathways in USneg future progressors toward effector and tissue-remodeling signatures in USpos future progressors. These findings suggest IFN-I-driven immune priming in specific immune subsets precedes the onset of subclinical joint inflammation, whereas tissue-directed inflammatory and cytotoxic programmes emerge at the onset of joint inflammation when clinical RA is imminent.

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.