BACKGROUND: Biologic therapies improve outcomes in severe chronic rhinosinusitis with nasal polyps (CRSwNP), but their comparative efficacy remains uncertain. OBJECTIVE: To compare the efficacy and safety of seven biolog...BACKGROUND: Biologic therapies improve outcomes in severe chronic rhinosinusitis with nasal polyps (CRSwNP), but their comparative efficacy remains uncertain. OBJECTIVE: To compare the efficacy and safety of seven biologic agents (dupilumab, omalizumab, mepolizumab, benralizumab, depemokimab, tezepelumab, and stapokibart) for the treatment of severe CRSwNP. METHODS: We systematically reviewed randomized trials in PubMed and EMBASE evaluating biologic agents for severe CRSwNP. Primary outcomes were changes in nasal-polyp score (NPS) and nasal congestion score (NCS) at 20-24 and 48-56 weeks. Secondary outcomes included changes in loss-of-smell, SNOT-22, UPSIT, Lund-Mackay scores, need for nasal-polyp surgery or systemic corticosteroids, and safety. We used mean differences (MDs) and odds ratios with 95% confidence intervals (CIs) for analysis. RESULTS: Fifteen randomized trials involving 3,642 patients were included. At 20-24 weeks, dupilumab and stapokibart produced greater reductions in NPS and NCS compared to depemokimab, omalizumab, and benralizumab, with no significant differences between dupilumab and stapokibart for NPS (MD: 0.29; 95%CI: [-0.97, 0.40]) and NCS (MD: 0.19; 95%CI: [-0.03, 0.42]). At 48-56 weeks, dupilumab and tezepelumab produced greater reductions in NPS and NCS than depemokimab, mepolizumab, or benralizumab; no significant differences were observed between dupilumab and tezepelumab for NPS (MD: 0.32; 95%CI: [-0.17, 0.81]) and NCS (MD: 0.06; 95%CI: [-0.19, 0.31]). Dupilumab, tezepelumab (at 48-56 weeks only) and stapokibart (at 20-24 weeks only) showed superior outcomes for secondary endpoints against other tested biologics. There were no analyzable data for stapokibart at 48-56 weeks and tezepelumab at 20-24 weeks. In the subgroup of patients with concomitant asthma, tezepelumab was superior to depemokimab and mepolizumab at 48-56 weeks, while at 20-24 weeks stapokibart was not superior to dupilumab with regards to NPS and NCS. In patients with concomitant aspirin-exacerbated respiratory disease, tezepelumab was superior to depemokimab in reducing NPS and NCS, while at 20-24 weeks, dupilumab was superior to omalizumab with regards to reductions in NPS and NCS. Safety profiles were comparable across agents. CONCLUSION: Dupilumab, tezepelumab, and stapokibart were associated with greater clinical benefit than other biologics in severe CRSwNP. Indirect comparisons did not demonstrate superiority of stapokibart (at 20-24 weeks) or tezepelumab (at 48-56 weeks) over dupilumab, highlighting the need for direct comparative trials.
Leung C, Yoo JW, Park HY
… +23 more, Bhutta H, Sidhu P, Guinto E, Koelwyn GJ, Vahedi M, Li X, Eddy RL, Leipsic JA, Leitao Filho FS, Yang JS, Milne S, Takiguchi H, Akata K, Ra SW, Moon JY, Kim HK, Cho Y, Yamasaki K, van Eeden SF, Shaipanich T, Lam S, Leung JM, Sin DD
BACKGROUND: In chronic obstructive pulmonary disease (COPD), patients with peripheral airways infiltrated by eosinophils and neutrophils ("mixed granulocytic COPD") show worse outcomes than those without. OBJECTIVES: To...BACKGROUND: In chronic obstructive pulmonary disease (COPD), patients with peripheral airways infiltrated by eosinophils and neutrophils ("mixed granulocytic COPD") show worse outcomes than those without. OBJECTIVES: To examine the expression of immune response and lung tissue remodelling pathways in patients with mixed granulocytic COPD. METHODS: In this post hoc study of the DISARM randomized controlled trial, mixed granulocytic COPD was defined by eosinophils > 1% and neutrophils > 3% of the total leukocyte count in bronchoalveolar lavage (BAL). We compared clinical outcomes of mixed granulocytic COPD with two other phenotypes (neutrophilic, pauci-granulocytic). We then examined canonical pathways using gene set enrichment analysis and expression of immune cell and tissue remodelling gene signatures in BAL across phenotypes. RESULTS: Among 54 patients, 33% had mixed granulocytic COPD. Patients with mixed granulocytic COPD had the lowest forced expiratory volume in 1 second (FEV), the most radiographic emphysema, and the highest annualized exacerbation rates. Cell pellets of BAL in mixed granulocytic COPD showed upregulated gene expression of type 1 (tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, and interferon (IFN)-gamma signaling) and type 2 (IL-4/13 signaling) immune responses relative to the neutrophilic and pauci-granulocytic phenotypes. Mixed granulocytic COPD was marked by increased expression of gene signatures for NK cells, B cells, and CD4 and CD8 naïve and memory/effector T cells. Mixed granulocytic COPD showed the highest expression of tissue remodelling processes, which significantly associated with lower FEV. CONCLUSIONS: Mixed granulocytic COPD is marked by complex immune responses in the peripheral airways and is associated with increased tissue remodelling that associates with more severe airflow limitation.
BACKGROUND: Transient increases in blood eosinophils may accompany dupilumab treatment, but these increases are rarely associated with clinical symptoms, and clinical significance in children needs further assessment. OB...BACKGROUND: Transient increases in blood eosinophils may accompany dupilumab treatment, but these increases are rarely associated with clinical symptoms, and clinical significance in children needs further assessment. OBJECTIVE: To evaluate the long-term efficacy and safety of dupilumab in children aged 6 to 11 years with type 2 asthma who completed the VOYAGE study and enrolled in the open-label extension study EXCURSION, and experienced an early increase in blood eosinophils. METHODS: This post hoc analysis assessed annualized severe exacerbation rates, change from baseline in pre-bronchodilator percent predicted (pp) FEV and Z-score, 5-item Asthma Control Questionnaire Interviewer Administered (ACQ-5IA), fractional exhaled nitric oxide (FeNO), blood eosinophils and total IgE, and safety, in subgroups with early eosinophil increase (children with <500 cells/μL at baseline and ≥500 cells/μL at VOYAGE week 12). RESULTS: At VOYAGE week 12, 22.4% (35/156) had ≥500 eosinophils/μL. Dupilumab reduced exacerbation rates versus placebo during VOYAGE across subgroups, with effects maintained in EXCURSION. Children switching from placebo to dupilumab also experienced consistent improvements similar to those who had been receiving dupilumab. Improvements in ppFEV and Z-score, ACQ-5IA, FeNO, and total IgE were observed in children with and without early blood eosinophil increases. No safety differences were observed across subgroups. CONCLUSION: Dupilumab versus placebo reduced exacerbations, improved lung function and asthma control, and decreased inflammatory biomarkers in children with type 2 asthma across subgroups with and without early blood eosinophil increases up to 2 years. No differences in the dupilumab safety profile were observed in children with early eosinophil increases. CLINICAL IMPLICATIONS: Early eosinophil increases during dupilumab treatment did not affect efficacy or safety, supporting continued therapy in the absence of symptoms. CAPSULE SUMMARY: Early eosinophilia occurred in approximately 20% of children on dupilumab and did not affect dupilumab's efficacy, safety, or biomarker improvements, supporting continued therapy when no symptoms of a hypereosinophilic syndrome are present.
BACKGROUND: Maternal antibiotic exposure during pregnancy has been associated with early childhood infection proneness, but the underlying mechanisms remain unknown. Longitudinal birth cohort studies with long follow-up...BACKGROUND: Maternal antibiotic exposure during pregnancy has been associated with early childhood infection proneness, but the underlying mechanisms remain unknown. Longitudinal birth cohort studies with long follow-up and multi-omics data are lacking. OBJECTIVE: To 1) investigate the association between prenatal antibiotics and offspring infection risk 2) investigate the potential mechanisms. METHODS: The Danish population-based COPSAC cohort with 663 mother-child pairs were followed from pregnancy until age 13 years. Detailed infection diaries age 0-3 years for common infections (cold, tonsillitis, otitis media, fever, gastrointestinal infections, and pneumonia) and moderate-to-severe (hospital diagnoses) infections were registered until age 13 years. We analyzed maternal antibiotic exposure vs risk of offspring infection risk with assessments of newborn child blood metabolome, gut and airway (age 1 week and 1 month) microbiome, and airway cytokine profiles (age 1 month). We adjusted for genetic, environmental, and socioeconomic factors. RESULTS: Children whose mothers were exposed to antibiotic treatment during pregnancy had a higher risk of infections until age 13 years: adjusted incidence rate ratio (aIRR): 1.75 (1.19-2.57), p=0.005) and pneumonia (aIRR: 1.81 (1.10-2.99), p=0.015). Maternal antibiotic exposure related changes in the newborn child metabolome profile associated with increased child pneumonia, tonsilitis and fever risk. Both number and types of maternal antibiotic treatments had an impact on offspring infection risk. There were no noticeable findings for microbiome, genetics and airway cytokine profiling. CONCLUSION: Maternal antibiotics during pregnancy increased long-term risk of childhood respiratory infection risk following a dose-response pattern, which was linked to newborn metabolomic alterations.
Thames AH, Rische CH, Krier-Burris RA
… +16 more, Cao Y, Hunt AC, Klug N, Zelenetz SR, Burleigh ER, Aw R, Wong DA, Shaver ZM, Seki K, Guerrero L, Fernandez R, Sharma S, Bochner BS, Jewett MC, Scott EA, O'Sullivan JA
BACKGROUND: Mast cell elimination through Siglec-6 is a minimally explored strategy for diseases characterized by mast cell overactivity or overproduction. OBJECTIVE: Here, we combine nanotechnology with cell-free protei...BACKGROUND: Mast cell elimination through Siglec-6 is a minimally explored strategy for diseases characterized by mast cell overactivity or overproduction. OBJECTIVE: Here, we combine nanotechnology with cell-free protein synthesis to develop a therapeutic strategy (anti-Sig6-NPmidoFab) for selectively eliminating mast cells. METHODS: Nanocarriers are loaded with the protein kinase inhibitor midostaurin and conjugated with cell-free protein synthesis-enabled clickable, synthetically dimerized anti-Siglec-6 antibody fragments to selectively target Siglec-6-expressing mast cells. RESULTS: Using human mast cell lines and primary human mast cells as well as a Siglec-6 knock-in mouse model and a humanized mast cell malignancy mouse model, we demonstrate selective elimination of Siglec-6 (+) mast cells with reduced off-target effects on Siglec-6 (-) cells. CONCLUSION: This approach offers new treatment strategies for malignant and non-malignant mast cell-mediated disease with potential for broad application.
Luo L, Yuan H, Srivastava A
… +17 more, Annusver K, Khera N, Saha P, Prieux R, Mahapatra KD, Kelemen E, Dholakia M, Freisenhausen JC, Petkova M, Agerberg K, Dompage DM, Mäkinen T, Fyhrquist N, Pejler G, Kasper M, Pivarcsi A, Sonkoly E
BACKGROUND: Keratinocytes play a central role in amplifying skin inflammation in psoriasis and atopic dermatitis (AD). However, the epithelial-intrinsic regulators involved in responsiveness to inflammatory cues remain p...BACKGROUND: Keratinocytes play a central role in amplifying skin inflammation in psoriasis and atopic dermatitis (AD). However, the epithelial-intrinsic regulators involved in responsiveness to inflammatory cues remain poorly defined. MiRNAs are fundamental regulators of gene expression. OBJECTIVE: To define the role of miR-149 in keratinocyte immune functions in healthy skin and chronic inflammatory skin diseases. METHODS: Keratinocyte-specific Mir149 knockout mice (Mir149) were generated. Experimental AD (Ovalbumin) and psoriasis (IL-23/Imiquimod) models were performed followed by severity scoring, qPCR, RNA sequencing, immunohistochemistry, single-cell RNA sequencing (scRNA-seq) and flow cytometry. Chemokine array was performed on keratinocyte supernatants. In mice, in vivo TWEAK antibody blockade was performed. Ex vivo skin biopsies from patients with psoriasis and allergic contact dermatitis were injected with synthetic miR-149. RESULTS: Mir149 mice exhibited a pre-inflammatory transcriptional state. In both AD and psoriasis models, Mir149 mice developed exaggerated skin inflammation with epidermal thickening, and increased immune infiltration with mast cell accumulation. MiR-149 represses the TNF receptor family member TWEAKR, and its loss led to enhanced TWEAK-induced NF-κB activation and chemokine production. scRNA-seq revealed expansion of activated basal keratinocytes enriched for TWEAK-responsive chemokines and immune cell accumulation in Mir149 skin. Antibody-mediated neutralization of TWEAK strongly attenuated enhanced inflammation in vivo. Notably, the miR-149/TWEAKR axis is dysregulated in human psoriasis and AD. Ex vivo delivery of synthetic miR-149 to inflamed skin suppressed inflammatory mediators. CONCLUSION: MiR-149 acts as a fundamental brake on epithelial-immune interactions, and its loss in AD and psoriasis can lead to amplification of keratinocyte inflammatory responses.
Yang Y, Kanerva M, Liira H
… +10 more, Vuokko A, Laakso S, Vangelova-Korpinen V, Wang S, Kvarnström K, Varonen M, Suojalehto H, Lauerma A, Karisola P, Alenius H
BACKGROUND: Persistent symptoms following SARS-CoV-2 infection, termed post-COVID-19 condition or long COVID (LC), impose substantial psychological and socioeconomic burdens. However, miRNA-mRNA interactions underlying L...BACKGROUND: Persistent symptoms following SARS-CoV-2 infection, termed post-COVID-19 condition or long COVID (LC), impose substantial psychological and socioeconomic burdens. However, miRNA-mRNA interactions underlying LC heterogeneity remain incompletely defined. OBJECTIVE: To determine whether integrative blood miRNA-mRNA profiling identifies molecular LC subclusters linked to clinical and immune-hematopoietic features. METHODS: We performed integrated miRNAome-transcriptome profiling of circulating blood RNA from individuals with LC and recovered controls. Differential miRNA and mRNA expression were assessed using LIMMA, and hierarchical clustering was used to define LC subclusters. Validated miRNA-mRNA interaction networks were constructed using miRNet. Clinical, functional, and biochemical parameters were compared between subclusters, and a random forest classifier was developed. RESULTS: Clustering identified an immune-hematopoietic LC subcluster, LC1, characterized by extensive miRNA-mRNA dysregulation, enrichment of erythropoietic, platelet, and immune pathways, and biochemical alterations including lower plasma sodium and elevated fibrin D-dimer and thrombin time. Compared with LC2, LC1 showed persistently greater symptom burden, functional impairment, reduced quality of life, lower resilience, and higher anxiety/depressive symptoms. Potential confounding by age, sex, comorbidities, and selected medication use was evaluated. Network and co-expression analyses identified regulatory nodes enriched for viral infection and natural killer cell activation pathways. A random forest classifier incorporating nine miRNAs and LRRFIP2 achieved an AUROC of 0.91 for LC1, distinguishing LC1 from LC2 and recovered controls. CONCLUSION: LC comprises biologically and clinically distinct subclusters shaped by coordinated miRNA-mRNA remodeling. The immune-hematopoietic LC1 subtype supports biomarker-based stratification of patients with persistent physiological and clinical impairment.
Dysregulation of type 2 (T2) immunity, which normally protects the host against large parasites, toxins, and venoms, leads to aberrant inflammatory responses underlying several allergic diseases. Recent advances have hig...Dysregulation of type 2 (T2) immunity, which normally protects the host against large parasites, toxins, and venoms, leads to aberrant inflammatory responses underlying several allergic diseases. Recent advances have highlighted the important role of innate immune responses in the initiation and persistence of these disorders, identifying innate immune cells as key drivers as well as potential biomarkers and therapeutic targets. In this review, we summarize recent findings on the molecular mechanisms through which innate immune cells interact with adaptive immunity to promote the development and chronification of T2-mediated diseases, including allergic rhinitis, chronic rhinosinusitis with nasal polyps, asthma, food allergy, eosinophilic esophagitis, and atopic dermatitis. We also discuss the emerging role of trained immunity and maladaptive trained immunity in either protecting against or promoting allergic disease development. A better understanding of innate immune pathways and their interplay with adaptive immunity might be crucial for the identification of novel biomarkers and therapeutic targets, fostering precision medicine approaches aimed at improving patients' quality of life while reducing the considerable socioeconomic burden of allergic diseases.
Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) function comprise a direct membrane-to-nucleus intracellular signaling pathway, facilitating rapid transcriptional changes in response t...Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) function comprise a direct membrane-to-nucleus intracellular signaling pathway, facilitating rapid transcriptional changes in response to cytokines, growth factors, and hormones. Since the first JAK inhibitor (JAKi) gained regulatory approval in 2011, targeting of the JAK-STAT pathway has expanded significantly with over a dozen approved agents and new indications in many immune mediated inflammatory diseases (IMIDs). Newer agents targeting the JAK-STAT pathway have been developed with improved JAK selectivity, delivery to specific tissues, and new mechanisms of action in an effort to improve efficacy and address ongoing safety concerns. This review covers the expanding clinical use of JAK-STAT inhibition across IMIDs as well as new therapeutic strategies and approaches.
Inflammaging, the aberrant chronic inflammatory state at advanced age, is an immunological phenomenon associated with detrimental long-term health consequences, morbidity, and mortality. Although the precise etiology of...Inflammaging, the aberrant chronic inflammatory state at advanced age, is an immunological phenomenon associated with detrimental long-term health consequences, morbidity, and mortality. Although the precise etiology of inflammaging is elusive, emerging evidence indicates that molecular and cellular changes in immune cells drive inflammaging directly through heightened cytokine production and indirectly via inflammatory cell death and ineffective neutralization of inflammatory cellular waste. Additionally, non-immune tissue cells, particularly senescent cells, amplify the heightened inflammatory environment with age via their secretome and by modulating the immune system. The systemic concentrations of inflammatory mediators during aging is in the same range as those seen in mild, acute viral infections. Intriguingly, centenarians, who exhibit exceptional health span and longevity do not evade inflammaging but appear to neutralize its downstream effects through negative molecular or cellular feedback mechanisms. Collectively, this review positions inflammaging as a dynamic and multifactorial process arising from coordinated immune and non-immune dysfunction while outlining opportunities to counter age-related inflammation.
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by esophageal dysfunction and tissue eosinophilia that is often associated with food impaction and dysphagia. The disease is triggered by all...Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by esophageal dysfunction and tissue eosinophilia that is often associated with food impaction and dysphagia. The disease is triggered by allergic hypersensitivity to food involving a strong type 2 immune response accompanied by tissue remodeling and, if left untreated, progression to strictures thought to be due, in part, to unabated lamina propria fibrosis. The composite finding of fibrosis and stenosis is referred to as "fibrostenosis". Current pharmacologic therapies include approved topical corticosteroid formulations and a precision monoclonal antibody targeting type 2 immunity, yet it is not clear whether these therapies universally reverse fibrosis. This could be due in part to the complexity of the underlying tissue remodeling process, involving a variety of cells and molecular pathways that extend beyond isolated type 2 immunity and that can create a feed-forward loop. This review discusses the need for prompt diagnosis and treatment in EoE, the identification of histologic parameters and/or biomarkers of potential progression to tissue remodeling, and the current state of research into key cellular and molecular mediators that drive tissue remodeling in EoE.
Olsthoorn SEM, Onrust-Van Schoonhoven A, de Bruijn MJW
… +12 more, Weekers J, van Nimwegen M, van Beek G, de Koning W, Trap L, van der Ploeg EK, van Weelden GH, Sanders MA, Surace L, Di Santo JP, Hendriks RW, Stadhouders R
BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are key effector cells of type 2 immunity. A subset of ILC2s, which expresses KIT (CD117), display increased phenotypic plasticity and have previously been linked to seve...BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are key effector cells of type 2 immunity. A subset of ILC2s, which expresses KIT (CD117), display increased phenotypic plasticity and have previously been linked to severe asthma and psoriasis. However, the molecular mechanisms promoting a KIT ILC2 state remain poorly understood. OBJECTIVE: We defined the molecular basis for the enhanced plasticity of KIT ILC2s and identified signals that induce this phenotype, including links with immune disease susceptibility. METHODS: We combined bulk as well as single-cell transcriptome (RNA sequencing) and epigenome (assay for transposase-accessible chromatin using sequencing) analysis with in vitro culture assays using primary human KIT or KIT ILC2s and multipotent ILC progenitors. Epigenomic data were integrated with genetic risk variants for major human immune diseases. RESULTS: Multiomic analyses revealed that KIT ILC2s maintain a unique hybrid character marked by expression and open chromatin of genes linked to both ILC progenitors and ILC2 biology. KIT ILC2s showed extensive epigenomic priming at gene loci related to naive lymphocyte biology, tissue homing, and ILC3 effector functions, including IL17 and IL23R-explaining why KIT ILC2s are poised to adopt an ILC3-like phenotype. Genetic risk variants for asthma and autoimmunity are enriched in the poised epigenome of KIT ILC2s. Common γ-chain cytokines IL-2/IL-7 induced and maintained a KIT phenotype in KIT ILC2s through STAT5 activation. CONCLUSIONS: Our study defines KIT ILC2s as existing in a developmentally immature state and carrying a precursor-like epigenome that promotes phenotypic plasticity and is linked to immune disease susceptibility. Importantly, we identify STAT5-mediated cytokine signals as candidates for therapeutic targeting of KIT ILC2s.
BACKGROUND: DNA methylation accurately predicts chronological age, including gestational age (GA). Previous studies have used CpGs on the EPIC or 450K arrays to generate epigenetic clocks for estimating GA. OBJECTIVE: Us...BACKGROUND: DNA methylation accurately predicts chronological age, including gestational age (GA). Previous studies have used CpGs on the EPIC or 450K arrays to generate epigenetic clocks for estimating GA. OBJECTIVE: Using the Asthma&Allergy (A&A) array, we estimated GA and calculated GA acceleration (GAA) in cord blood DNA from 2,451 ancestrally diverse participants from seven birth cohorts investigating early life risk factors for asthma and allergic diseases and disease onset in childhood. METHODS: Two gestational epigenetic clocks were constructed: one used GA-associated CpGs in an epigenome-wide association study (EWAS) and a second used CpGs associated with GA in specific cell types. For both, we calculated GAA and tested for associations with six prenatal variables and eight allergy-related childhood outcomes. We then conducted pathway analysis of expressed genes correlated with GAA and validated gene expression signatures in peripheral blood at age 2. RESULTS: Strong correlations between reported GA and estimated GA were observed using the EWAS and the cell-specific clocks (r=0.90 and r=0.83, respectively). Using the cell-specific clock, GAA was associated with two outcomes (higher birthweight, P=1.69x10; less allergic asthma, P=0.025), while the EWAS clock was associated with birthweight (P=4.68x10). A significant sex by GAA interaction effect on birthweight, with a larger effect size in females, was observed with both clocks (EWAS, P=5.77x10; cell-specific, P=0.021). Cord blood RNA-seq analysis revealed upregulated IL-6 and TNF and downregulated IL-10 signaling pathways associated with GAA, and gene expression in blood at age 2 further revealed associations with asthma at age 7. CONCLUSION: Positive correlations between GAA and inflammatory gene expression and the negative association with allergic asthma suggest that increased expression of inflammatory genes in cord blood and at age 2 is protective against developing asthma. CpGs on the A&A array are accurate predictors of GA, capturing aging aspects specifically related to inflammatory programs.