Interleukin-1 (IL-1) was the first cytokine to be discovered and remains one of the most instructive molecules in immunology, linking fundamental mechanisms of innate immune activation to human inflammatory disease and targeted therapy. While it was initially identified for its relationship to fever in the 1970s, pathologic effects of IL-1 became a cornerstone for our understanding of rare monogenic disorders of autoinflammation in the early 2000s. Since that time, the number of disorders implicating a role for IL-1 has expanded to more complex inborn errors of immunity, as well as more common polygenic disorders diagnosed and treated by the practicing allergologist, including asthma, allergic rhinitis and neutrophilic and atopic dermatoses. In this review, we highlight the historical discovery of IL-1, its involvement in various pathologies, and its role as a therapeutic target, with focus on its role in disorders pertinent to the clinical allergist/immunologist.

Interleukin (IL)-31 has emerged as a pivotal mediator of pruritus. Since its initial identification, substantial progress has been made in elucidating the role of IL-31 in itch pathophysiology, particularly its direct effects on peripheral sensory neurons. Elevated IL-31 expression has been documented in a wide range of pruritic skin diseases, including atopic dermatitis, prurigo nodularis, and systemic disorders. Beyond its pruritogenic activity, IL-31 is increasingly recognized as a neuroimmune cytokine that links immune-cell activation to sensory-neuronal circuits and, in some contexts, may also exert immunomodulatory effects.

IL-31 signals through a heterodimeric receptor complex composed of IL-31 receptor α and oncostatin M receptor β, activating downstream pathways. In sensory neurons, IL-31 receptor signaling defines a distinct pruritic pathway, but emerging human transcriptomic data indicate that IL-31-responsive neurons are more heterogeneous than the canonical murine NP3 subset, highlighting an important translational consideration.

In this review, we summarize current knowledge regarding IL-31 biology, including its cellular sources, receptor expression, and signaling mechanisms, and discuss its role in both pruritic and non-pruritic diseases. We further evaluate therapeutic strategies targeting the IL-31/IL-31 receptor axis and consider the emerging concept that IL-31 blockade may relieve itch while simultaneously disinhibiting dendritic cell–driven type 2 inflammatory programs in selected contexts.

The interleukin-36 (IL-36) cytokine family is an important regulator of inflammatory responses at epithelial barrier surfaces, with particularly prominent roles in skin immunity and inflammatory disease. As members of the IL-1 superfamily, IL-36 cytokines include three agonists (IL-36α, IL-36β, and IL-36γ) and two antagonists (IL-36Ra and IL-38), which signal through a shared heterodimeric receptor complex to activate MyD88-dependent pathways, including NF-κB and MAPK, and induce pro-inflammatory cytokines, chemokines, and antimicrobial peptides. A defining feature of IL-36 biology is its dependence on proteolytic activation, whereby neutrophil- and pathogen-derived proteases convert low-activity precursors into highly active cytokines, enabling rapid amplification of inflammation and linking epithelial stress to neutrophil recruitment.

The clinical relevance of IL-36 signaling was established by the identification of loss-of-function mutations in IL36RN, encoding IL-36Ra, in generalized pustular psoriasis (GPP), a severe and potentially life-threatening neutrophilic dermatosis. These discoveries validated IL-36R as a therapeutic target and culminated in regulatory approval of IL-36R blockade for the treatment of GPP flares. Beyond GPP, accumulating evidence implicates IL-36 in inflammatory processes across multiple organ systems.

This review summarizes IL-36 molecular biology, receptor trafficking and signaling, and protease-dependent activation, and discusses roles in barrier immunity and host defense. We also synthesize evidence for pathogenic contributions of IL-36 across inflammatory skin diseases and extra-cutaneous disorders, and highlight emerging therapeutic strategies, biomarkers of response, and future clinical directions.

Among the five antibody isotypes, immunoglobulin E (IgE) is unique in both its biological potency and clinical associations. Secreted by a specialized subset of plasma cells, IgE plays a critical role in host defense against helminths and other parasitic infections. Its effector functions are mediated through two main mechanisms: (1) opsonization of parasite surfaces, which enables eosinophil recognition of the Fc region of IgE, leading to eosinophil degranulation and parasite destruction; and (2) potent activation of mast cells and basophils through high-affinity binding to FcεRI. Among all immunoglobulin (Ig) isotypes, IgE exhibits the strongest affinity for FcεRI on mast cells, underscoring its ability to trigger robust immune activation. However, despite the IgE signaling axis providing protection against parasites, it is also a central driver of allergic pathology, with elevated systemic IgE being strongly implicated in atopic diseases such as allergic rhinitis, asthma, and eczema. Emerging research has refined our understanding of the IgE signaling axis, revealing the existence of two distinct subsets of IgE-secreting plasma cells: short-lived (SLPC) and long-lived (LLPC). This distinction has profound implications: SLPC are responsible for acute reactions, whereas LLPC are responsible for chronic IgE-mediated inflammatory conditions. This review aims to synthesize current knowledge on the development and regulation of IgE-producing plasma cells, and to explore how their longevity may influence the pathogenesis of atopic conditions. We further discuss emerging therapeutic strategies designed to target the regulatory networks that support IgE plasma cell survival, with the goal of attenuating chronic IgE-mediated pathology.

Background: The underlying pathomechanisms of wheal reaction enlargement in chronic spontaneous urticaria (CSU) remain largely unclear. We hypothesized that the activation of mast cells (MCs) and recruitment of basophils to locally inflamed skin would be enhanced by lipid mediators (LMs) following initial skin MC activation. This study aimed to identify the LMs responsible for enhancing the aggregation of IgE-mediated MC activation and basophil chemotaxis.

Methods: We enrolled 77 CSU patients and 36 non-atopic control (NC) subjects. Lipid profiling of plasma from these subjects was performed using liquid chromatography-tandem mass spectrometry/mass spectrometry. We compared LMs before and after omalizumab treatment between responders and non-responders.

Results: The concentration of 5-lipoxygenase-mediated LMs was significantly higher in the plasma obtained from patients than in the plasma obtained from NC subjects. The stepwise model demonstrated that 5-hydroxyeicosatetraenoic acid (HETE) (odds ratio, 3.34; 95 % confidence interval, 1.91–5.86; p = 0.0001) was the strongest independent marker of CSU. Here, 5-HETE significantly upregulated IgE-dependent basophil and MC activation. 12-hydroxyeicosapentaenoic acid (HEPE) demonstrated statistically significant correlations between changes in basophil counts and changes in the LM levels before and after omalizumab administration (p = 0.0146). Additionally, 12-HEPE significantly inhibits TNF-α/IFN-β-induced CCL2 mRNA expression in human keratinocytes. Furthermore, 12-HEPE showed a significant increase in concentration after omalizumab treatment in responders (p = 0.0095), but not in non-responders.

Conclusions: In conclusion, 5-HETE and 12-HEPE may regulate IgE-mediated activation of MCs and basophils and recruitment of basophils in the CSU, respectively, suggesting that these LMs may be involved in the enlargement of wheal reactions.

Background: Biologic therapies are pivotal in managing severe asthma. Despite their efficacy, some patients discontinue biologics, with varying outcomes. Predictors of successful versus unsuccessful discontinuation remain poorly defined. This study aimed to identify clinical factors associated with post-discontinuation outcomes in a real-world practice.

Methods: This retrospective cohort included adults with severe asthma who had received biologics for at least 12 months and subsequently discontinued therapy for a minimum of three consecutive months. We assessed the effects of baseline blood eosinophilia (≥300 cells/μL), residual sputum symptoms during biologic therapy, treatment responsiveness, biologic class, and discontinuation reasons on post-discontinuation asthma exacerbation rates using multivariable Cox models.

Results: A total of 118 patients were analyzed. The Kaplan–Meier analysis estimated a 65 % exacerbation-free probability at 12 months after discontinuation. Factors associated with successful discontinuation included a robust clinical response and absence of exacerbations before cessation. Conversely, baseline eosinophilia, residual sputum symptoms during biologics, and discontinuation due to inadequate therapeutic response or financial burden were associated with post-discontinuation exacerbations. In class-stratified restricted models, persistent sputum remained significantly associated with post-discontinuation exacerbations after stopping anti-IL-5 therapies, while baseline eosinophilia was associated with post-discontinuation exacerbations after stopping anti-IgE or anti-IL-4Rα. Among patients with sputum symptoms or poor-response discontinuation, the overall frequency of exacerbations declined after discontinuation.

Conclusions: Baseline eosinophilia, persistent sputum during therapy, and discontinuation prompted by poor response or cost may serve as risk factors for post-discontinuation exacerbations; however, risk is phenotype- and class-dependent. Careful patient selection and monitoring are essential when considering the discontinuation of biologic treatment.

Background: Advances in pharmacologic therapy have improved asthma outcomes, yet persistent symptoms can challenge a subset of patients, thereby hindering clinical remission. This study aimed to assess longitudinal trends in symptom control and identify factors associated with persistent symptoms in adult patients with asthma receiving established treatments in Japan.

Methods: We analyzed data from the SApporo Real-world Asthma Survey, a repeated cross-sectional study conducted in Japan over a 26-year period (1997-2023). The participants were adult patients with asthma receiving guideline-based care from respiratory and/or allergy specialists. Data were collected through patient questionnaires and physician records. Multivariable logistic regression analysis was performed to identify risk factors for persistent symptoms.

Results: The median age of the analyzed 13,243 patients increased during the study (from 52 years in 1997 to 60 years in 2023), as did the proportion of women. Although nighttime symptoms, dyspnea, and unscheduled visits for exacerbation declined, 10 %-30 % of patients reported persistent cough and 20 %-40 % had sputum despite therapeutic advances. Chronic rhinosinusitis and current smoking were significant predictors of persistent symptoms. Patients undergoing intensive therapies had a higher symptom burden, although the symptom severity and unscheduled visit rates decreased within each treatment category over time.

Conclusions: Despite therapeutic advances and guideline-based specialist care, residual symptoms, especially cough and sputum, persisted in a significant proportion of Japanese adult patients with asthma. Comprehensive management strategies targeting comorbidities such as chronic rhinosinusitis and smoking are essential to achieve clinical remission and improve patient-centered outcomes.

Background: Research on asthma clinical remission has mainly focused on severe asthma with biologic therapy. This study aimed to determine the prevalence and predictors of clinical remission in patients with adult-onset asthma receiving non-biologic treatment.

Methods: Data were retrieved from the Chang Gung Research Database (CGRD), the largest electronic medical records-based database in Taiwan. A total of 14,935 patients diagnosed with asthma between 2002 and 2022 were screened. There were 8043 on-treatment patients enrolled. We defined on-treatment clinical remission as follows: (1) absence of symptoms (ACT score ≥20); (2) no use of systemic steroids; (3) no clinical exacerbation for at least 12 months.

Results: These patients were categorized according to clinical remission status: those who achieved clinical remission (n = 2185), and those who had persistent asthma (n = 5858). The on non-biologic treatment clinical remission rate of adult-onset asthma was 27.2 %. Factors associated with persistent asthma included female, smoking history, forced expiratory volume in 1 s <50 %, high blood eosinophil count, sputum fungal colonization, worse baseline asthma control test (ACT) score, high inhaled corticosteroid dose, and acute exacerbation and hospitalization in the previous 1 year. Baseline ACT score <23 had the best predictive value (area under the curve [AUC] = 0.616) for persistent asthma, while a combination of sputum fungal colonization, blood eosinophil count >300 cell/ul, baseline ACT score <23, and acute exacerbation (AE) last year were presented the greatest predictive value of persistent asthma (AUC = 0.673).

Conclusions: In this 20-year cohort study, nearly one third of the asthmatics achieved clinical remission under non-biologic treatment. Patients at the highest risk of persistent asthma require timely and targeted treatment strategies.

Background: The expression of betacellulin (BTC), which functions as a ligand for the EGF receptor (EGFR), is markedly reduced in the lesional skin of individuals with atopic dermatitis (AD), and it can improve Th2-type cytokine-mediated impairment of skin barrier function. However, the therapeutic potential of BTC in AD is poorly understood. Therefore, we sought to explore the therapeutic role and mechanisms of BTC in AD.

Methods: An MC903-induced AD mouse model was established to evaluate the therapeutic effects of BTC. Staphylococcus aureus internalization in human primary keratinocytes was assessed using fluorescein isothiocyanate labeling and immunofluorescence. In vivo S. aureus invasion was evaluated using a bacterial loading assay. An erlotinib-treated AD mouse model was used to investigate the involvement of EGFR signaling in the BTC-mediated alleviation of AD-like symptoms. Western blotting, immunofluorescence, and electron microscopy were used to assess BTC-induced autophagy. Conditional autophagy knockout mice were used to investigate the role of active autophagy in the therapeutic effects of BTC.

Results: BTC significantly ameliorated MC903-induced AD-like skin inflammation in a murine model, as evidenced by improvements in skin barrier function, reductions in inflammatory cytokine levels, and the suppression of S. aureus invasion. Mechanistically, BTC activates autophagy in keratinocytes through the EGFR-JNK/ERK signaling pathway. Importantly, the therapeutic effects of BTC were abolished in mice pretreated with an EGFR inhibitor and in mice with keratinocyte-specific autophagy deficiency.

Conclusions: BTC is a promising therapeutic candidate for AD through the activation of EGFR-JNK/ERK-dependent autophagy, highlighting the potential of BTC for clinical translation in AD management.

Background: Elevated palmitic acid (PA) levels have been associated with increased asthma risk, but its pathogenic role remains unclear. This study aims to investigate the relationship between serum PA levels and asthma severity and explores the pro-inflammatory effects of PA on airway epithelial cells and the underlying mechanism.

Methods: Serum samples were collected from asthmatic patients, and the concentrations of PA were quantified by ELISA. An HDM-induced mouse model of asthma was established and treated with PA. RNA sequencing and metabolomic profiling were used to identify PA-responsive genes and metabolites in airway epithelial cells, and key targets were validated by qPCR, Western blot, and ELISA.

Results: We found that elevated serum PA levels correlated with worse lung function, higher blood neutrophil percentages, and increased steroid needs in asthma patients. In a murine asthma model, PA exacerbated airway inflammation, hyperresponsiveness, and neutrophil infiltration. In vitro, PA stimulated airway epithelial cells to express high levels of neutrophil chemokines (CXCL2/CXCL8) via Src-ERK pathway activation. In addition, metabolomic analyses revealed that PA triggered pro-inflammatory metabolic reprogramming in airway epithelial cells, characterized by dysregulation of acylcarnitine/fatty acid β-oxidation, sphingolipid signaling, and arachidonic acid metabolism. Using of CD36 inhibitors significantly suppressed pro-inflammatory chemokines expression, Src/ERK signaling activation, and metabolic reprogramming in airway epithelial cells, as well as in the asthma mouse model.

Conclusions: our study demonstrated elevated PA exacerbates airway inflammation in asthma by inducing neutrophil chemokine expression and metabolic reprogramming in airway epithelial cells, providing novel insights into the pathophysiology of metabolically dysregulated asthma.

Background: Although Schizophyllum commune is a common causative fungus of allergic bronchopulmonary mycosis, it is often underrecognized in clinical practice. This is because it rarely forms spores under routine culture conditions, typically appears as white, non-sporulating colonies indistinguishable from other fungi, and is frequently dismissed as a contaminant rather than subjected to molecular identification. To minimize the risk of being overlooked, we established a practical protocol for the identification of S. commune based on its ability to produce hydrogen sulfide.

Methods: To evaluate the clinical utility of this protocol, we studied consecutive lower respiratory tract specimens collected for fungal culture from adult patients who visited a tertiary hospital for allergy and respirology. Fungal cultures were performed in accordance with this protocol between January 2023 and December 2024. We calculated the positive and negative predictive value of this protocol as a clinical test for identifying S. commune by detecting genetic analysis-proven S. commune as the reference outcome.

Results: Overall, 196 specimens were assessed during the study period. Based on the protocol, 19 specimens (10 %) were diagnosed as “a specimen CONTAINING S. commune.” All these specimens contained genetically-proven S. commune (positive predictive value: 100 %). S. commune was not recovered from any specimens that the protocol diagnosed as “NOT containing S. commune” (negative predictive value: 100 %).

Conclusions: This protocol enables the efficient and cost-effective detection of S. commune in clinical laboratories in a general medical facility, potentially reducing the underdiagnosis of S. commune-related allergic airway diseases and improving medical resource use.

Background: IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by IgG4-positive plasma cell infiltration and ectopic lymphoid structure formation. Although glucocorticoids are effective, relapse rates and adverse effects highlight the need for novel therapeutic targets. The immunological basis of IgG4-RD remains incompletely understood.

Methods: We analyzed peripheral blood mononuclear cells and inflammatory cells from the affected submandibular glands of patients with IgG4-RD using FACS. We assessed T peripheral helper (Tph) cell subsets and CD11c⁺CD21^- B cells and examined their associations with immunological and clinical parameters.

Results: Tph2 cells in peripheral blood and submandibular glands were significantly increased in patients with IgG4-RD, and circulating Tph2 cells expressed granzyme B, indicating their cytotoxic potential. Their frequency correlated positively with serum IgG4, soluble IL-2 receptor levels, plasmablast expansion, eosinophil counts, number of affected organs, and IgG4-RD Responder Index. CD11c⁺CD21^- B cells were also expanded and enriched in IgG4-producing subsets. These cells showed strong correlations with serum IgG4 levels, the IgG4/IgG ratio, and disease activity, but were inversely related to T follicular helper cells. Notably, Tph2 cells exhibited a robust positive correlation with CD11c⁺CD21^- B cells, defining a distinct extrafollicular immune axis. Glucocorticoid treatment reduced Tph2 frequencies in parallel with serum IgG4 decline.

Conclusions: This study identifies a novel Tph2-CD11c⁺CD21^- B cell axis driving extrafollicular immune dysregulation in IgG4-RD. Tph2 cells link humoral activation with cytotoxicity, and CD11c⁺CD21^- B cells serve as producers of IgG4 associated with disease severity. Targeting this axis may provide therapeutic strategies for refractory or relapsing IgG4-RD beyond glucocorticoids.

Introduction: Dysanapsis, a structural disproportion in which airways are small relative to lung size, has been identified as a risk factor for obstructive lung diseases, but its clinical significance in asthma remains unclear. This study aimed to evaluate dysanapsis on chest computed tomography (CT) and investigate its association with allergen sensitization.

Methods: A total of 159 asthmatic patients from the Hi-CARAT cohort without visible emphysema were evaluated. Allergen sensitization was assessed by the Multiple Allergen Simultaneous Test (MAST)-33. The cumulative allergen sensitization score (CASS) was calculated as the sum of class values: inhalant (iCASS, 18 allergens) and food (fCASS, 15 allergens). Dysanapsis was assessed by the CT-derived airway-to-lung ratio (ALR4), defined as the geometric mean of airway luminal diameters at four central sites divided by the cubic root of total lung volume. Principal component analysis (PCA) was also performed including inhalant allergen and serum total IgE levels.

Results: Compared with iCASS = 0 (G1), patients with the highest iCASS (G4) showed significantly smaller tracheal and truncus intermedius areas (228.9 vs 258.9 mm², P = 0.003; 92.8 vs 105.4 mm², P = 0.010). ALR4 was also significantly lower in G4 than in G1 (0.0809 vs 0.0865, P = 0.004). In contrast, fCASS categories showed no significant association with airway size or ALR4. PCA showed that patients with the highest iCASS displayed broader sensitization across indoor, pollen, and fungal allergens.

Conclusions: Inhalant allergen sensitization, but not food sensitization, was associated with dysanapsis, particularly narrowing of the central airways, in asthma.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting up to 10% of the global population, characterized by eczematous lesions and intense pruritus. Although immune mechanisms in AD are increasingly recognized, the precise role of regulatory T cells (Tregs) remains controversial, with conflicting reports on their frequency and suppressive capacity. This study aimed to delineate immune dysregulation underlying AD, focusing on the heterogeneity and functional states of Tregs.

Methods: Utilizing a 39-parameter CyTOF panel, we analyzed peripheral blood mononuclear cells (PBMCs) from 48 AD patients and 48 healthy controls. Findings were validated using public single-cell RNA sequencing datasets of PBMCs and skin, in vitro suppression assays, and immunofluorescence staining of skin lesions.

Results: AD patients exhibited an increased frequency of circulating Tregs, accompanied by altered expression of markers linked to function and activation. We identified a distinct CLA⁺ Treg subset expressing OX40, which impairs Treg function, and CRTH2, a marker of type 2 immunity. The frequency of this OX40⁺CRTH2⁺ subset correlated with disease severity, suggesting that these CLA⁺ Tregs are functionally compromised in AD. These OX40⁺ Tregs displayed a Th2-skewed transcriptional signature and showed markedly reduced suppressive capacity in vitro compared to OX40⁺ Tregs from healthy controls.

Conclusions: These results provide novel insights into AD immunopathology and highlight OX40⁺ Tregs as key drivers of immune imbalance. Our findings provide a mechanistic rationale for emerging OX40-targeted therapies, supporting precision medicine approaches in AD treatment.