Antonio Musolino, Marco Roversi, Mariateresa Romaniello
et al.
Introduction: Pneumococcal vaccination has significantly decreased the burden of invasive pneumococcal disease in the general population, however studies on effectiveness in Down syndrome (DS) are heterogeneous. In this cross-sectional study we evaluated the prevalence of adequate immune response in children with DS after pneumococcal vaccination and we searched for possible clinical predictors associated with it, in order to provide data to optimize vaccination strategies in this high-risk group. Methods: Data of children with DS referred to the DS outpatient Clinic of Bambino Gesù Children's Hospital, Rome, Italy, between September 2021 and March 2022 were reviewed. Clinical and laboratory predictors of immunological response to PCV vaccine, defined as an anti-pneumococcal IgG titer threshold above 0.35 μg/mL were compared and evaluated with bivariate analyses and logistic regression. Results: In this cohort of 406 patients the mean age was 8.4 years and 56.2 % of individuals were male. Most of them had congenital cardiopathy (57.8 %) and recurrent respiratory infections (57.4 %). An anti-pneumococcal Ig titer ≥0.35 μg/mL was found in 50.5 % of patients. Those with Ig < 0.35 μg/mL were significantly younger (p < 0.001) and less likely to have autoimmune disorders or hypothyroidism. Logistic regression showed that a positive history of previous surgery increased the likelihood of Ig ≥ 0.35 μg/mL (OR 2.25, p = 0.001), as well as hypothyroidism (OR 3.14, p = 0.016) and celiac disease (OR 3.70, p = 0.030). Additionally, older age at last PCV13 dose positively correlated with higher Ig levels (p = 0.018). Conclusion: Our findings confirm a lower prevalence of adequate immune response after anti-pneumococcal vaccination in individuals with DS. Older age at last PCV13 dose was found to be correlated to higher specific IgG titers; we suggest a tailored vaccination schedule or a booster dose in individuals with DS that could improve their immune protection.
Air pollution, particularly from fine particulate matter (PM2.5), poses a significant threat to respiratory health, yet the molecular mechanisms underlying PM2.5-induced lung injury remain incompletely understood. This study investigated the role of N6-methyladenosine (m6A) methyltransferase METTL3 in regulating mitophagy-dependent ferroptosis in bronchial epithelial cells exposed to PM2.5. Using in vitro and in vivo models, we demonstrated that PM2.5 exposure induced histological alterations in mouse lung tissues, including inflammatory cell infiltration, goblet cell hyperplasia, and mucus hypersecretion, concurrent with enhanced ferroptosis and mitophagy in bronchial epithelial cells. Gain-of-function and loss-of-function experiments showed that METTL3 overexpression exacerbated mitophagy and ferroptosis, while METTL3 silencing attenuated these processes, rescuing cell viability and reducing pulmonary inflammation. In vivo, intratracheal administration of METTL3 recombinant protein recapitulated these effects, confirming its role in amplifying PM2.5-induced lung injury. Mechanistically, PM2.5 upregulated METTL3 expression, which promoted PINK1 mRNA stability through m6A modification, activating the PINK1-dependent mitophagy pathway. This led to the excessive clearance of damaged mitochondria, culminating in iron-dependent lipid peroxidation, dysregulation of ferroptosis-related proteins (ACSL4 and xCT), and ferroptotic cell death. Critically, the inhibition of mitophagy with Mdivi-1 protected against histological damage and ferroptosis in mice, underscoring the therapeutic potential of targeting this pathway. Collectively, our findings established a hierarchical regulatory axis where m6A–mitophagy–ferroptosis drove lung injury. This study uncovered a novel link between epigenetic modification, mitophagy, and ferroptosis, identifying METTL3-mediated m6A modification and mitophagy as potential targets for preventing PM2.5-related respiratory diseases.
Jaromir Hunia, Jaromir Hunia, Jaromir Tomasik
et al.
The recent advancement of mRNA technology has opened new therapeutic avenues for treating hematologic malignancies, offering innovative approaches to enhance existing immunotherapies. This review examines the expanding role of in vitro transcribed (IVT)-mRNA-based platforms in hemato-oncology, focusing on key areas: monoclonal antibody production, bispecific antibody development, and CAR-T cell engineering. Unlike conventional biologics, mRNA allows for in vivo expression of therapeutic proteins, reducing manufacturing complexity and expanding access through scalable, cell-free synthesis. IVT-mRNA-encoded monoclonal and bispecific antibodies can overcome limitations such as short half-life and the need for continuous infusion, while enabling innovations like Fc silencing, protease-activated masking, and combinatorial immunotherapies. In CAR-T cell therapy, IVT-mRNA provides transient, safer alternatives to viral vector-based approaches and facilitates emerging strategies such as in vivo CAR programming and IVT-mRNA vaccine-like boosters. Despite these advantages, challenges remain, including delivery precision, durability of therapeutic effects, and limited clinical trial success. Beyond therapeutic mechanisms, the integration of bioinformatics and AI in IVT-mRNA design is accelerating the development of personalized and efficient cancer treatments. Overall, mRNA technology is redefining immunotherapy in hematology and holds the potential to broaden access to advanced treatments globally.
Surajit Dey, Wenying Lu, Prabuddha S. Pathinayake
et al.
IntroductionAsthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is a term used to describe a patient with coexisting clinical features of asthma and COPD. We have previously reported that epithelial to mesenchymal transition (EMT) is active in the lungs of patients with COPD however, EMT in ACO remains an unexplored area. We hypothesize that EMT is an active process in ACO.MethodsIn this cross-sectional study, large airway endobronchial biopsy (EBB) tissues from patients with asthma (14), COPD (22), current (CS) and ex-smokers (ES), and ACO (12) were immunohistochemically stained for EMT markers (E and N cadherin, vimentin, S100A4, and Collagen IV) and compared with 12 current smokers with normal lung function (NLFS) and 10 non-smoking healthy control (HC) subjects. In addition, air-liquid interface (ALI) cell cultures were performed and cells from patients with ACO and HC were treated with TGF-β, IL-13 and cigarette smoke extract (CSE). Later cells from ALI cultures were lysed for Immunoblotting. Immunostained tissues were enumerated for percent expression of E and N-Cadherin in the epithelium, vimentin and S100A4 positive cells both in the epithelium and reticular basement membrane (RBM). Additionally, the degree of RBM fragmentation was evaluated, a key tissue structural marker of EMT.ResultsCompared to healthy controls and asthmatics, ACO had the greatest fragmentation of RBM (P < 0.01). ACO also had substantially decreased percentage expression of E-cadherin (P <0.01), increase percentage of N-cadherin expression, and higher vimentin and S100A4 positive basal cells, in comparison to healthy controls. In the RBM of ACO, S100A4 positive cells (P <0.05) and Vimentin-positive cells were markedly higher in comparison to HC. Similar changes were observed with western blots in response to Th-2 cytokine IL-13, CSE and EMT activator TGF-β.ConclusionsThese data are suggestive of active EMT in ACO. Additionally, 50% of the patients with ACO were on 800 mcg/day inhaled corticosteroid (ICS) treatment which may have abrogated some EMT activity; however, it suggests protective effects of ICS as we previously reported in COPD. Studies with larger cohorts are needed to further confirm ICS effects in ACO.
Tsuyoshi Shirai, Tomonori Ishii, Tomonori Ishii
et al.
ObjectivesThe feasibility of corticosteroid withdrawal (CW) for Takayasu arteritis (TAK) remains uncertain. Two autoantibodies (Abs) are identified against endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) in TAK, determining its three subgroups. This study aimed to evaluate CW using tocilizumab (TCZ) and its association with the Ab profile.MethodsThis prospective study, lasted for 24 weeks, included patients with relapsed but stable TAK. Scheduled tapering of prednisolone (PSL) was performed with subcutaneous TCZ (CW at week 20). The primary endpoint was the difference in type A remission, defined by CW and the absence of inflammatory signs, according to the Ab profile at week 24.ResultsTwenty patients were included and 18 patients with a mean PSL dose of 4.9 ± 2.8 mg/day were analysed. Anti-EPCR Ab-positive (E+), anti-SR-BI Ab-positive (S+), and double-negative (DN) groups included four (22.2%), eight (44.4%), and six (33.3%) patients, respectively. At week 24, the mean PSL dose was 2.0 ± 2.7 mg/day. Type A remission was observed in eight patients (44.4%), with significant differences based on the Ab profile: E+ (three patients, 75%), S+ (five patients, 62.5%), and DN (zero patients, 0%) (P=0.018). Besides, age, disease duration, PSL dose, type V arterial lesion, arterial dilation, and C-reactive protein >0.01 mg/dL were identified as risks for CW failure.ConclusionCW using TCZ was achieved in 44.4% of patients with TAK relapse and was significantly higher in E+ and S+ patients. CW can be a feasible target, and the precise selection of patients is critical.
Abstract Background Radiation‐induced lung injury (RILI) is a common consequence of thoracic radiation therapy that lacks effective preventative and treatment strategies. Dihydroartemisinin (DHA), a derivative of artemisinin, affects oxidative stress, immunomodulation, and inflammation. It is uncertain whether DHA reduces RILI. In this work, we investigated the specific mechanisms of action of DHA in RILI. Methods Twenty‐four C57BL/6J mice were randomly divided into four groups of six mice each: Control group, irradiation (IR) group, IR + DHA group, and IR + DHA + Brusatol group. The IR group received no interventions along with radiation treatment. Mice were killed 30 days after the irradiation. Morphologic and pathologic changes in lung tissue were observed with hematoxylin and eosin staining. Detection of hydroxyproline levels for assessing the extent of pulmonary fibrosis. Tumor necrosis factor α (TNF‐α), transforming growth factor‐β (TGF‐β), glutathione peroxidase (GPX4), Nuclear factor erythroid 2‐related factor 2 (Nrf2), and heme oxygenase‐1 (HO‐1) expression in lung tissues were detected. In addition, mitochondrial ultrastructural changes in lung tissues were also observed, and the glutathione (GSH) content in lung tissues was assessed. Results DHA attenuated radiation‐induced pathological lung injury and hydroxyproline levels. Additionally, it decreased TNF‐α and TGF‐β after irradiation. DHA may additionally stimulate the Nrf2/HO‐1 pathway. DHA upregulated GPX4 and GSH levels and inhibited cellular ferroptosis. Brusatol reversed the inhibitory effect of DHA on ferroptosis and its protective effect on RILI. Conclusion DHA modulated the Nrf2/HO‐1 pathway to prevent cellular ferroptosis, which reduced RILI. Therefore, DHA could be a potential drug for the treatment of RILI.
Dong-Wei Zhang, Dong-Wei Zhang, Dong-Wei Zhang
et al.
The prevalence rate of acute respiratory distress syndrome (ARDS) is estimated at approximately 10% in critically ill patients worldwide, with the mortality rate ranging from 17% to 39%. Currently, ARDS mortality is usually higher in patients with COVID-19, giving another challenge for ARDS treatment. However, the treatment efficacy for ARDS is far from satisfactory. The relationship between the gut microbiota and ARDS has been substantiated by relevant scientific studies. ARDS not only changes the distribution of gut microbiota, but also influences intestinal mucosal barrier through the alteration of gut microbiota. The modulation of gut microbiota can impact the onset and progression of ARDS by triggering dysfunctions in inflammatory response and immune cells, oxidative stress, cell apoptosis, autophagy, pyroptosis, and ferroptosis mechanisms. Meanwhile, ARDS may also influence the distribution of metabolic products of gut microbiota. In this review, we focus on the impact of ARDS on gut microbiota and how the alteration of gut microbiota further influences the immune function, cellular functions and related signaling pathways during ARDS. The roles of gut microbiota-derived metabolites in the development and occurrence of ARDS are also discussed.
Sara Elena Rebuzzi, Giuseppe Fornarini, Alessio Signori
et al.
The first-line therapy of metastatic renal cell carcinoma (mRCC) has revolutionized with the approval of immune checkpoint inhibitors (ICIs) in combination with or without tyrosine kinase inhibitors (TKIs). The choice among the many different immuno-combinations (ICI-ICI or ICI-TKI) is challenging due to the lack of predictive factors. The different shapes of the Kaplan–Meier survival curves (e.g. “banana-shaped curves”) have raised many questions on the long-term survival benefit. Here, we analyzed the factors that could have impacted the different long-term survival, including the prognostic factors distribution (IMDC score), histological factors (sarcomatoid features, PD-L1 expression), and treatment characteristics (mechanism of action, duration, discontinuation rate). This overview highlights the factors that should be considered in the first-line setting for the patients’ therapeutic choice and prognostic assessment. They are also fundamental parameters to examined for head-to-head studies and real-life, large-scale studies.
Nieves Fernández-Gallego, Raquel Castillo-González, N. Méndez-Barbero
et al.
Allergic diseases are allergen‐induced immunological disorders characterized by the development of type 2 immunity and IgE responses. The prevalence of allergic diseases has been on the rise alike cardiovascular disease (CVD), which affects arteries of different organs such as the heart, the kidney and the brain. The underlying cause of CVD is often atherosclerosis, a disease distinguished by endothelial dysfunction, fibrofatty material accumulation in the intima of the artery wall, smooth muscle cell proliferation, and Th1 inflammation. The opposed T‐cell identity of allergy and atherosclerosis implies an atheroprotective role for Th2 cells by counteracting Th1 responses. Yet, the clinical association between allergic disease and CVD argues against it. Within, we review different phases of allergic pathology, basic immunological mechanisms of atherosclerosis and the clinical association between allergic diseases (particularly asthma, atopic dermatitis, allergic rhinitis and food allergy) and CVD. Then, we discuss putative atherogenic mechanisms of type 2 immunity and allergic inflammation including acute allergic reactions (IgE, IgG1, mast cells, macrophages and allergic mediators such as vasoactive components, growth factors and those derived from the complement, contact and coagulation systems) and late phase inflammation (Th2 cells, eosinophils, type 2 innate‐like lymphoid cells, alarmins, IL‐4, IL‐5, IL‐9, IL‐13 and IL‐17).
Jessica Marie Medrano, Pauline Maiello, Tara Rutledge
et al.
AbstractMycobacterium tuberculosis infection outcomes have been described as active tuberculosis or latent infection but a spectrum of outcomes is now recognized. We used a nonhuman primate model, which recapitulates human infection, to characterize the clinical, microbiologic, and radiographic patterns associated with developing latent M. tuberculosis infection. Four patterns were identified. “Controllers” had normal erythrocyte sedimentation rate (ESR) without M. tuberculosis growth in bronchoalveolar lavage or gastric aspirate (BAL/GA). “Early subclinicals” showed transient ESR elevation and/or M. tuberculosis growth on BAL/GA for 60 days postinfection, “mid subclinicals” were positive for 90 days, and “late subclinicals” were positive intermittently, despite the absence of clinical disease. Variability was noted regarding granuloma formation, lung/lymph node metabolic activity, lung/lymph node bacterial burden, gross pathology, and extrapulmonary disease. Like human M. tuberculosis infection, this highlights the heterogeneity associated with the establishment of latent infection, underscoring the need to understand the clinical spectrum and risk factors associated with severe disease.
Jeffrey M. Wilson, Alexander J. Schuyler, L. Workman
et al.
BACKGROUND Red meat allergy has historically been understood as a rare disease of atopic children, but the discovery of the "α-Gal syndrome," which relates to IgE to the oligosaccharide galactose-α-1,3-galactose (α-Gal), has challenged that notion. OBJECTIVE To describe the clinical and immunologic characteristics of a large group of subjects with self-reported allergy to mammalian meat. METHODS This was an observational study of 261 children and adults (range, 5-82 years) who presented for evaluation for allergic reactions to mammalian meat. Results were based on serum assays and a detailed questionnaire. RESULTS α-Gal specific IgE ≥ 0.35 IU/mL was detected in 245 subjects and symptom onset occurred ≥2 hours after eating mammalian meat in 211 (81%). Component testing supported a diagnosis of α-Gal syndrome in 95%, pork-cat syndrome in 1.9%, and primary beef allergy in 1.1%. Urticaria was reported by 93%, anaphylaxis by 60%, and gastrointestinal symptoms by 64%. Levels of IgE and IgG specific to α-Gal were similar in subjects who reported early- or delayed-onset symptoms, and in those with and without anaphylaxis. Levels of α-Gal specific IgE and severity of reactions were similar among those with and without traditional atopy, and among children (n = 35) and adults (n = 226). Blood group B trended toward being under-represented among α-Gal-sensitized subjects; however, α-Gal specific IgE titers were high in symptomatic cases with B-antigen. CONCLUSIONS The α-Gal syndrome is a regionally common form of food allergy that has a characteristic but not universal delay in symptom onset, includes gastrointestinal symptoms, can develop at any time in life, and is equally common in otherwise nonatopic individuals.
The prevalence of allergic diseases is regarded as one of the key challenges in health worldwide. Although the precise mechanisms underlying this rapid increase in prevalence are unknown, emerging evidence suggests that genetic and environmental factors play a significant role. The immune system, microbiota, viruses, and bacteria have all been linked to the onset of allergy disorders in recent years. Avoiding allergen exposure is the best treatment option; however, steroids, antihistamines, and other symptom-relieving drugs are also used. Allergen bioinformatics encompasses both computational tools/methods and allergen-related data resources for managing, archiving, and analyzing allergological data. This study highlights allergy-promoting mechanisms, algorithms, and concepts in allergen bioinformatics, as well as major areas for future research in the field of allergology.
K. Yamamoto-Hanada, K. Pak, Mayako Saito-Abe
et al.
Background Capturing epidemiological signatures is essential to document burdens of disease and to design health care services, including prevention measures, clinical interventions, and policies. There are large geographical and ethnic variations in the epidemiology of allergic and immunological diseases. Various data are available from North America and Europe, but the epidemiology of allergic and immunological diseases in Asia is not well documented. Objective To characterize epidemiological signatures of allergic and immunological disease in young children in Japan. Methods This was a national, multicenter, prospective birth cohort study: Japan Environment and Children's Study (JECS). A general population of 103,060 women was enrolled during pregnancy. Allergic and immunological outcomes were assessed among young children using questionnaire data. Results The prevalence of caregiver-reported immediate food allergy was 7.6%, 6.7%, and 4.9% at age 1, 2, and 3 years, respectively. Hen egg allergy was most common (5.4% prevalence at age 1 year) followed by allergies to cow milk and wheat. Several patterns of allergic symptom clusters were identified. Physician diagnosed, as reported by the caregiver, non-IgE mediated gastrointestinal food allergy affected 0.5% of infants. By contrast, caregiver-reported gastrointestinal food allergies affected 1.4% of children. Kawasaki disease affected 0.3% and 0.4% children, respectively, at age 1 and 3 years. Primary immunodeficiency disorders affected 0.005% children at age 3 years. Conclusion These data provide important epidemiological signatures of allergy and immunology in young Japanese children including the age-specific prevalence of allergic disease, Kawasaki disease, and primary immune deficiency.
Increase of allergic conditions has occurred at the same pace with the Great Acceleration, which stands for the rapid growth rate of human activities upon earth from 1950s. Changes of environment and lifestyle along with escalating urbanization are acknowledged as the main underlying causes. Secondary (tertiary) prevention for better disease control has advanced considerably with innovations for oral immunotherapy and effective treatment of inflammation with corticosteroids, calcineurin inhibitors, and biological medications. Patients are less disabled than before. However, primary prevention has remained a dilemma. Factors predicting allergy and asthma risk have proven complex: Risk factors increase the risk, while protective factors counteract them. Interaction of human body with environmental biodiversity with micro‐organisms and biogenic compounds as well as the central role of epigenetic adaptation in immune homeostasis have given new insight. Allergic diseases are good indicators of the twisted relation to environment. In various non‐communicable diseases, the protective mode of the immune system indicates low‐grade inflammation without apparent cause. Giving microbes, pro‐ and prebiotics, has shown some promise in prevention and treatment. The real‐world public health programme in Finland (2008–2018) emphasized nature relatedness and protective factors for immunological resilience, instead of avoidance. The nationwide action mitigated the allergy burden, but in the lack of controls, primary preventive effect remains to be proven. The first results of controlled biodiversity interventions are promising. In the fast urbanizing world, new approaches are called for allergy prevention, which also has a major cost saving potential.
Allergies are rapidly worsening in recent decades, representing the most common immunological diseases. The mechanism of disorders such as asthma, rhinocongiuntivitis, urticaria, atopic dermatitis, food and drug allergies, and anaphylaxis still remain unclear and consequently treatments is mostly still symptomatic and aspecific while developments of new therapies are limited. A growing amount of data in the literature shows us how the prevalence of allergic diseases is different in both sexes and its changes over the course of life. Genes, hormones, environmental and immunological factors affect sex disparities associated with the development and control of allergic diseases, while they more rarely are considered and reported regarding their differences related to social, psychological, cultural, economic, and employment aspects. This review describes the available knowledge on the role of sex and gender in allergies in an attempt to improve the indispensable gender perspective whose potential is still underestimated while it represents a significant turning point in research and the clinic. It will offer insights to stimulate exploration of the many aspects still unknown in this relationship that could ameliorate the preventive, diagnostic, and therapeutic strategies in allergic diseases.
Increased prevalence of food allergies in the last thirty years has been attributed to lifestyle changes in Westernized countries. Among the environmental factors, nutritional factors and their interaction with the gut microbiome in early life are thought to have an important role in the observed epidemiological change. The gut microbiome synthesizes bacterial metabolites, which represent a link among gut microbiome, nutrition, and immune system. The main metabolites produced by gut microbiome are short-chain fatty acids (SCFAs). SCFAs have multiple beneficial effects on human health including protective effects in autoimmune and inflammatory diseases. Among SCFAs, butyrate is essential for maintaining gut immune homeostasis and exerts a pivotal role in immune tolerance with strong anti-inflammatory effects in allergic diseases. Recent findings suggest that butyrate takes part in the development of immunological tolerance to food, especially in the first 1000 days of life. Herein, we provide a critical review of the scientific literature on the role of butyrate for prevention and treatment of food allergies with focus on the complex interplay among early life nutrition, gut microbiome, and immune system.