Nanoplastics Penetrate Human Bronchial Smooth Muscle and Small Airway Epithelial Cells and Affect Mitochondrial Metabolism.

Micro- and nanoplastic particles, including common forms like polyethylene and polystyrene, have been identified as relevant pollutants, potentially causing health problems in living organisms. The mechanisms at the cellular level largely remain to be elucidated. This study aims to visualize nanoplastics in bronchial smooth muscle (BSMC) and small airway epithelial cells (SAEC), and to assess the impact on mitochondrial metabolism. Healthy and asthmatic human BSMC and SAEC in vitro cultures were stimulated with polystyrene nanoplastics (PS-NPs) of 25 or 50 nm size, for 1 or 24 h. Live cell, label-free imaging by holotomography microscopy and mitochondrial respiration and glycolysis assessment were performed. Furthermore, 25 and 50 nm NPs were shown to penetrate SAEC, along with healthy and diseased BSMC, and they impaired bioenergetics and induce mitochondrial dysfunction compared to cells not treated with NPs, including changes in oxygen consumption rate and extracellular acidification rate. NPs pose a serious threat to human health by penetrating airway tissues and cells, and affecting both oxidative and glycolytic metabolism.

Clinical validation of grass pollen exposure chamber in patients with allergic rhinitis triggered by timothy grass.

BACKGROUND: The fluctuation in concentrations of airborne allergens frequently presents a challenge to assessing the efficacy of allergen immunotherapy (AIT) in 'field' studies. Allergen exposure chambers (AECs) are specialized medical installations developed to expose individuals to allergens at defined and consistent concentrations under a controlled environment. The aim of the study was to validate the provocation test with timothy grass pollen as well as to assess its safety in the AEC in patients with allergic rhinitis. METHODS: In the ALLEC® AEC, varying concentrations of timothy grass pollen were dispersed. Allergic symptoms were measured by total nasal symptom score (TNSS), acoustic rhinometry, peak nasal inspiratory flow (PNIF) and nasal discharge volume. Lung function, assessed through peak expiratory flow rate (PEFR) and forced expiratory volume in the first second (FEV1), was used to evaluate safety. RESULTS: The consistency of the test was proved by the stability of environmental conditions, including temperature, humidity and CO2 levels, as well as constant concentrations of grass pollen at predetermined levels ranging from 1000 to 10,000 particles per cubic meter (p/m3). Allergic individuals developed symptoms at concentrations of 3000 p/m3 and above, across all measured endpoints. Lung function was not affected throughout all the challenges. The reproducibility of symptoms was confirmed throughout the tests. The concentration of 8000 p/m3 together with a challenge duration of 120 min was found to be optimal. CONCLUSION: The study demonstrates that the ALLEC® grass pollen exposure chamber provides a reliable and safe method for inducing repeatable symptoms in patients with allergic rhinitis. This approach can be effectively applied for allergy diagnostics and clinical endpoint determination during AIT.

The potential impact of nano- and microplastics on human health: Understanding human health risks.

Plastics are used all over the world. Unfortunately, due to limited biodegradation, plastics cause a significant level of environmental pollution. The smallest recognized to date are termed nanoplastics (1 nm [nm] up to 1 µm [µm]) and microplastics (1 µm-5 mm). These nano- and microplastics can enter the human body through the respiratory system via inhalation, the digestive tract via consumption of contaminated food and water, or penetration through the skin via cosmetics and clothes contact. Bioaccumulation of plastics in the human body can potentially lead to a range of health issues, including respiratory disorders like lung cancer, asthma and hypersensitivity pneumonitis, neurological symptoms such as fatigue and dizziness, inflammatory bowel disease and even disturbances in gut microbiota. Most studies to date have confirmed that nano- and microplastics can induce apoptosis in cells and have genotoxic and cytotoxic effects. Understanding the cellular and molecular mechanisms of plastics' actions may help extrapolate the risks to humans. The article provides a comprehensive review of articles in databases regarding the impact of nano- and microplastics on human health. The review included retrospective studies and case reports of people exposed to nanoplastics and microplastics. This research highlights the need for further research to fully understand the extent of the impact of plastics on human health.

Hot topics in allergen immunotherapy, 2023: Current status and future perspective.

The importance of allergen immunotherapy (AIT) is multifaceted, encompassing both clinical and quality-of-life improvements and cost-effectiveness in the long term. Key mechanisms of allergen tolerance induced by AIT include changes in memory type allergen-specific T- and B-cell responses towards a regulatory phenotype with decreased Type 2 responses, suppression of allergen-specific IgE and increased IgG1 and IgG4, decreased mast cell and eosinophil numbers in allergic tissues and increased activation thresholds. The potential of novel patient enrolment strategies for AIT is taking into account recent advances in biomarkers discoveries, molecular allergy diagnostics and mobile health applications contributing to a personalized approach enhancement that can increase AIT efficacy and compliance. Artificial intelligence can help manage and interpret complex and heterogeneous data, including big data from omics and non-omics research, potentially predict disease subtypes, identify biomarkers and monitor patient responses to AIT. Novel AIT preparations, such as synthetic compounds, innovative carrier systems and adjuvants, are also of great promise. Advances in clinical trial models, including adaptive, complex and hybrid designs as well as real-world evidence, allow more flexibility and cost reduction. The analyses of AIT cost-effectiveness show a clear long-term advantage compared to pharmacotherapy. Important research questions, such as defining clinical endpoints, biomarkers of patient selection and efficacy, mechanisms and the modulation of the placebo effect and alternatives to conventional field trials, including allergen exposure chamber studies are still to be elucidated. This review demonstrates that AIT is still in its growth phase and shows immense development prospects.

AIT 2023: Current innovation and future outlook.

Although used for over 100 years, allergen immunotherapy (AIT) is still an indispensable tool in modern allergy managemen20t due to its potential to cure allergic diseases. Its current rapid development through the application of personalized and precision medicine approaches is strongly supported by advances in mHealth, component-resolved diagnosis (CRD)-based diagnostics, validation of novel biomarkers, advanced data management, and development of novel preparations. This review summarizes the key advances in the field and shows the perspectives for further development of next-generation AIT treatments.

Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper.

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nano-technologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime.

Assessment of autoantibodies in paediatric population with primary immunodeficiencies: a pilot study.

BACKGROUND: The correlation between primary immunodeficiencies (PIDs) and autoimmunity shows ethnic and geographical diversity. The aim of our study was to accumulate more data in paediatric PID population. METHODS: 58 children aged 1-17 and with PID (study group) and 14 age-matched immunocompetent individuals (control group) were included in the study. Serum levels of 17 different specific IgG antibodies against autoantigens were measured by means of a quantitative enzyme immunoassay. Immunoglobulin levels were analysed in relation to a detailed medical examination. RESULTS: Autoantibodies against one or more antigens were detected in the sera of 24.14% (n = 14) subjects in the study group. The most frequent were anti-thyroid peroxidase (anti-TPO) antibodies (n = 8; 13.8%). Anti-TPO antibody levels were elevated more often in PID patients with a positive family history of autoimmune diseases (p = 0.04). The screening for anti-deamidated gliadin peptide (DGP) and anti-tissue transglutaminase (tTG) antibodies in our series allowed identifying two previously undiagnosed cases of coeliac disease in PID patients. There was no statistically significant difference between the study and the control group in terms of the autoantibodies prevalence. CONCLUSIONS: This study provides data on the prevalence of autoantibodies in paediatric population diagnosed with PID. Selected autoantibodies (i.e. anti-tTG, anti-DGP) might be useful for the screening of PID to avoid the delay of diagnosis of an autoimmune disease.

The One Health approach for allergic diseases and asthma.

The One Health approach is a collaborative and interdisciplinary strategy with focal point on human, animal, and environmental health interconnections. One Health can support the advanced management of allergic diseases and asthma, as complex, multifactorial diseases driven by interactions between the resilience response to the exposome. According to the One Health concept allergic diseases and asthma arising from exposures to a wide range of allergens, infectious agents and irritants (such as pollutants) occurring indoors and outdoors can be heavily influenced by environmental health (air, water, and soil quality) intermingled with animal health. These are currently heavily impacted by climate change, land use, urbanization, migration, overpopulation, and many more. Thus, a coordinated response to address the underlying factors that contribute to the development of allergic diseases and asthma needs to focus on the environment, human, and animal health altogether. Collaborative efforts across multiple sectors, including public health, veterinary medicine, environmental science, and community engagement are thus needed. A wide range of activities, including monitoring and surveillance of environmental and health data, targeted interventions to reduce exposures to allergens and irritants, and research on the underlying mechanisms that drive the development of allergic diseases and asthma are needed to move the field forward. In this consensus document elaborated by the European Academy of Allergy and Clinical Immunology (EAACI) and American Academy of Allergy, Asthma, and Immunology (AAAAI) under the practical allergy (PRACTALL) series, we provide insights into the One Heath approach aiming to provide a framework for addressing the complex and multifactorial nature of allergic diseases and asthma.

Symptom Assessment of Patients with Allergic Rhinitis Using an Allergen Exposure Chamber.

Allergen exposure chambers (AECs) are clinical facilities that allow the exposure of participants to allergenic and non-allergenic airborne particles. They provide stable particle concentrations under controlled environmental conditions. This is of great importance both for diagnostic purposes and for the monitoring of treatment effects. Here, a protocol and the technical prerequisites for performing a safe and effective allergen challenge in subjects sensitized to airborne allergens (i.e., house dust mite [HDM]) in the ALL-MED AEC are presented. With this method, triggering allergic symptoms corresponds to natural exposure. This can be used for an allergy diagnosis or as a plausible endpoint in clinical trials, particularly for allergen immunotherapy (AIT). A controlled environment (temperature, humidity, and carbon dioxide [CO2]) in the chamber must be maintained. Allergen particles must be dispersed evenly within the AEC at stable levels throughout the challenge. For this presentation, allergic rhinitis (AR) patients sensitive to HDM allergens were enrolled. AR symptoms were assessed by the following parameters: total nasal symptom score (TNSS), acoustic rhinometry (ARM), peak nasal inspiratory flow (PNIF), and nasal secretion weight. The safety of the procedure was assessed by the peak expiratory flow rate (PEFR) and the forced expiratory volume in the first second (FEV1). The allergic subjects developed symptoms within 120 min of the trial. On average, the most intense symptoms appeared after 60-90 min and, after reaching a plateau, remained stable until the end of the trial.

EAACI guidelines on environmental science in allergic diseases and asthma - Leveraging artificial intelligence and machine learning to develop a causality model in exposomics.

Allergic diseases and asthma are intrinsically linked to the environment we live in and to patterns of exposure. The integrated approach to understanding the effects of exposures on the immune system includes the ongoing collection of large-scale and complex data. This requires sophisticated methods to take full advantage of what this data can offer. Here we discuss the progress and further promise of applying artificial intelligence and machine-learning approaches to help unlock the power of complex environmental data sets toward providing causality models of exposure and intervention. We discuss a range of relevant machine-learning paradigms and models including the way such models are trained and validated together with examples of machine learning applied to allergic disease in the context of specific environmental exposures as well as attempts to tie these environmental data streams to the full representative exposome. We also discuss the promise of artificial intelligence in personalized medicine and the methodological approaches to healthcare with the final AI to improve public health.

Validated allergen exposure chamber is plausible tool for the assessment of house dust mite-triggered allergic rhinitis.

BACKGROUND: Allergen exposure chamber (AEC) is a clinical facility that allows exposure to allergenic airborne particles in controlled environment. Although AECs offer stable levels of airborne allergens, the validation of symptoms and other endpoints induced by allergen challenge is key for their recommendation as a plausible tool for the assessment of patients, especially in clinical research. This study aimed to demonstrate the reproducibility of defined clinical endpoints after AEC house dust mite (HDM) challenge under optimal conditions in patients with allergic rhinitis (AR). METHOD: HDM was distributed at different concentrations. The assessment was subjective by the patients: total nasal symptom score (TNSS), visual analog scale (VAS), and objective by the investigator: acoustic rhinometry, peak nasal inspiratory flow (PNIF), and nasal secretion weight. Safety was assessed clinically and by peak expiratory flow rate (PEFR) and forced expiratory volume in the first second (FEV1 ). RESULTS: Constant environment: temperature, humidity, and carbon dioxide (CO2 ) concentration were maintained during all challenges. The concentration of HDM on average remained stable within the targeted values: 1000, 3000, 5000, 7000 particles (p)/m3 . Most symptoms were observed at concentrations 3000 p/m3 or higher. The symptoms severity and other endpoints results were reproducible. 5000 p/m3 , and challenge duration of 120 min were found optimal. The procedure was safe with no lung function abnormalities due to challenge. CONCLUSION: HDM challenge in ALL-MED AEC offers a safe and reliable method for inducing symptoms in AR patients for the use in controlled clinical studies including allergen immunotherapy.

Metal Allergy: State-of-the-Art Mechanisms, Biomarkers, Hypersensitivity to Implants.

Metal allergy is mainly an environmental disorder which can cause allergic contact dermatitis. Environmental metal exposures include jewelry, everyday metal items, mobile phones, leather, metal-rich food and implants, including stents or anchors. While consumer exposure is liable for the majority of metal hypersensitivity cases, the significance of occupational exposure to metals remains relevant. Although the most common metal allergens are nickel, chromium, and cobalt; however, lately, gold, palladium, titanium, and some others have also attracted attention. This review highlights advances in metal allergy mechanisms, biomarkers for potential patients' stratification as well as biological treatments. The most recent evidence of human exposure to metal for risk assessment is discussed, as well as the relationship between the occurrence of metal hypersensitivity and implanted devices, including non-characteristic symptoms. The latest data on the diagnosis of metal hypersensitivity are also reported.

Immunotherapy: State-of-the-art review of therapies and theratypes.

Through its disease-modifying potential, immunotherapy is the keystone to curing allergic diseases. Allergen immunotherapy, applied for more than a century, is currently supported by novel modalities such as mAb-based therapies or small molecules targeting the key nodes of the allergic inflammation network. In this review, a summary of the most significant advances in immunotherapy is presented, addressing not only novel approaches to stratifying patients but also major controlled clinical trials and real-world evidence that strengthen the role of immunotherapy in the treatment of allergies.

Contact Hypersensitivity as a Murine Model of Allergic Contact Dermatitis.

Contact hypersensitivity (CHS) is an experimental model of allergic contact dermatitis (ACD) that can be studied in mice. This study aims to present an objective laboratory method that may help to study the CHS reaction in mice, which can be measured and quantified by various tests. To induce CHS, on day "0", mice were sensitized on a previously shaved spot by abdominal skin painting with the hapten 2,4,6-trinitrochlorobenzene (TNCB) in an acetone-ethanol mixture, whereas negative control mice were sham sensitized with vehicle alone-acetone-ethanol mixture. On day "4", the baseline ear thickness was measured with a micrometer prior to the elicitation of CHS (challenge) by painting both ears with diluted TNCB both in the test and control groups. After 24 h, the ear swelling was measured with a micrometer. CHS is an example of a T cell-mediated immune response that causes swelling in inflamed tissue, peaking 24 h after the skin challenge with the same hapten. An increase in ear edema correlated with augmented ear weight, myeloperoxidase (MPO) activity, pro-inflammatory cytokine concentration in the ear extracts, increased thickening of the edematous dermis in the histological examination, and ear vascular permeability. There was also an increase in the concentration of TNP-specific IgG1 antibodies in the sera of the test group when compared with the control mice. Additionally, CHS can be successfully transferred with the CHS-effector cells obtained from donors previously sensitized with TNCB. The CHS-effector cells were administered intravenously into naïve recipient mice, which were subsequently challenged with the same diluted hapten. Ear swelling was measured with a micrometer 24 h later.

Interferon Gamma Targeted Therapy: Is It Justified in Primary Sjögren's Syndrome?

Background: The pathomechanism of primary Sjögren syndrome (pSS) is multifactorial. Many cytokines take part in this process, including interferon. The study aimed to quantify certain cytokines involved in the pathomechanism of primary Sjögren syndrome (IL2, IL5, IL6, IL10, IL13, TNFα, IFNγ) and determine their common clinical correlation. On this basis, we discuss the potential use of anti-cytokine drugs in pSS therapy. Methods: The study group consisted of adult patients with a confirmed diagnosis of pSS. Results: The most frequently detected cytokines were IFNγ (82% of patients), TNFα (70%), IL6 (50%), and IL2 (42.5%). In all patients, except for one patient, IFNγ was found in the presence of other specific cytokines. There was no difference in clinical symptoms, age, and laboratory test results between the group of patients with IL-6 + TNFα + IFNγ positive cytokine, and the group of patients in whom they were not detected. There was no correlation between the presence of IL5, IL13, IL2, IL6, IL10, TNFα and musculoskeletal symptoms, skin lesions, glandular domains, pulmonary neurological, lymphadenopathy, biological and hematological domains in ESSDAI (p > 0.05). Conclusions: IFNγ most likely plays a central role in the pathomechanism of the disease. We have not noticed a clinical correlation between the three most common cytokines (IL6, IFNγ and TNFα), preliminary research results open up the possibility of searching for new treatments for pSS. The lower percentage of patients with detectable levels of TNFα and IL6 may explain the ineffectiveness of drugs targeting cytokines in clinical trials to date.

Serum Allergen-Specific IgE among Pediatric Patients with Primary Immunodeficiency.

Background: Allergy is a clinical condition that reflects a deviated function of the immune system. The purpose of this study was to evaluate serum allergen-specific IgE (sIgE) along with clinical manifestations of allergy in patients with diagnosed primary immunodeficiency (PID). Methods: 72 patients, aged 1−17 years, diagnosed with PID and hospitalized between July 2020 and February 2021 were included in the study. Blood samples were obtained by venipuncture. sIgE (30 allergens), blood eosinophil count, as well as total IgE and IgG were measured and assessed in relation to a detailed medical examination. Results: Serum sIgE was detected in the blood of 50% of the patients in the study group, which significantly correlated (p < 0.0001) with clinical symptoms of allergy. During the period of the study, 61.1% of the patients showed symptoms of allergy, with 77.27% of them having tested positive for sIgE. The total IgE level was elevated in 18.06% of the patients and correlated with clinical symptoms of allergy (p = 0.004). An elevated total IgE level was not observed in children receiving immunoglobulin replacement therapy. Conclusion: The study showed that serum sIgE and total IgE together might be a plausible diagnostic tool for PID patients. However, for patients receiving immunoglobulin replacement therapy, the assessment of total IgE is not useful.

COVID-19 vaccination in patients receiving allergen immunotherapy (AIT) or biologicals-EAACI recommendations.

Immune modulation is a key therapeutic approach for allergic diseases, asthma and autoimmunity. It can be achieved in an antigen-specific manner via allergen immunotherapy (AIT) or in an endotype-driven approach using biologicals that target the major pathways of the type 2 (T2) immune response: immunoglobulin (Ig)E, interleukin (IL)-5 and IL-4/IL-13 or non-type 2 response: anti-cytokine antibodies and B-cell depletion via anti-CD20. Coronavirus disease 2019 (COVID-19) vaccination provides an excellent opportunity to tackle the global pandemics and is currently being applied in an accelerated rhythm worldwide. The vaccine exerts its effects through immune modulation, induces and amplifies the response against the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Thus, as there may be a discernible interference between these treatment modalities, recommendations on how they should be applied in sequence are expected. The European Academy of Allergy and Clinical Immunology (EAACI) assembled an expert panel under its Research and Outreach Committee (ROC). This expert panel evaluated the evidence and have formulated recommendations on the administration of COVID-19 vaccine in patients with allergic diseases and asthma receiving AIT or biologicals. The panel also formulated recommendations for COVID-19 vaccine in association with biologicals targeting the type 1 or type 3 immune response. In formulating recommendations, the panel evaluated the mechanisms of COVID-19 infection, of COVID-19 vaccine, of AIT and of biologicals and considered the data published for other anti-infectious vaccines administered concurrently with AIT or biologicals.

Advances and highlights in asthma in 2021.

Last year brought a significant advance in asthma management, unyielding to the pressure of the pandemics. Novel key findings in asthma pathogenesis focus on the resident cell compartment, epigenetics and the innate immune system. The precision immunology unbiased approach was supplemented with novel tools and greatly facilitated by the use of artificial intelligence. Several randomised clinical trials and good quality real-world evidence shed new light on asthma treatment and supported the revision of several asthma guidelines (GINA, Expert Panel Report 3, ERS/ATS guidelines on severe asthma) and the conception of new ones (EAACI Guidelines for the use of biologicals in severe asthma). Integrating asthma management within the broader context of Planetary Health has been put forward. In this review, recently published articles and clinical trials are summarised and discussed with the goal to provide clinicians and researchers with a concise update on asthma research from a translational perspective.

The Clinical and Immunological Activity Depending on the Presence of Interferon γ in Primary Sjögren's Syndrome-A Pilot Study.

The upregulation of IFN pathways and their stimulated genes is associated with primary Sjögren's syndrome (pSS). The recent studies also indicate the involvement of interferon γ (IFNγ) in the pathogenesis of pSS. The study aimed to assess the clinical and immunological activity depending on the concentration of IFNγ in the peripheral blood in pSS patients. METHODS: The study group consisted of patients over 18 years of age with a confirmed diagnosis of pSS. Based on the collected data, disease activity was assessed using the EULAR Sjögren's syndrome disease activity index (ESSDAI) and the EULAR Sjögren's syndrome patient reported index (ESSPRI). RESULTS: Among 40 pSS patients, 33 (82%) showed increased levels of IFNγ. The group with positive IFNγ was younger (43 years) than the group with negative IFNγ (57 years) (p < 0.05). In the positive IFNγ group, the time to diagnosis was shorter (p < 0.05). There was a difference in ESSDAI among patients with and without IFNγ (p < 0.05). There were no differences between the groups in ESSPRI and the presence of cryoglobulins, specific anti-SSA, and anti-SSB antibodies and in C3 and C4 hypocomplementemia. RF occurred in both groups with a similar frequency (p = 0.6), but in patients with IFNγ presence, significantly higher RF titers were observed (34.9 vs. 10.5; p < 0.05). CONCLUSION: In the group of patients with positive IFNγ, the mean value of RF and ESSDAI was higher. This group was also younger than patients with pSS without IFNγ.