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Trained immunity has emerged as a new concept in immunology that is associated with the memory of innate immune cells and linked to specific metabolic and epigenetic reprogramming of these cells. Trained immunity may confer nonspecific and sustained protection against a broad range of pathogens, and recent findings show that it might also be involved in allergy mechanisms. Some conventional vaccines have demonstrated trained immunity induction as the mechanism underlying their heterologous protection. The development of novel vaccines designed especially for this purpose (trained immunity-based vaccines) might be useful in the absence of conventional vaccines or in specific clinical settings. Under certain circumstances, trained immunity could lead to persistent inflammatory innate immune cell responses in subjects with allergy, which could be associated with the development and worsening of allergy by promoting and amplifying aberrant type 2 immune responses. In other cases, trained immunity may help promote healthy immune responses to allergens, such as type 1 responses that counterbalance the type 2 inflammation or regulatory T cells that induce tolerance. Trained immunity-based allergen vaccines could become the next generation of allergen-specific immunotherapy vaccines, harnessing the potential of trained immunity to induce allergen tolerance. The identification and characterization of proper training inducers might well pave the way for the development of novel immunotherapies., Competing Interests: Disclosure statement Supported by the Spain Ministry of Science, Innovation and Universities (grant PID2020-114396RB-I00 [to O.P.]); and by the Margarita Salas contract UCM-CT18/22 to A.A cofinanced from Complutense University of Madrid, the Ministry of Universities and the Plan of Recuperación, Transformación y Resilencia. Disclosure of potential conflict of interest: O. Palomares reports research grants from CAM, Inmunotek SL, Novartis, and AstraZeneca and fees for giving scientific lectures or participation in advisory boards from AstraZeneca, Pfizer, GlaxoSmithKline, Inmunotek SL, Novartis, and Sanofi-Genzyme. J. L. Subiza is the founder and CEO of Inmunotek SL. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The traditional healthcare model is focused on diseases (medicine and natural science) and does not acknowledge patients' resources and abilities to be experts in their own lives based on their lived experiences. Improving healthcare safety, quality, and coordination, as well as quality of life, is an important aim in the care of patients with chronic conditions. Person-centered care needs to ensure that people's values and preferences guide clinical decisions. This paper reviews current knowledge to develop (1) digital care pathways for rhinitis and asthma multimorbidity and (2) digitally enabled, person-centered care. 1 It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally enabled, patient-centered care. The paper includes (1) Allergic Rhinitis and its Impact on Asthma (ARIA), a 2-decade journey, (2) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (3) mHealth impact on airway diseases, (4) From guidelines to digital care pathways, (5) Embedding Planetary Health, (6) Novel classification of rhinitis and asthma, (7) Embedding real-life data with population-based studies, (8) The ARIA-EAACI (European Academy of Allergy and Clinical Immunology) strategy for the management of airway diseases using digital biomarkers, (9) Artificial intelligence, (10) The development of digitally enabled, ARIA person-centered care, and (11) The political agenda. The ultimate goal is to propose ARIA 2024 guidelines centered around the patient to make them more applicable and sustainable., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Dysregulation of type 2 (T2) immune response leads to an aberrant inflammatory reaction that constitutes the pathophysiological basis of diseases involving various organs. For this reason, several disorders can coexist in a single patient; however, as different specialists often treat these pathologies, T2 dysregulation, particularly when mild, is not always the first diagnostic suspicion. A breakdown in interdisciplinary communication or the lack of adequate tools to detect these entities can delay diagnosis, and this, together with a lack of coordination, can lead to suboptimal care. In this context, a multidisciplinary group of specialists in pneumology, immunology, allergology, dermatology and otorhinolaryngology compiled a list of the cardinal symptoms reported by patients presenting with T2 inflammation-related diseases: asthma, chronic rhinosinusitis, allergic rhinitis, allergic conjunctivitis, IgE-mediated food allergy, atopic dermatitis, eosinophilic oesophagitis, and NSAID-exacerbated respiratory disease (NERD). Using this information, we propose a simple, patient-friendly questionnaire that can be administered at any level of care to initially screen patients for suspected coexisting T2 diseases and referral to the appropriate specialist., Competing Interests: OP has received fees for lectures or participation in advisory boards from AstraZeneca, Diater, GSK, Pfizer, Immunotek SL, Novartis, Regeneron, and Sanofi Genzyme. OP has received research grants from Immunotek SL, Novartis SL, AstraZeneca, MINECO, MICINNIN, and CAM. CC states that she has received financial support in the past three years from AstraZeneca, Chiesi, Novartis, Sanofi, Mundifarma, GSK, Menarini, Pfizer, Gebro Pharma, and TEVA for advisory services, articles, research studies, attending congresses or training courses. FO has received honoraria for serving on advisory boards from Novartis, Astellas, Uriach, Sanofi, GSK, Pfizer, Abbvie, Lilly, and Leo; for participation in lectures from Leo, BDF, Astellas, Novartis, MSD, and Sanofi; for participation in clinical trials from Astellas, Novartis, Bayer, Sanofi, Leo, Lilly, Pfizer, and Abbvie; and has received grants for congresses from Isdin, Menarini, Astellas, Novartis, MSD, Sanofi, Leti, Leo, and Abbvie. JV has received honoraria for serving on advisory boards from AstraZeneca, GlaxoSmithKline, and Sanofi, and for participation in lectures from Cinfa, GlaxoSmithKline, Sanofi, and Viatris. In the past three years. ID has received payment for lectures, including serving on speaker's bureaus from Allergy Therapeutics, AstraZeneca, Chiesi, Diater, GSK, Leti, Novartis, Sanofi; for a consultancy from Allergy Therapeutics, ALK-Abello, AstraZeneca, GSK, Merck, MSD, Novartis, Sanofi; and grants from Thermofisher Diagnostics, ISCIII and Junta de Castilla y León. The authors declare that this study received funding from Sanofi. The funder had the following involvement in the study: Writing and editorial assistance was provided by Laura Hidalgo, Ph.D. (Medical Science Consulting, Valencia, Spain), funded by Sanofi., (© 2024 Palomares, Cisneros, Ortiz de Frutos, Villacampa and Dávila.)

Background: Polymerized allergoids conjugated with mannan represent a novel approach of allergen immunotherapy targeting dendritic cells. In this study, we aimed to determine the optimal dose of mannan-allergoid conjugates derived from grass pollen ( Phleum pratense and Dactylis glomerata ) administered via either the subcutaneous or sublingual route., Methods: A randomized, double-blind, placebo-controlled trial with a double-dummy design was conducted, involving 162 participants across 12 centers in Spain. Subjects were randomly allocated to one of nine different treatment groups, each receiving either placebo or active treatment at doses of 500, 1,000, 3,000, or 5,000 mTU/mL over four months. Each participant received five subcutaneous (SC) doses of 0.5 mL each, every 30 days, and a daily sublingual (SL) dose of 0.2 mL. Participants who received active treatment through SC, received placebo through SL. Participants who received active treatment through SL, received placebo SC. One Group, as control, received bot SC and SL placebo. The primary efficacy outcome was the improvement in titrated nasal provocation tests (NPT) at the end of the study compared to baseline. Secondary outcomes included specific antibody (IgG4, IgE) and cellular (IL-10 producing and regulatory T cell) responses. All adverse events and side reactions were recorded and assessed., Results: Post-treatment, the active groups showed improvements in NPT ranging from 33% to 53%, with the highest doses showing the greatest improvements regardless of the administration route. In comparison, the placebo group showed a 12% improvement. Significant differences over placebo were observed at doses of 3,000 mTU/mL (p=0.049 for SL, p=0.015 for SC) and 5,000 mTU/mL (p=0.011 for SL, p=0.015 for SC). A dose-dependent increase in IgG4 was observed following SC administration, and an increase in IL-10 producing cells for both routes of administration. No serious systemic or local adverse reactions were recorded, and no adrenaline was required., Conclusion: Grass pollen immunotherapy with mannan-allergoid conjugates was found to be safe and efficacious in achieving the primary outcome, whether administered via the subcutaneous or sublingual routes, at doses of 3,000 and 5,000 mTU/mL., Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search (EudraCT), identifier 2014-005471-88; https://www.clinicaltrials.gov, identifier NCT02654223., Competing Interests: JLS and MC are shareholders of Inmunotek. RC, SP, MG-P and IS are employees of Inmunotek. OP received research grants from the Spanish Ministry of Science and Innovation, Inmunotek, and Novartis and fees for giving scientific lectures or participation in Advisory Boards from: AstraZeneca, Pfizer, GlaxoSmithKline, Inmunotek, Novartis and Sanofi-Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ojeda, Barjau, Subiza, Moreno, Ojeda, Solano, Alonso, Caballero, Del Pozo, Gómez-Perosanz, Sánchez-Trincado, Benito-Villalvilla, Angelina, Soria, Reche, Palomares, Subiza and Casanovas.)

Background: Allergy represents a major health problem of increasing prevalence worldwide with a high socioeconomic impact. Our knowledge on the molecular mechanisms underlying allergic diseases and their treatments has significantly improved over the last years. The generation of allergen-specific regulatory T cells (Tregs) is crucial in the induction of healthy immune responses to allergens, preventing the development and worsening of allergic diseases., Summary: In the last decades, intensive research has focused on the study of the molecular mechanisms involved in Treg development and Treg-mediated suppression. These mechanisms are essential for the induction of sustained tolerance by allergen-specific immunotherapy (AIT) after treatment discontinuation. Compelling experimental evidence demonstrated altered suppressive capacity of Tregs in patients suffering from allergic rhinitis, allergic asthma, food allergy, or atopic dermatitis, as well as the restoration of their numbers and functionality after successful AIT., Key Message: The better understanding of the molecular mechanisms involved in Treg generation during allergen tolerance induction might well contribute to the development of novel strategies for the prevention and treatment of allergic diseases., (© 2024 S. Karger AG, Basel.)

Functional Tregs play a key role in tumor development and progression, representing a major barrier to anticancer immunity. The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood. Herein, by using NMR, chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses, we demonstrate that the tumoral carbohydrate A10 (Ca10), a cell-surface carbohydrate derived from Ehrlich's tumor (ET) cells, is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs. Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming, PD-L1, IL-10, and IDO. Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features. In solid ET-bearing mice, we found positive correlations between Ca10 serum levels, tumor size and splenic Treg numbers. Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice. Remarkably, we provide evidence supporting the presence of a circulating human Ca10 counterpart (Ca10H) and show, for the first time, that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals. Of note, these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases. Collectively, we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer. The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment., (© 2023. The Author(s).)

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., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Over the past two decades, significant progress in understanding of the pathogenesis of type 2 chronic inflammatory diseases has enabled the identification of compounds for more than 20 novel targets, which are approved or at various stages of development, finally facilitating a more targeted approach for the treatment of these disorders. Most of these newly identified pathogenic drivers of type 2 inflammation and their corresponding treatments are related to mast cells, eosinophils, T cells, B cells, epithelial cells and sensory nerves. Epithelial barrier defects and dysbiotic microbiomes represent exciting future drug targets for chronic type 2 inflammatory conditions. Here, we review common targets, current treatments and emerging therapies for the treatment of five major type 2 chronic inflammatory diseases - atopic dermatitis, chronic prurigo, chronic urticaria, asthma and chronic rhinosinusitis with nasal polyps - with a high need for targeted therapies. Unmet needs and future directions in the field are discussed., (© 2023. Springer Nature Limited.)

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Ligelizumab is an anti-IgE monoclonal antibody binding IgE with higher affinity than omalizumab that is under clinical investigation for several IgE-mediated diseases. We previously showed that omalizumab removes IgE bound to FcεRI on plasmacytoid dendritic cells (pDCs) and restores their ability to produce IFN-α and regulatory T cells (Tregs). The aim of this work is to investigate the capacity of ligelizumab to regulate functional properties of pDCs in comparison with omalizumab., Methods: pDCs were isolated from atopic donors and IgE was detached from FcεRI on pDCs with designed ankyrin repeat protein (DARPin) bi53-79. pDCs were resensitized with IgE alone or in the presence of ligelizumab or omalizumab prior to IgE-FcεRI crosslinking and Toll-like receptor 9 (TLR9) stimulation. Flow cytometry, ELISA, coculture experiments and intranuclear staining were performed to determine cytokine production and Treg generation. An antigen-specific model of resensitization and IgE-crosslinking was also performed., Results: The levels of serum total free IgE show a non-linear positive correlation with the frequency of IgE + pDCs displaying IgE bound to FcεRI within the 43 individual donors included in the study. Ligelizumab displays stronger capacity than omalizumab to block the binding of free IgE to FcεRI on human pDCs, resulting in a greater restoration of TLR9-L-induced IFN-α production. Ligelizumab also restores the ability of pDCs to generate FOXP3 + Tregs as previously reported for omalizumab., Conclusions: The uncovered novel molecular mechanisms of ligelizumab to regulate functional properties of pDCs from atopic donors might have important clinical implications for anti-IgE treatments in different IgE-mediated diseases., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Fibroblasts and others mesenchymal cells have recently been identified as critical cells triggering tissue-specific inflammatory responses. Persistent activation of fibroblasts inflammatory program has been suggested as an underlying cause of chronic inflammation in a wide range of tissues and pathologies. Nevertheless, the role of fibroblasts in the emergence of chronic inflammation in the upper airway has not been previously addressed. We aimed to elucidate whether fibroblasts could have a role in the inflammatory response in chronic rhinosinusitis with nasal polyps (CRSwNP)., Methodology: We performed whole-transcriptome microarray in fibroblast cultured from CRSwNP samples and confirmed our results by qRT-PCR. We selected patients without other associated diseases in upper airway. To investigate shifts in transcriptional profile we used fibroblasts from nasal polyps and uncinate mucosae from patient with CRSwNP, and fibroblasts from uncinate mucosae from healthy subjects as controls., Results: This study exposes activation of a pro-inflammatory and pro-fibrotic transcriptional program in nasal polyps and CRSwNP fibroblasts when compared to controls. Our Gene-set Enrichment Analysis (GSEA) pointed to common up-regulation of several pro-inflammatory pathways in patients-derived fibroblasts, along with higher mRNA expression levels of cytokines, growth factors and extracellular matrix components., Conclusions: Our work reveals a potential new source of inflammatory signaling in CRSwNP. Furthermore, our results suggest that deregulated inflammatory signaling in tissue-resident fibroblasts could support a Type-2 inflammatory response. Further investigations will be necessary to demonstrate the functionality of these novel results.

Introduction: Chronic or uncontrolled activation of myeloid cells including monocytes, macrophages and dendritic cells (DCs) is a hallmark of immune-mediated inflammatory disorders. There is an urgent need for the development of novel drugs with the capacity to impair innate immune cell overactivation under inflammatory conditions. Compelling evidence pointed out cannabinoids as potential therapeutic tools with anti-inflammatory and immunomodulatory capacity. WIN55,212-2, a non-selective synthetic cannabinoid agonist, displays protective effects in several inflammatory conditions by mechanisms partially depending on the generation of tolerogenic DCs able to induce functional regulatory T cells (Tregs). However, its immunomodulatory capacity on other myeloid cells such as monocytes and macrophages remains incompletely understood., Methods: Human monocyte-derived DCs (hmoDCs) were differentiated in the absence (conventional hmoDCs) or presence of WIN55,212-2 (WIN-hmoDCs). Cells were stimulated with LPS, cocultured with naive T lymphocytes and their cytokine production and ability to induce T cell responses were analysed by ELISA or flow cytometry. To evaluate the effect of WIN55,212-2 in macrophage polarization, human and murine macrophages were activated with LPS or LPS/IFNγ, in the presence or absence of the cannabinoid. Cytokine, costimulatory molecules and inflammasome markers were assayed. Metabolic and chromatin immunoprecipitation assays were also performed. Finally, the protective capacity of WIN55,212-2 was studied in vivo in BALB/c mice after intraperitoneal injection with LPS., Results: We show for the first time that the differentiation of hmoDCs in the presence of WIN55,212-2 generates tolerogenic WIN-hmoDCs that are less responsive to LPS stimulation and able to prime Tregs. WIN55,212-2 also impairs the pro-inflammatory polarization of human macrophages by inhibiting cytokine production, inflammasome activation and rescuing macrophages from pyroptotic cell death. Mechanistically, WIN55,212-2 induced a metabolic and epigenetic shift in macrophages by decreasing LPS-induced mTORC1 signaling, commitment to glycolysis and active histone marks in pro-inflammatory cytokine promoters. We confirmed these data in ex vivo LPS-stimulated peritoneal macrophages (PMΦs), which were also supported by the in vivo anti-inflammatory capacity of WIN55,212-2 in a LPS-induced sepsis mouse model., Conclusion: Overall, we shed light into the molecular mechanisms by which cannabinoids exert anti-inflammatory properties in myeloid cells, which might well contribute to the future rational design of novel therapeutic strategies for inflammatory disorders., Competing Interests: OP has received fees for lectures or participation in Advisory Boards from AstraZeneca, GSK, Pfizer, Inmunotek SL, Novartis, Sanofi Genzyme, and Regeneron. OP has received research grants from Inmunotek SL, Novartis SL, Amgen-AstraZeneca, MINECO, MICINNIN and CAM. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pérez-Diego, Angelina, Martín-Cruz, de la Rocha-Muñoz, Maldonado, Sevilla-Ortega and Palomares.)

Purpose of Review: Allergic diseases represent a major health problem of increasing prevalence worldwide. In allergy, dendritic cells (DCs) contribute to both the pathophysiology and the induction of healthy immune responses to the allergens. Different studies have reported that some common allergens contain glycans in their structure. C-type lectin receptors (CLRs) expressed by DCs recognize carbohydrate structures and are crucial in allergen uptake, presentation, and polarization of T cell responses. This review summarizes the recent literature regarding the role of CLRs in the regulation of type 2 immune responses to allergens., Recent Findings: In this review, we highlight the capacity of CLRs to recognize carbohydrates in common allergens triggering different signaling pathways involved in the polarization of CD4 + T cells towards specific Th2 responses. Under certain conditions, specific CLRs could also promote tolerogenic responses to allergens, which might well be exploited to develop novel therapeutic approaches of allergen-specific immunotherapy (AIT), the single treatment with potential disease-modifying capacity for allergic disease. At this regard, polymerized allergens conjugated to non-oxidized mannan (allergoid-mannan conjugated) are next-generation vaccines targeting DCs via CLRs that promote regulatory T cells, thus favoring allergen tolerance both in preclinical models and clinical trials. A better understanding of the role of CLRs in the development of allergy and in the induction of allergen tolerance might well pave the way for the design of novel strategies for allergic diseases., (© 2023. The Author(s).)

Background: Emerging research suggests that local lymphatic tissue such as tonsils have important role in regulating the immune responses. However, allergen sensitization-induced alterations in transcriptome of tonsils are not known., Objectives: To examine the key differences in tonsillar gene expression between atopic and non-atopic subjects and further by type of sensitization., Methods: RNA-sequencing was performed on 52 tonsillar samples from atopic and non-atopic tonsillectomy patients. Sensitization to common food- and aero-allergen was defined by allergen specific IgE. Following groups were studied: (1) aero- and food-allergen sensitized (AS+FS) versus non-sensitized (NS), (2) aeroallergen-sensitized (AS) versus food-allergen sensitized (FS), (3) AS versus NS, (4) FS versus NS. Bioinformatics analysis was done using DESeq2(v3.10.2), WGCNA and GATK pipeline in R software (v3.3.1). Protein-protein interaction network was made from String database., Results: We studied 13 aeroallergen-sensitized, 6 food-allergen sensitized, 4 both food-and aero-allergen-sensitized and 29 non-sensitized tonsillectomy patients. Overall, 697 unique differentially expressed genes (DEGs) were detected in all sensitized subgroups including chemokines (CXCL2, CXCL8, CXCL10, CXCL11), IL-20RA, MUC1 and MUC20. When comparing different groups, the gene expression profiles overlapped except the AS versus FS group comparison, suggesting significantly different gene expression between the two sensitization subgroups. Furthermore, aeroallergen-sensitized subjects had more prominent immune responses compared with non-sensitized and food-allergen sensitized subjects including gene expression for IL-17 pathway and Toll-like receptor signalling pathway., Conclusion: Allergic sensitization is associated with extensive tonsillar transcriptomic alterations and changes in immune related genes and pathways. Distinct differences were found between aero-allergen and food-allergen sensitization., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Innate immune cells experience long lasting metabolic and epigenetic changes after an encounter with specific stimuli. This facilitates enhanced immune responses upon secondary exposition to both the same and unrelated pathogens, a process termed trained immunity. Trained immunity-based vaccines (TIbV) are vaccines able to induce innate immune memory, thus conferring heterologous protection against a broad range of pathogens. While trained immunity has been well documented in the context of infections and multiple immune-mediated diseases, the role of innate immune memory and its contribution to the initiation and maintenance of chronic allergic diseases remains poorly understood. Over the last years, different studies attempting to uncover the role of trained immunity in allergy have emerged. Exposition to environmental factors impacting allergy development such as allergens or viruses induces the reprogramming of innate immune cells to acquire a more pro-inflammatory phenotype in the context of asthma or food allergy. Several studies have convincingly demonstrated that prevention of viral infections using TIbV contributes to reduce wheezing attacks in children, which represent a high-risk factor for asthma development later in life. Innate immune cells trained with specific stimuli might also acquire anti-inflammatory features and promote tolerance, which may have important implications for chronic inflammatory diseases such as allergies. Recent findings showed that allergoid-mannan conjugates, which are next generation vaccines for allergen-specific immunotherapy (AIT), are able to reprogram monocytes into tolerogenic dendritic cells by mechanisms depending on metabolic and epigenetic rewiring. A better understanding of the underlying mechanisms of trained immunity in allergy will pave the way for the design of novel trained immunity-based allergen vaccines as potential alternative strategies for the prevention and treatment of allergic diseases., (© 2022 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Introduction: Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems all over the world. Antibiotics and antifungals are widely used for such infectious diseases, which is linked with microbial resistances and microbiota deleterious effects. The development of novel approaches for genitourinary tract infections (GUTIs) such as trained immunity-based vaccines (TIbV) is therefore highly required. MV140 is a sublingual whole-cell heat-inactivated polybacterial preparation with demonstrated clinical efficacy for RUTIs. The sublingual heat-inactivated Candida albicans vaccine V132 has been developed for RVVCs. We previously showed that the combination of MV140 and V132 promotes potent Th1/Th17 and regulatory T-cell responses against antigens contained in the formulation and unrelated antigens. The specific contribution of each preparation to such effects and the underlying molecular mechanisms remain incompletely understood., Methods: PBMC and monocytes were isolated from healthy donors and in vitro stimulated with V132, MV140 or MV140/V132. After 6 days of resting, cells were reestimulated with LPS and MV140. Analysis of cytokine production by ELISA, Seahorse assays for functional metabolic experiments and chromatin immunoprecipitation assays were performed. BALB/c mice were intraperitoneally and sublingually immunized with V132., Results: We uncover that V132 induces trained immunity in human PBMCs and purified monocytes, significantly increasing the responses triggered by subsequent stimulation with MV140. Mechanistically, V132 drives metabolic rewiring towards increased glycolysis and oxidative phosphorylation and induces epigenetic reprogramming that enhances the transcription of the pro-inflammatory genes IL6 and TNFA . Splenocytes and peritoneal cells from V132-immunize mice show increased responses upon in vitro stimulation with MV140. Remarkably, splenocytes from sublingually V132-immunized and MV140 in vivo treatment mice show stronger Th17 responses than mice exposed to excipients upon in vitro stimulation with MV140., Conclusion: Overall, we provide novel mechanistic insights into how V132-induced trained immunity enhances both innate and adaptive immune responses triggered by MV140, which might open the door for new interventions for GUTIs with important clinical implications., Competing Interests: OP has received fee for lectures or participation in Advisory Boards from Allergy Therapeutics, Amgen, AstraZeneca, Diater, GSK, Pfizer, Inmunotek SL, Novartis, Sanofi Genzyme, Stallergenes and Regeneron. OP has received research grants from Inmunotek SL, Novartis SL, MINECO, MICINNIN and CAM. JS is the founder and CEO of Inmunotek SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Martín-Cruz, Angelina, Baydemir, Bulut, Subiza, Netea, Domínguez-Andrés and Palomares.)

Background: Allergen-specific immunotherapy (AIT) is currently the only treatment with potential long-term disease-modifying effects for patients suffering from allergic diseases such as allergic rhinitis, allergic asthma, venom allergy, or IgE-mediated food allergy. A better understanding of the molecular mechanisms underlying immune responses during successful AIT is of utmost importance and it may help to develop more effective and safer treatments., Materials and Methods: PubMed literature review was performed using keywords such as allergen-specific immunotherapy; regulatory T cells; regulatory B cells; regulatory innate lymphoid cells; and allergen-specific antibody from years 2018 to 2021., Results: The proposed mechanism of long-term tolerance induction in AIT, even upon treatment discontinuation, involves basophils, mast cells, innate lymphoid cells, dendritic cells, allergen-specific regulatory T and B cells, downregulation of effector type 2 responses, decrease in the production of IgE and increase in production of allergen-specific blocking antibodies, such as IgG2 and IgG4., Conclusion: We summarize the most recent advances related to mechanisms involved in the restoration of healthy immune responses to allergens during AIT. Our knowledge in this regard has significantly improved over the last years, which might well contribute to design novel and improved therapeutic approaches., (© Dustri-Verlag Dr. K. Feistle.)

Autoimmune diseases have a prevalence of approximately 7 to 9% and are classified as either organ-specific diseases, including type I diabetes, multiple sclerosis, inflammatory bowel disease and myasthenia gravis, or systemic diseases, including systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. While many advancements have been made in understanding of the mechanisms of autoimmune disease, including the nature of self-tolerance and its breakdown, there remain unmet needs in terms of effective and highly targeted treatments. T regulatory cells (Tregs) are key mediators of peripheral tolerance and are implicated in many autoimmune diseases, either as a result of reduced numbers or altered function. Tregs may be broadly divided into those generated in the thymus (tTregs) and those generated in the periphery (pTregs). Tregs target many different immune cell subsets and tissues to suppress excessive inflammation and to support tissue repair and homeostasis: there is a fine balance between Treg cell stability and the plasticity that is required to adjust Tregs' regulatory purposes to particular immune responses. The central role of immunoglobulin E (IgE) in allergic disease is well recognized, and it is becoming increasingly apparent that this immunoglobulin also has a wider role encompassing other diseases including autoimmune disease. Anti-IgE treatment restores the capacity of plasmacytoid dendritic cells (pDCs) impaired by IgE- high-affinity IgE receptor (FcεR1) cross-linking to induce Tregs in vitro in atopic patients. The finding that anti-IgE therapy restores Treg cell homeostasis, and that this mechanism is associated with clinical improvement in asthma and chronic spontaneous urticaria suggests that anti-IgE therapy may also have a potential role in the treatment of autoimmune diseases in which Tregs are involved., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Non-steroidal anti-inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti-inflammatory, antipyretic, and analgesic effects are applied against symptoms of respiratory infections, including SARS-CoV-2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID-19 also revealed the gaps in our understanding of their mechanism of action, selectivity, and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs-exacerbated respiratory disease (NERD). In this context, the consensus report summarizes currently available knowledge, novel discoveries, and controversies regarding the use of NSAIDs in COVID-19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID-19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarize the major knowledge gaps and unmet needs in current eicosanoid research., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)