AllergoOncology: Biomarkers and refined classification for research in the allergy and glioma nexus-A joint EAACI-EANO position paper.

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE-mediated diseases and glioma. Allergic disease stems from a Th2-biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour-immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro-Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult-type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune-glioma interactions to ultimately improve patient prognosis and survival.

Platelet-Derived Extracellular Vesicles as Lipid Carriers in Severe Allergic Inflammation.

The resolution of inflammation is a complex process that is critical for removing inflammatory cells and restoring tissue function. The dysregulation of these mechanisms leads to chronic inflammatory disorders. Platelets, essential cells for preserving homeostasis, are thought to play a role in inflammation as they are a source of immunomodulatory factors. Our aim was to identify key metabolites carried by platelet-derived extracellular vesicles (PL-EVs) in a model of allergic inflammation. PL-EVs were isolated by serial ultracentrifugation using platelet-rich plasma samples obtained from platelet apheresis from severely (n = 6) and mildly (n = 6) allergic patients and non-allergic individuals used as controls (n = 8). PL-EVs were analysed by a multiplatform approach using liquid and gas chromatography coupled to mass spectrometry (LC-MS and GC-MS, respectively). PL-EVs obtained from severely and mildly allergic patients and control individuals presented comparable particle concentrations and sizes with similar protein concentrations. Strikingly, PL-EVs differed in their lipid and metabolic content according to the severity of inflammation. L-carnitine, ceramide (Cer (d18:0/24:0)), and several triglycerides, all of which seem to be involved in apoptosis and regulatory T functions, were higher in PL-EVs from patients with mild allergic inflammation than in those with severe inflammation. In contrast, PL-EVs obtained from patients with severe allergic inflammation showed an alteration in the arachidonic acid pathway. This study demonstrates that PL-EVs carry specific lipids and metabolites according to the degree of inflammation in allergic patients and propose novel perspectives for characterising the progression of allergic inflammation.

Transcriptomics reveals a distinct metabolic profile in T cells from severe allergic asthmatic patients.

The reasons behind the onset and continuation of chronic inflammation in individuals with severe allergies are still not understood. Earlier findings indicated that there is a connection between severe allergic inflammation, systemic metabolic alterations and impairment of regulatory functions. Here, we aimed to identify transcriptomic alterations in T cells associated with the degree of severity in allergic asthmatic patients. T cells were isolated from severe (n = 7) and mild (n = 9) allergic asthmatic patients, and control (non-allergic, non-asthmatic healthy) subjects (n = 8) to perform RNA analysis by Affymetrix gene expression. Compromised biological pathways in the severe phenotype were identified using significant transcripts. T cells' transcriptome of severe allergic asthmatic patients was distinct from that of mild and control subjects. A higher count of differentially expressed genes (DEGs) was observed in the group of individuals with severe allergic asthma vs. control (4,924 genes) and vs. mild (4,232 genes) groups. Mild group also had 1,102 DEGs vs. controls. Pathway analysis revealed alterations in metabolism and immune response in the severe phenotype. Severe allergic asthmatic patients presented downregulation in genes related to oxidative phosphorylation, fatty acid oxidation and glycolysis together with increased expression of genes coding inflammatory cytokines (e.g. IL-19, IL-23A and IL-31). Moreover, the downregulation of genes involved in TGFß pathway together with a decreased tendency on the percentage of T regulatory cell (CD4 + CD25+), suggest a compromised regulatory function in severe allergic asthmatic patients. This study demonstrates a transcriptional downregulation of metabolic and cell signalling pathways in T cells of severe allergic asthmatic patients associated with diminished regulatory T cell function. These findings support a link between energy metabolism of T cells and allergic asthmatic inflammation.

Mechanisms of Allergen Immunotherapy and Potential Biomarkers for Clinical Evaluation.

Allergen-immunotherapy (AIT) is an efficacious and disease-modifying treatment option for IgE-mediated diseases. Among these allergic rhinitis, insect venom allergy, food allergy, and allergic asthma are the most common candidates for AIT. AIT gives rise to clinical immunotolerance which may last for years after the treatment cessation. Mechanisms of AIT include suppression of allergic inflammation in target tissues and stimulation of the production of blocking antibodies, especially IgG4 and IgA. These mechanisms are followed by a reduction of underlying allergen-specific Th2 cell-driven responses to the allergens. Tolerance induction takes place through the desensitization of effector cells and stimulation of regulatory T cells that show their effects by mechanisms involving cell-cell cross-talk, but also other mechanisms, e.g., by the production of immunomodulatory cytokines such as, e.g., IL-10 and TGF-beta. From a personalized medical perspective, there is a need for clinical biomarkers of value in selecting responders and optimizing patient care during AIT. Also, a deeper understanding of underlying mechanistic processes will improve AIT's future outcomes. In this paper, the current knowledge of mechanisms in AIT is reviewed with a special focus on biomarkers of this therapy.

Determinants of poor clinical outcome in patients with influenza pneumonia: A systematic review and meta-analysis.

BACKGROUND: The clinical burden of influenza is increasing worldwide. Aging, immunosuppression, and underlying respiratory illness are determinants of poor clinical outcomes, including greater mortality. Bacterial infections seem to be the main reason. Updated information on the role of bacterial infection as the cause of complications would be of value in improving the prognosis of patients with influenza. METHODS: A systematic review and meta-analysis were performed by using the PubMed repository using keywords like: Influenza, H1N1, Streptococcus pneumoniae, bacterial coinfection, secondary coinfection, bacterial complications in pneumonia, and seasonal influenza. Only articles written in English were included in publications from 2010 to 2020. The analyses were conducted following the preferred reporting items for systematic review and meta-analyses guidelines. The results were independently validated using a TrinetX database cohort of roughly 4 million patients. RESULTS: We included 135 studies that contained data from 48,259 patients hospitalized with influenza of any age. Bacterial infections were diagnosed in 5391 (11.2%). Streptococcus pneumoniae (30.7%) and Staphylococcus aureus (30.4%) were the most frequent microorganisms, followed by Haemophilus influenzae (7.1%) and Pseudomonas aeruginosa (5.9%). The random-effects model of the meta-analysis indicated that bacterial infections posed a 3.4-fold increased risk of death compared with influenza infection alone. Unexpectedly, asthma was protective (odds ratio 0.8). CONCLUSION: Bacterial infections diagnosed in 11.2% of patients with influenza increase 3.4-fold the mortality risk. S. pneumoniae, S. aureus, H. influenzae, and P. aeruginosa account for nearly 75% of the cases. Earlier diagnosis and use of antibiotics should improve outcomes in this population.

Deciphering the role of platelets in severe allergy by an integrative omics approach.

BACKGROUND: Mechanisms causing the onset and perpetuation of inflammation in severe allergic patients remain unknown. Our previous studies suggested that severe allergic inflammation is linked to platelet dysfunction. METHODS: Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) samples were obtained by platelet-apheresis from severe (n = 7) and mild (n = 10) allergic patients and nonallergic subjects (n = 9) to perform platelet lipidomics by liquid chromatography coupled to mass spectrometry (LC-MS) and RNA-seq analysis. Significant metabolites and transcripts were used to identify compromised biological pathways in the severe phenotype. Platelet and inflammation-related proteins were quantified by Luminex. RESULTS: Platelets from severe allergic patients were characterized by high levels of ceramides, phosphoinositols, phosphocholines, and sphingomyelins. In contrast, they showed a decrease in eicosanoid precursor levels. Biological pathway analysis performed with the significant lipids revealed the alteration of phospholipases, calcium-dependent events, and linolenic metabolism. RNAseq confirmed mRNA overexpression of genes related to platelet activation and arachidonic acid metabolism in the severe phenotypes. Pathway analysis indicated the alteration of NOD, MAPK, TLR, TNF, and IL-17 pathways in the severe phenotype. P-Selectin and IL-17AF proteins were increased in the severe phenotype. CONCLUSIONS: This study demonstrates that platelet lipid, mRNA, and protein content is different according to allergy severity. These findings suggest that platelet load is a potential source of biomarkers and a new chance for therapeutic targets in severe inflammatory pathologies.

Biomarkers of AIT: Models of prediction of efficacy.

Allergic rhinitis is an IgE-mediated inflammation that remains a clinical challenge, affecting 40% of the UK population with a wide range of severity from nasal discomfort to life-threatening anaphylaxis. It can be managed by pharmacotherapeutics and in selected patients by allergen immunotherapy (AIT), which provides long-term clinical efficacy, especially during peak allergy season. However, there are no definitive biomarkers for AIT efficacy. Here, we aim to summarize the key adaptive, innate, humoral, and metabolic advances in biomarker identification in response to AIT. Mechanisms of efficacy consist of an immune deviation towards TH1-secreting IFN-γ, as well as an induction of IL10+ cTFR and TREG have been observed. TH2 cells undergo exhaustion after AIT due to chronic allergen exposure and correlates with the exhaustion markers PD-1, CTLA-4, TIGIT, and LAG3. IL10+ DCREG expressing C1Q and STAB are induced. KLRG1+ IL10+ ILC2 were shown to be induced in AIT in correlation with efficacy. BREG cells secreting IL-10, IL-35, and TGF-ß are induced. Blocking antibodies IgG, IgA, and IgG4 are increased during AIT; whereas inflammatory metabolites, such as eicosanoids, are reduced. There are multiple promising biomarkers for AIT currently being evaluated. A panomic approach is essential to better understand cellular, molecular mechanisms and their correlation with clinical outcomes. Identification of predictive biomarkers of AIT efficacy will hugely impact current practice allowing physicians to select eligible patients that are likely to respond to treatment as well as improve patients' compliance to complete the course of treatment.

Contribution of allergy in the acquisition of uncontrolled severe asthma.

Asthma is a multifactorial, heterogeneous disease that has a challenging management. It can be divided in non-allergic and allergic (usually associated with house dust mites (HDM) sensitization). There are several treatments options for asthma (corticosteroids, bronchodilators, antileukotrienes, anticholinergics,…); however, there is a subset of patients that do not respond to any of the treatments, who can display either a T2 or a non-T2 phenotype. A deeper understanding of the differential mechanisms underlying each phenotype will help to decipher the contribution of allergy to the acquisition of this uncontrolled severe phenotype. Here, we aim to elucidate the biological pathways associated to allergy in the uncontrolled severe asthmatic phenotype. To do so, twenty-three severe uncontrolled asthmatic patients both with and without HDM-allergy were recruited from Hospital Universitario de Gran Canaria Dr. Negrin. A metabolomic fingerprint was obtained through liquid chromatography coupled to mass spectrometry, and identified metabolites were associated with their pathways. 9/23 patients had uncontrolled HDM-allergic asthma (UCA), whereas 14 had uncontrolled, non-allergic asthma (UCNA). 7/14 (50%) of the UCNA patients had Aspirin Exacerbated Respiratory Disease. There were no significant differences regarding gender or body mass index; but there were significant differences in age and onset age, which were higher in UCNA patients; and in total IgE, which was higher in UCA. The metabolic fingerprint revealed that 103 features were significantly different between UCNA and UCA (p < 0.05), with 97 being increased in UCA and 6 being decreased. We identified lysophosphocholines (LPC) 18:2, 18:3 and 20:4 (increased in UCA patients); and deoxycholic acid and palmitoleoylcarnitine (decreased in UCA). These metabolites were related with a higher activation of phospholipase A2 (PLA2) and other phospholipid metabolism pathways. Our results show that allergy induces the activation of specific inflammatory pathways, such as the PLA2 pathway, which supports its role in the development of an uncontrolled asthma phenotype. There are also clinical differences, such as higher levels of IgE and earlier onset ages for the allergic asthmatic group, as expected. These results provide evidences to better understand the contribution of allergy to the establishment of a severe uncontrolled phenotype.

Mast Cell Desensitization in Allergen Immunotherapy.

Allergen immunotherapy (AIT) is the only treatment with disease-transforming potential for allergic disorders. The immunological mechanisms associated with AIT can be divided along time in two phases: short-term, involving mast cell (MC) desensitization; and long-term, with a regulatory T cell (Treg) response with significant reduction of eosinophilia. This regulatory response is induced in about 70% of patients and lasts up to 3 years after AIT cessation. MC desensitization is characteristic of the initial phase of AIT and it is often related to its success. Yet, the molecular mechanisms involved in allergen-specific MC desensitization, or the connection between MC desensitization and the development of a Treg arm, are poorly understood. The major AIT challenges are its long duration, the development of allergic reactions during AIT, and the lack of efficacy in a considerable proportion of patients. Therefore, reaching a better understanding of the immunology of AIT will help to tackle these short-comings and, particularly, to predict responder-patients. In this regard, omics strategies are empowering the identification of predictive and follow-up biomarkers in AIT. Here, we review the immunological mechanisms underlying AIT with a focus on MC desensitization and AIT-induced adverse reactions. Also, we discuss the identification of novel biomarkers with predictive potential that could improve the rational use of AIT.

Development of a Novel Targeted Metabolomic LC-QqQ-MS Method in Allergic Inflammation.

The transition from mild to severe allergic phenotypes is still poorly understood and there is an urgent need of incorporating new therapies, accompanied by personalized diagnosis approaches. This work presents the development of a novel targeted metabolomic methodology for the analysis of 36 metabolites related to allergic inflammation, including mostly sphingolipids, lysophospholipids, amino acids, and those of energy metabolism previously identified in non-targeted studies. The methodology consisted of two complementary chromatography methods, HILIC and reversed-phase. These were developed using liquid chromatography, coupled to triple quadrupole mass spectrometry (LC-QqQ-MS) in dynamic multiple reaction monitoring (dMRM) acquisition mode and were validated using ICH guidelines. Serum samples from two clinical models of allergic asthma patients were used for method application, which were as follows: (1) corticosteroid-controlled (ICS, n = 6) versus uncontrolled (UC, n = 4) patients, and immunotherapy-controlled (IT, n = 23) versus biologicals-controlled (BIO, n = 12) patients. The results showed significant differences mainly in lysophospholipids using univariate analyses in both models. Multivariate analysis for model 1 was able to distinguish both groups, while for model 2, the results showed the correct classification of all BIO samples within their group. Thus, this methodology can be of great importance for further understanding the role of these metabolites in allergic diseases as potential biomarkers for disease severity and for predicting patient treatment response.

The impact of type 2 immunity and allergic diseases in atherosclerosis.

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).

A method based on plateletpheresis to obtain functional platelet, CD3+ and CD14+ matched populations for research immunological studies.

BACKGROUND: In previous studies with peripheral blood cells, platelet factors were found to be associated with severe allergic phenotypes. A reliable method yielding highly concentrated and pure platelet samples is usually not available for immunological studies. Plateletpheresis is widely used in the clinics for donation purposes. In this study, we designed a protocol based on plateletpheresis to obtain Platelet-Rich Plasma (PRP), Platelet-Poor Plasma (PPP) as well as CD3+ and CD14+ cells matched samples from a waste plateletpheresis product for immunological studies. METHODS: Twenty-seven subjects were voluntarily subjected to plateletpheresis. PRP, PPP and blood cell concentrate contained in a leukocyte reduction system chamber (LRSC) were obtained in this process. CD3+ and CD14+ cells were isolated from the LRSC by density-gradient centrifugation and positive magnetic bead isolation. RNA was isolated from PRP, CD3+ and CD14+ cell samples and used for transcriptomic studies by Affymetrix. PRP and PPP samples were used for platelet protein quantification by multiplex assays. RESULTS: A reliable high yield method to obtain matched samples of PRP, PPP, CD3+ and CD14+ from a single donor for RNA and protein analyses has been designed. The RNA quality indicators (RQI) routinely used for other cell types were not suitable for platelet RNA characterization. Despite this, the platelet RNA was valid for transcriptomic studies by Affymetrix, as platelet transcripts obtained in our previous studies were confirmed in PRP samples. Platelet samples were enriched in platelet factors as determined in protein multiplex analysis. CONCLUSIONS: We have developed a method that yields not only high content and pure platelet samples from a single donor but also CD3+ and CD14+ matched samples that can be used for RNA and protein analyses in immunological studies.

Omics technologies in allergy and asthma research: An EAACI position paper.

Allergic diseases and asthma are heterogenous chronic inflammatory conditions with several distinct complex endotypes. Both environmental and genetic factors can influence the development and progression of allergy. Complex pathogenetic pathways observed in allergic disorders present a challenge in patient management and successful targeted treatment strategies. The increasing availability of high-throughput omics technologies, such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics allows studying biochemical systems and pathophysiological processes underlying allergic responses. Additionally, omics techniques present clinical applicability by functional identification and validation of biomarkers. Therefore, finding molecules or patterns characteristic for distinct immune-inflammatory endotypes, can subsequently influence its development, progression, and treatment. There is a great potential to further increase the effectiveness of single omics approaches by integrating them with other omics, and nonomics data. Systems biology aims to simultaneously and longitudinally understand multiple layers of a complex and multifactorial disease, such as allergy, or asthma by integrating several, separated data sets and generating a complete molecular profile of the condition. With the use of sophisticated biostatistics and machine learning techniques, these approaches provide in-depth insight into individual biological systems and will allow efficient and customized healthcare approaches, called precision medicine. In this EAACI Position Paper, the Task Force "Omics technologies in allergic research" broadly reviewed current advances and applicability of omics techniques in allergic diseases and asthma research, with a focus on methodology and data analysis, aiming to provide researchers (basic and clinical) with a desk reference in the field. The potential of omics strategies in understanding disease pathophysiology and key tools to reach unmet needs in allergy precision medicine, such as successful patients' stratification, accurate disease prognosis, and prediction of treatment efficacy and successful prevention measures are highlighted.

Understanding uncontrolled severe allergic asthma by integration of omic and clinical data.

BACKGROUND: Asthma is a complex, multifactorial disease often linked with sensitization to house dust mites (HDM). There is a subset of patients that does not respond to available treatments, who present a higher number of exacerbations and a worse quality of life. To understand the mechanisms of poor asthma control and disease severity, we aim to elucidate the metabolic and immunologic routes underlying this specific phenotype and the associated clinical features. METHODS: Eighty-seven patients with a clinical history of asthma were recruited and stratified in 4 groups according to their response to treatment: corticosteroid-controlled (ICS), immunotherapy-controlled (IT), biologicals-controlled (BIO) or uncontrolled (UC). Serum samples were analysed by metabolomics and proteomics; and classifiers were built using machine-learning algorithms. RESULTS: Metabolomic analysis showed that ICS and UC groups cluster separately from one another and display the highest number of significantly different metabolites among all comparisons. Metabolite identification and pathway enrichment analysis highlighted increased levels of lysophospholipids related to inflammatory pathways in the UC patients. Likewise, 8 proteins were either upregulated (CCL13, ARG1, IL15 and TNFRSF12A) or downregulated (sCD4, CCL19 and IFNγ) in UC patients compared to ICS, suggesting a significant activation of T cells in these patients. Finally, the machine-learning model built including metabolomic and clinical data was able to classify the patients with an 87.5% accuracy. CONCLUSIONS: UC patients display a unique fingerprint characterized by inflammatory-related metabolites and proteins, suggesting a pro-inflammatory environment. Moreover, the integration of clinical and experimental data led to a deeper understanding of the mechanisms underlying UC phenotype.

Metabolomics in the Identification of Biomarkers of Asthma.

Asthma is a major non-communicable disease characterized by recurrent attacks of breathlessness and wheezing [...].

Understanding Systemic and Local Inflammation Induced by Nasal Polyposis: Role of the Allergic Phenotype.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent symptoms associated to the development of nasal polyps. To this day, the molecular mechanisms involved are still not well defined. However, it has been suggested that a sustained inflammation as allergy is involved in its onset. In this exploratory study, the aim was to investigate the effect of the allergic status in the development of CRSwNP. To achieve this, we recruited 22 patients with CRSwNP and classified them in non-allergic and allergic using ImmunoCAP ISAC molecular diagnosis. Plasma samples were analyzed using liquid chromatography coupled to mass spectrometry (LC-MS). Subsequently, significant metabolites from plasma that were commercially available were then analyzed by targeted analysis in some nasal polyps. Additionally, nasal polyp and nasal mucosa samples were examined for eosinophils, neutrophils, CD3+ and CD11c+ cells, as well as collagen deposition and goblet cell hyperplasia. We found that 9 out of the 22 patients were sensitized to some aeroallergens (named as allergic CRSwNP). The other 13 patients had no sensitizations (non-allergic CRSwNP). Regarding metabolomics, bilirubin, cortisol, lysophosphatidylcholines (LPCs) 16:0, 18:0 and 20:4 and lysophosphatidylinositol (LPI) 20:4, which are usually related to a sustained allergic inflammation, were unexpectedly increased in plasma of non-allergic CRSwNP compared to allergic CRSwNP. LPC 16:0, LPC 18:0 and LPI 20:4 followed the same trend in nasal polyp as they did in plasma. Comparison of nasal polyps with nasal mucosa showed a significant increase in eosinophils (p < 0.001) and neutrophils (p < 0.01) in allergic CRSwNP. There were more eosinophils in polyps of non-allergic CRSwNP than in their nasal mucosa (p < 0.01). Polyps from non-allergic CRSwNP had less eosinophils than the polyps of allergic CRSwNP (p < 0.05) and reduced amounts of collagen compared to their nasal mucosa (p < 0.001). Our data suggests that there is a systemic inflammatory response associated to CRSwNP in the absence of allergy, which could be accountable for the nasal polyp development. Allergic CRSwNP presented a higher number of eosinophils in nasal polyps, suggesting that eosinophilia might be connected to the development of nasal polyps in this phenotype.

Molecular allergology and its impact in specific allergy diagnosis and therapy.

Progressive knowledge of allergenic structures resulted in a broad availability of allergenic molecules for diagnosis. Component-resolved diagnosis allowed a better understanding of patient sensitization patterns, facilitating allergen immunotherapy decisions. In parallel to the discovery of allergenic molecules, there was a progressive development of a regulation framework that affected both in vitro diagnostics and Allergen Immunotherapy products. With a progressive understanding of underlying mechanisms associated to Allergen immunotherapy and an increasing experience of application of molecular diagnosis in daily life, we focus in analyzing the evidences of the value provided by molecular allergology in daily clinical practice, with a focus on Allergen Immunotherapy decisions.

Oral Mucosa as a Potential Site for Diagnosis and Treatment of Allergic and Autoimmune Diseases.

Most prevalent food allergies during early childhood are caused by foods with a high allergenic protein content, such as milk, egg, nuts, or fish. In older subjects, some respiratory allergies progressively lead to food-induced allergic reactions, which can be severe, such as urticaria or asthma. Oral mucosa remodeling has been recently proven to be a feature of severe allergic phenotypes and autoimmune diseases. This remodeling process includes epithelial barrier disruption and the release of inflammatory signals. Although little is known about the immune processes taking place in the oral mucosa, there are a few reports describing the oral mucosa-associated immune system. In this review, we will provide an overview of the recent knowledge about the role of the oral mucosa in food-induced allergic reactions, as well as in severe respiratory allergies or food-induced autoimmune diseases, such as celiac disease.