Development Of IgE-mediated Food Allergy Research Articles

The Immunobiology and Treatment of Food Allergy.

IgE-mediated food allergy (IgE-FA) occurs due to a breakdown in immune tolerance that leads to a detrimental type 2 helper Tcell (TH2) adaptive immune response. While the processes governing this loss of tolerance are incompletely understood, several host-related and environmental factors impacting the risk of IgE-FA development have been identified. Mounting evidence supports the role of an impaired epithelial barrier in the development of IgE-FA, with exposure of allergens through damaged skin and gut epithelium leading to the aberrant production of alarmins and activation of TH2-type allergic inflammation. The treatment of IgE-FA has historically been avoidance with acute management of allergic reactions, but advances in allergen-specific immunotherapy and the development of biologics and other novel therapeutics are rapidly changing the landscape of food allergy treatment. Here, we discuss the pathogenesis and immunobiology of IgE-FA in addition to its diagnosis, prognosis, and treatment. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Food allergy and infant feeding practices: Are they related?

BackgroundImmunoglobulin (Ig)E-mediated food allergy is a growing health problem affecting up to 10% of children. It is well-established that early introduction to peanuts and eggs from 4 months of age has a preventive effect. In contrast, there is no consensus about the effect of breastfeeding on food allergy development. ObjectiveTo evaluate the effect of breastfeeding and cows' milk formula (CMF) feeding on the development of IgE-mediated food allergy. MethodsInfants in the Cow's Milk Early Exposure Trial were followed for 12 months. The cohort was divided according to parental feeding preferences for the first 2 months of life: group 1: exclusive breastfeeding (EBF); group 2: breastfeeding with at least 1 daily meal of CMF; and group 3: feeding with CMF only. ResultsAmong a total of 1989 infants, 1071 were on EBF (53.8%), 616 were breastfed with addition of CMF (31%), and 302 were fed with CMF only (15.2%), from birth. By 12 months, 43 infants developed an IgE-mediated food allergy (2.2%); 31 in the EBF group (2.9%), 12 in the breastfeeding and CMF combined group (1.9%), and none in the CMF feeding-only group (P = .002). Family atopic comorbidity did not affect the results. ConclusionIn this prospective cohort, breastfed infants developed significantly higher rates of IgE-mediated food allergy during the first year of life. Perhaps the mechanism is related to compounds ingested by the mother and secreted in the breastmilk. Future larger cohorts should validate these results and offer the lactating mother recommendations. Trial RegistrationThe COMEET study and its derivatives were approved by the Ethics Committee of Meir Medical Center, IRB number 011-16-MMC. It was registered at the National Institutes of Health Clinical Trials Registry: NCT02785679.

Genetic risk factors of food allergy: a review of genome-wide studies

BACKGROUND: Food allergy (FA) is an urgent problem for public health worldwide. This disease reduces the quality of life of patients and increases the risk of developing unpredictable anaphylactic reactions.
 AIM: Conduct an analysis of genetic studies in cohorts of patients with FA aimed at assessing the role of genetic factors in the development of this pathology.
 MATERIALS AND METHODS: The results of genome-wide association studies aimed at studying the influence of genetic factors in FA development. The review includes original articles published for the period from January 1, 2012 to December 31, 2021.
 RESULTS: This systematic review analyzed data on the relationship of genetic variations associated with FA. Eight studies were analyzed, and the maximum effect with the development of IgE-mediated FA on peanuts was found for the rs10018666 variant of the SLC2A9 gene in Europeans. Some allergens associated with specific loci have been found, for example, variants rs9273440 (HLA-DQB1), rs115218289 (ITGA6), rs10018666 (SLC2A9), and others are unique to peanut. Associated variants are predominantly associated with disorders of the innate/adaptive immune response and functioning of the epithelial barrier, confirming their leading role in FA development. In addition to associations with FA, most of the identified genes affect the development of other allergic march phenotypes, including atopic dermatitis, bronchial asthma, allergic rhinitis, and non-allergic (type 2 diabetes mellitus, Parkinsons disease, myocardial infarction, and others) diseases.
 CONCLUSIONS: Summarizing the results of genome-wide associative studies, it should be noted that the development of food allergies involves variants localized both in known atopic and newly identified loci that are not related to the development of other allergic diseases. The peculiarities of the structure of food sensitization and the lack of research on the susceptibility to food allergies in Russia determine the direction of further scientific research in this area.

Immunoproteomics of cow's milk allergy in Mexican pediatric patients

Immunological mechanisms of non-IgE-mediated cow's milk protein allergy (CMPA) are not well understood. Such a circumstance requires attention with the aim of discovering new biomarkers that could lead to better diagnostic assays for early treatment. Here, we sought both to investigate the mechanism that underlies non-IgE-mediated CMPA and to identify cow's milk immunoreactive proteins in a Mexican pediatric patient group (n = 34). Hence, we determined the IgE and IgG1–4 subclass antibody levels against cow's milk proteins (CMP) by ELISA. Then, we performed 2D-Immunoblots using as first antibody immunoglobulins in the patients'serum that bound specifically against CMP together with CMP enrichment by ion-exchange chromatography. Immunoreactive proteins were identified by mass spectrometry-based proteomics. The serological test confirmed absence of specific IgE in the CMPA patients but showed significant increase in antigen-specific IgG1. Additionally, we identified 11 proteins that specifically bound to IgG1. We conclude that the detection of specific IgG1 together with an immunoproteomics approach is highly relevant to the understanding of CMPA's physiopathology and as a possible aid in making a prognosis since current evidence indicates IgG1 occurrence as an early signal of potential risk toward development of IgE-mediated food allergy. SignificanceAllergies are one of the most studied topics in the field of public health and novel protein allergens are found each year. Discovery of new principal and regional allergens has remarkable repercussions in precise molecular diagnostics, prognostics, and more specific immunotherapies. In this context, specific IgE is widely known to mediate physiopathology; however, allergies whose mechanism does not involve this immunoglobulin are poorly understood although their incidence has increased. Therefore, accurate diagnosis and adequate treatment are delayed with significant consequences on the health of pediatric patients. The study of type and subtypes of immunoglobulins associated with the immunoreactivity of cow's milk proteins together with an immunoproteomics approach allows better comprehension of physiopathology, brings the opportunity to discover new potential cow's milk protein allergens and may help in prognosis prediction (IgG1 occurrence as an early signal of possible risk toward development of IgE-mediated food allergy).

Risk Factors for the Development of IgE-Mediated Food Allergy in Preschool Children with Asthma.

Food allergy is a component of the atopic march and may have effects on asthma. This study aimed to evaluate the risk factors for confirmed immunoglobulin E-mediated food allergies and their impact on the clinical picture in preschool children with asthma. Clinical history and allergic assessment results were obtained from medical records and analyzed retrospectively. Preschool children with asthma were included in the study and the characteristics of food allergy and asthma were evaluated. The patients were grouped as those with food allergy (Group I, n = 60) and those without (Group II, n = 98). In patients with food allergy and asthma, the number of episodes requiring systemic steroids in the last year (p = 0.002), atopic dermatitis (p = 0.001), parental atopic disease (p = 0.009) and aeroallergen sensitivity rates (p < 0.001) was higher than patients without food allergies. The use of medium or high doses of inhaled steroids to achieve asthma control was more frequent in patients with food allergies (p = 0.014). Parental history of atopic disease [p = 0.007, odds ratio (OR): 3.27, 95% confidence interval (CI) 1.37-7.77)], atopic dermatitis (p = 0.017, OR: 2.80, 95% CI: 1.19-6.57), starting complementary food after 6 months (p = 0.004, OR: 3.9, 95% CI: 1.5-10.0) and having aeroallergen sensitivity (p < 0.001, OR: 6.01, 95% CI: 2.21-16.29) were identified as significant risk factors for food allergy. Asthmatic preschool children with food allergies are more likely to have a parental atopic disease, atopic dermatitis, aeroallergen sensitivity and starting complementary food after 6 months. These patients experience more asthma attacks and need higher doses of steroids.

Dysfunctional Gut Microbiome Networks in Childhood IgE-Mediated Food Allergy.

The development of food allergy has been reported to be related with the changes in the gut microbiome, however the specific microbe associated with the pathogenesis of food allergy remains elusive. This study aimed to comprehensively characterize the gut microbiome and identify individual or group gut microbes relating to food-allergy using 16S rRNA gene sequencing with network analysis. Faecal samples were collected from children with IgE-mediated food allergies (n = 33) and without food allergy (n = 27). Gut microbiome was profiled by 16S rRNA gene sequencing. OTUs obtained from 16S rRNA gene sequencing were then used to construct a co-abundance network using Weighted Gene Co-expression Network Analysis (WGCNA) and mapped onto Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We identified a co-abundance network module to be positively correlated with IgE-mediated food allergy and this module was characterized by a hub taxon, namely Ruminococcaceae UCG-002 (phylum Firmicutes). Functional pathway analysis of all the gut microbiome showed enrichment of methane metabolism and glycerolipid metabolism in the gut microbiome of food-allergic children and enrichment of ubiquinone and other terpenoid-quinone biosynthesis in the gut microbiome of non-food allergic children. We concluded that Ruminococcaceae UCG-002 may play determinant roles in gut microbial community structure and function leading to the development of IgE-mediated food allergy.

Mechanisms Underlying the Skin-Gut Cross Talk in the Development of IgE-Mediated Food Allergy.

Immune-globulin E (IgE)-mediated food allergy is characterized by a variety of clinical entities within the gastrointestinal tract, skin and lungs, and systemically as anaphylaxis. The default response to food antigens, which is antigen specific immune tolerance, requires exposure to the antigen and is already initiated during pregnancy. After birth, tolerance is mostly acquired in the gut after oral ingestion of dietary proteins, whilst exposure to these same proteins via the skin, especially when it is inflamed and has a disrupted barrier, can lead to allergic sensitization. The crosstalk between the skin and the gut, which is involved in the induction of food allergy, is still incompletely understood. In this review, we will focus on mechanisms underlying allergic sensitization (to food antigens) via the skin, leading to gastrointestinal inflammation, and the development of IgE-mediated food allergy. Better understanding of these processes will eventually help to develop new preventive and therapeutic strategies in children.

The significance of cow’s milk proteins in the development of IgE-mediated food allergy among children

Identification of offending allergens in patients with food allergy is a very important part of an allergist’s activity. Objective. To study the structure оf sensitization to food allergens among children in Moscow and Moscow region and to determine the significance of sensitization to milk proteins . Methods. The level and class of specific IgE in blood serum of children with IgEmediated allergic diseases were examined with RIDA AllergyScreen method. Serum of children with high level of specific IgE to milk allergenic proteins was studied. The level and ratio of specific IgE to individual milk allergens were revealed. Results. The structure of sensitization to food allergens was determined. It was revealed that cow’s milk allergens are the leading triggers of food allergy, especially in early childhood in Moscow and the Moscow region. The features of sensitization to cow’s milk proteins among children were analyzed. Conclusions. According to the study, about half of children with IgEmediated food allergies in Moscow and the Moscow region have sensitization to cow’s milk proteins. The leading role in the frequency of sensitization belongs to whey proteins of milk. Among them sensitization to а-lactalbumin was detected more often. The questions about the selection of hypoallergenic milk formulas for feeding of children with allergy to cow’s milk proteins were discussed.

Factors Associated with Development of Food Allergy in Young Children after Liver Transplantation: A Retrospective Analysis of 10 Years' Experience

Although development of food allergy after liver transplantation is most commonly described in young children, little is known about identification of young liver-transplant recipients who are at risk of food allergy. This study aimed to identify the types of food allergy and the risk factors for the development of food allergy after liver transplantation. This was a retrospective analysis of pediatric liver transplant recipients in our organ transplantation center during 2005-2015. Relevant data of all patients who underwent liver transplantation were extracted from the center's database and the medical records. Differences in patients' characteristics were evaluated for associations between food allergy and potential risk factors. Logistic regression models were used to calculate adjusted odds ratios. We obtained the data of 206 patients under 36 months of age, 42 (20.4%) of whom developed food allergy after liver transplantation. The allergy was IgE-mediated-only in 30 (71.4%) and non-IgE-mediated-only in 10 (23.8%). Multivariate analysis found eczema at liver transplantation to be a significant risk factor (adjusted odds ratio [aOR] 2.41, 95% confidence interval [CI] 1.14-4.77, P < .05). Eczema increased the risk of developing IgE-mediated food allergy after liver transplantation (aOR 3.13, 95% CI 1.41-6.93, P < .01), whereas no significant association was observed with non-IgE-mediated food allergy. We identified eczema at liver transplantation as a significant risk factor for the development of IgE-mediated food allergy after liver transplantation, but not non-IgE-mediated food allergy. Our findings may contribute to a better understanding of the susceptible subgroup requiring special caution and to the establishment of effective strategies for prevention.

IL-9-producing cells in the development of IgE-mediated food allergy.

Food allergy is a harmful immune reaction driven by uncontrolled type 2 immune responses. Considerable evidence demonstrates the key roles of mast cells, IgE, and TH2 cytokines in mediating food allergy. However, this evidence provides limited insight into why only some, rather than all, food allergic individuals are prone to develop life-threatening anaphylaxis. Clinical observations suggest that patients sensitized to food through the skin early in life may later develop severe food allergies. Aberrant epidermal thymic stromal lymphopoietin and interleukin (IL) 33 production and genetic predisposition can initiate an allergic immune response mediated by dendritic cells and CD4+TH2 cells in inflamed skin. After allergic sensitization, intestinal IL-25 and food ingestion enhance concerted interactions between type 2 innate lymphoid cells (ILC2s) and CD4+TH2 cells, which perpetuate allergic reactions from the skin to the gut. IL-4 and cross-linking of antigen/IgE/FcεR complexes induce emigrated mast cell progenitors to develop into the multi-functional IL-9-producing mucosal mast cells, which produce prodigious amounts of IL-9 and mast cell mediators to drive intestinal mastocytosis in an autocrine loop. ILC2s and TH9 cells may also serve as alternative cellular sources of IL-9 to augment the amplification of intestinal mastocytosis, which is the key cellular checkpoint in developing systemic anaphylaxis. These findings provide a plausible view of how food allergy develops and progresses in a stepwise manner and that atopic signals, dietary allergen ingestion, and inflammatory cues are fundamental in promoting life-threatening anaphylaxis. This information will aid in improving diagnosis and developing more effective therapies for food allergy-triggered anaphylaxis.

IL-10 Enhances IgE-Mediated Mast Cell Responses and Is Essential for the Development of Experimental Food Allergy in IL-10-Deficient Mice.

IL-10 is a key pleiotropic cytokine that can both promote and curb Th2-dependent allergic responses. In this study, we demonstrate a novel role for IL-10 in promoting mast cell expansion and the development of IgE-mediated food allergy. Oral OVA challenge in sensitized BALB/c mice resulted in a robust intestinal mast cell response accompanied by allergic diarrhea, mast cell activation, and a predominance of Th2 cytokines, including enhanced IL-10 expression. In contrast, the development of intestinal anaphylaxis, including diarrhea, mast cell activation, and Th2 cytokine production, was significantly attenuated in IL-10(-/-) mice compared with wild-type (WT) controls. IL-10 also directly promoted the expansion, survival, and activation of mast cells; increased FcεRI expression on mast cells; and enhanced the production of mast cell cytokines. IL-10(-/-) mast cells had reduced functional capacity, which could be restored by exogenous IL-10. Similarly, attenuated passive anaphylaxis in IL-10(-/-) mice could be restored by IL-10 administration. The adoptive transfer of WT mast cells restored allergic symptoms in IL-10(-/-) mice, suggesting that the attenuated phenotype observed in these animals is due to a deficiency in IL-10-responding mast cells. Lastly, transfer of WT CD4 T cells also restored allergic diarrhea and intestinal mast cell numbers in IL-10(-/-) mice, suggesting that the regulation of IL-10-mediated intestinal mast cell expansion is T cell dependent. Our observations demonstrate a critical role for IL-10 in driving mucosal mast cell expansion and activation, suggesting that, in its absence, mast cell function is impaired, leading to attenuated food allergy symptoms.

IL-10 enhances mast cell activation and is essential for the development of IgE-mediated experimental food allergy

Abstract IL-10 is a key pleiotropic cytokine that can both promote and curb Th2-dependent allergic responses. Herein we demonstrate a novel role for IL-10 in the development of IgE-mediated food allergy. Oral ovalbumin challenge in sensitized BALB/c mice resulted in a robust intestinal mast cell response accompanied by allergic diarrhea, mast cell activation and a predominance of Th2 cytokines, including enhanced IL-10 expression. In contrast, the development of intestinal anaphylaxis including diarrhea, mast cell activation, and Th2 cytokine production was significantly attenuated in IL-10−/− mice compared to WT controls. Furthermore, IL-10 directly promoted the activation of mast cells. Administration of IgE and antigen induced the development of passive anaphylaxis in WT mice, which was attenuated in IL-10−/− animals. However, treatment of IL-10−/− mice with recombinant IL-10 prior to IgE administration restored the development of passive anaphylaxis in these animals. Finally, adoptive transfer of WT mast cells restored allergic symptoms in IL-10−/− mice. Our observations demonstrate a critical role for IL-10 in driving mucosal mast cell activation, suggesting that in its absence, mast cell function is impaired, leading to attenuated food allergy symptoms.

Pearls and Pitfalls in Diagnosing IgE-Mediated Food Allergy.

The term "food allergy" is used by many patients and clinicians to describe a range of symptoms that occur after ingestion of specific foods. However, not all symptoms occurring after food exposure are due to an allergic, or immunologic, response. It is important to properly evaluate and diagnose immunoglobulin E (IgE)-mediated food allergy as this results in reproducible, immediate onset, allergic reactions that can progress toward life-threatening anaphylaxis. Proper diagnosis requires understanding of the common foods that cause these reactions in addition to key historical elements such as symptoms, timing and duration of reaction, and risk factors that may predispose to development of IgE-mediated food allergy. Diagnostic testing for food-specific IgE can greatly aid the diagnosis. However, false-positive test results are very common and can lead to overinterpretation, misdiagnosis, and unnecessary dietary elimination. This review discusses important aspects to consider during evaluation of a patient for suspected IgE-mediated food allergy.

Early exposure hypothesis: where are we now?

Despite increasing efforts to prevent food allergies in children, IgE-mediated food allergies continue to rise in westernized countries. The World Health Organisation recommends that during the first six months of life, infants be exclusively breast fed, and that weaning onto solids and milk formula should only occur after that period. Specific avoidance of foods such as egg and peanut in atopic infants has been believed to prevent the development of these allergies. While there is data suggesting that exclusive breast-feeding and the use of extensively hydrolyzed formula may prevent the development of eczema, there is insufficient evidence that such dietary interventions prevent the development of IgE-mediated food allergy. The dual exposure to allergen hypothesis posits that tolerance to antigens occurs in the neonate through high-dose oral exposure and that allergic sensitisation occurs through low dose cutaneous exposure. It has been shown that exposure of mice to ovalbumin or peanut on abraded skin led to significant specific IgE responses. In human subjects, there are studies in which food allergen–specific T cells have been isolated from lesional skin in patients with eczema. In a prospective birth cohort study it was found that low-dose exposure to peanut in the form of arachis oil applied to inflamed skin on infants was associated with increased risk of peanut allergy at age 5 years. Recent studies suggest that infants who are exposed to food allergens early through the oral route are less likely to have food allergies than infants without such exposure, but such observational cohort studies are subject to confounding and the possibility of reverse causality. An ongoing randomized trial involving infants at high risk for food allergy is comparing early exposure to high doses of food allergens with complete avoidance of these allergens during infancy (http://www.leapstudy.co.uk). The concept of oral tolerance induction to food allergy is being further investigated in another randomized controlled study to determine whether early weaning and exposure to food allergens (from 3 months of age) prevents the development of food allergies (http://www.eatstudy.co.uk).