Immunoglobulin G4 (IgG4), a unique subclass of IgG antibodies, plays diverse roles in human health and disease. Its distinct features, such as Fab-arm exchange and specific mutations, confer reduced effector functions compared to other IgG subclasses. In health, IgG4 responses contribute to immune tolerance, particularly in the context of allergen-specific immunotherapy (AIT), where they can mediate tolerance to environmental antigens, inhibit IgE-dependent mast cell degranulation, and compete with IgE for allergen binding. This helps in attenuating allergic symptoms and is associated with increased levels of allergen-specific IgG4. However, in disease scenarios, the role of IgG4 is complex. IgG4 lacks complement fixation and, thus, shows a reduced ability to activate immune effector pathways, it was initially thought to be protective against autoimmune diseases. However, emerging evidence suggests that it can contribute to pathology. For instance, IgG4 autoantibodies against specific antigens can aggravate conditions in certain autoimmune disorders. In some cancers, it may play a role in immune evasion, with higher levels correlating with poor patient survival, albeit in others, its exact function remains elusive. Overall, understanding the precise role of IgG4 in various physiological and pathological conditions is crucial for developing targeted therapeutic strategies and improving patient outcomes.

Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition characterized by eosinophil infiltration in the esophagus, leading to symptoms such as food impaction and growth delays. Despite its increasing recognition, there is significant variability in diagnostic and treatment practices, particularly in pediatric populations.

This study aimed to evaluate the current diagnostic and treatment practices for EoE in children across multiple centers in Mexico, identify common clinical presentations, and assess the role of IgG4 in EoE.

A retrospective analysis was conducted on 32 pediatric patients diagnosed with EoE. Data on clinical symptoms, endoscopic findings, histologic analysis, allergy assessments, and treatment approaches were collected. The presence of IgG4-positive plasma cells was also evaluated.

The median age was 10.6 years, with a diagnostic delay of 15.5 months. Acute food impaction was the most common symptom, and 82% had a personal history of atopy. Endoscopic abnormalities were observed in 71% of patients. Histologic analysis confirmed EoE in 83.8% of biopsy samples, with eosinophil counts averaging 17 to 24 per high-power field. IgG4-positive plasma cells were present in 76.5% of patients. Treatment varied, with many receiving proton pump inhibitors and topical corticosteroids, but patients treated with dupilumab showed significant improvement.

The study highlights the challenges in diagnosing and managing EoE in children, emphasizing the need for standardized practices and comprehensive evaluations. The presence of IgG4-positive plasma cells suggests a potential role in EoE pathophysiology. Further research is needed to establish effective treatment guidelines and confirm the potential of dupilumab as a therapeutic option.

Recent studies have shown deposition of immunoglobulin G4 (IgG4) and food proteins in the esophageal mucosa of eosinophilic esophagitis (EoE) patients. Our aims were to assess whether co-localization of IgG4 and major cow's milk proteins (CMPs) was associated with EoE disease activity and to investigate the proteins enriched in proximity to IgG4 deposits.

This study included adult subjects with EoE (n = 13) and non-EoE controls (n = 5). Esophageal biopsies were immunofluorescence stained for IgG4 and CMPs. Co-localization in paired samples from active disease and remission was assessed and compared to controls. The proteome surrounding IgG4 deposits was evaluated by the novel technique, AutoSTOMP. IgG4-food protein interactions were confirmed with co-immunoprecipitation and mass spectrometry.

IgG4-CMP co-localization was higher in the active EoE group compared to paired remission samples (Bos d 4, p = .02; Bos d 5, p = .002; Bos d 8, p = .002). Co-localization was also significantly higher in the active EoE group compared to non-EoE controls (Bos d 4, p = .0013; Bos d 5, p = .0007; Bos d 8, p = .0013). AutoSTOMP identified eosinophil-derived proteins (PRG 2 and 3, EPX, RNASE3) and calpain-14 in IgG4-enriched areas. Co-immunoprecipitation and mass spectrometry confirmed IgG4 binding to multiple food allergens.

These findings further contribute to the understanding of the interaction of IgG4 with food antigens as it relates to EoE disease activity. These data strongly suggest the immune complex formation of IgG4 and major cow's milk proteins. These immune complexes may have a potential role in the pathophysiology of EoE by contributing to eosinophil activation and disease progression.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by eosinophilic infiltration, leading to esophageal dysfunction, inflammation, and fibrotic remodeling. In the last few decades, there has been an increased prevalence of EoE at an alarming rate in the pediatric age. The pathogenesis of EoE is still largely undefined, and this limits the definition of effective strategies for the prevention and management of this condition. EoE is considered a multifactorial disease arising from a negative interaction between environmental factors and genetic background, causing an impaired esophageal epithelial barrier with subsequent abnormal allergen exposure activating type 2 (Th2) inflammation. Food antigens have been suggested as key players in Th2 inflammation in pediatric patients with EoE, but emerging evidence suggests a potential role of other dietary factors, including ultraprocessed foods, as possible triggers for the occurrence of EoE. In this paper, we discuss the potential role of these dietary factors in the development of the disease, and we propose a new approach for the management of pediatric patients with EoE.

Eosinophilic esophagitis (EoE) can coexist in individuals with food allergy.

To evaluate the characteristics of food-allergic patients with and without coexisting EoE using a large food allergy patient registry.

Data were derived from 2 Food Allergy Research & Education, Inc, Patient Registry surveys. A series of multivariable regression models were used to evaluate associations between demographic, comorbidity, and food allergy characteristics and the likelihood of reporting EoE.

Five percent (n = 309) of registry participants (n = 6074; ages <1 year->80 years, mean, 20.20 ± 15.37 years) reported having EoE. The odds of having EoE were significantly greater in male participants (adjusted odds ratio [aOR], 1.3; 95% CI, 1.04-1.72) and those with comorbid asthma (aOR, 2.0; 95% CI, 1.55-2.49), allergic rhinitis (aOR, 1.8; 95% CI, 1.37-2.22), oral allergy syndrome (aOR, 2.8; 95% CI, 2.09-3.70), food protein-induced enterocolitis syndrome (aOR, 2.5; 95% CI, 1.34-4.84), and hyper-IgE syndrome (aOR, 7.6; 95% CI, 2.93-19.92), though not atopic dermatitis (aOR, 1.3; 95% CI, 0.99-1.59), when adjusting for demographics (sex, age, race, ethnicity, and geographic location). Those with a greater number of food allergies (aOR, 1.3; 95% CI, 1.23-1.32), more frequent food-related allergic reactions (aOR, 1.2; 95% CI, 1.11-1.24), previous anaphylaxis (aOR, 1.5; 95% CI, 1.15-1.83), and health care utilization for food-related allergic reactions (aOR, 1.3; 95% CI, 1.01-1.67)-specifically intensive care unit admission (aOR, 1.2; 95% CI, 1.07-1.33)-were more likely to have EoE after controlling for demographics. However, no significant difference in ever using epinephrine for food-related allergic reactions was detected.

These self-reported data showed that coexisting EoE is associated with an increased number of food allergies, food-related allergic reactions per year, and measures of reaction severity, calling attention to the likely increased health care needs of food-allergic patients with EoE.

High levels of serum food-specific IgG4 (sIgG4) have been reported in patients with EoE. The objective of this study was to examine whether serum sIgG4 levels to foods and aeroallergens are higher in EoE patients than allergic controls and to investigate the association between sIgG4 and EoE clinical characteristics.

This was a case-control study nested in a prospective EoE Cohort. EoE cases were defined per consensus guidelines, and controls were individuals with symptoms who were confirmed to be EoE-negative on upper endoscopy. Demographic and clinical information was prospectively collected. Serum IgE and sIgG4 were measured to foods and aeroallergens by ImmunoCAP. Mean levels of sIgG4 were compared between cases and controls, and logistic regression models were used to examine predictors of elevated milk sIgG4 levels.

The analysis included 123 individuals (EoE n = 93, control n = 30) with a similar distribution of allergic disease between EoE patients and controls (86% vs. 93%; p = .30). EoE patients had significantly higher sIgG4 levels to all allergens evaluated, with the exception of birch (p = .24). Milk sIgG4 levels were independently associated with milk consumption (OR 4.95; p = .01) and the presence of sIgE to milk (OR 4.23; p = .008).

Serum sIgG4 levels to food and aeroallergen proteins were higher in patients with EoE than non-EoE controls, and higher levels of milk sIgG4 were independently associated with milk consumption and the presence of sIgE to milk proteins. Whether sIgG4 plays a pathogenic role in EoE or could be used as an EoE biomarker remains unknown and warrants further study.

Recent studies have shown that IgG4 is increased in the esophageal tissue of eosinophilic esophagitis patients, including the presence of IgG4+ plasma cells.

Our aim was to determine whether IgG4 is elevated in the gastric or duodenal tissue of pediatric patients with eosinophilic gastritis or duodenitis (EoG or EoD).

This was a retrospective single center study. Pediatric patients were characterized as having active EoG, EoD, or as controls based on clinical symptoms and histologic features. Immunohistochemistry for IgG4 was performed in gastric and duodenal tissue, and peak IgG4+ cells were compared between groups and after treatment.

The frequency of IgG4+ cells was significantly higher in patients with EoG and EoD compared to controls in the stomach [EoG 6.5 cells/hpf (3.6-10.9), control 0 cells/hpf (0-0.7), p<0.0001] and duodenum [EoD 7.5 cells/hpf (2.8-37), control 0.5 cells/hpf (0.3-1.3), p<0.001)] respectively, and positively correlated with eosinophil counts (stomach: r 0.74, p<0.0001; duodenum: r 0.57, p<0.0001). The amount of tissue IgG4 was significantly decreased in patients in remission but not in persistently active disease.

These data suggest local tissue production of IgG4 may be a universal feature of eosinophilic gastrointestinal disease that tracks with disease activity.

The pathogenesis of eosinophilic esophagitis involves immunoglobulin G4 (IgG4) deposition. However, the relationship between IgG4 and eosinophilic gastroenteritis (EGE) is unclear.

To investigate gastrointestinal deposition of IgG4 in EGE.

Biopsies of the esophagus, stomach, and small intestine were evaluated in patients with and without EGE. Immunohistochemical staining for IgG4 was performed, and the proportions of the stained areas were compared. Sera from patients with EGE were assayed for food-specific IgG4, including egg white, wheat, rice, soy, and cow milk.

Seventeen patients were included in this study (EGE group, n = 10; control group, n = 7). Compared with the control group, the proportion of IgG4-stained area in the EGE group was approximately threefold higher (40.2% [32.3-49.5]) vs. 12.1% [4.0-21.9], p = 0.014) in the esophagus, fivefold higher in the stomach (17.3% [11.1-26.2] vs. 3.7% [1.5-5.2], p = 0.014), and sixfold higher in the small intestine (28.0% [15.0-33.2] vs. 4.5% [2.6-9.8], p = 0.019). There was no significant association between the proportion of IgG4-stained area and the number of infiltrating eosinophils. Serum egg white-specific IgG4 levels were correlated with the proportion of IgG4-stained areas in the small intestine (R = 0.7, p = 0.035).

IgG4 accumulated within the gastrointestinal mucosa in EGE. The positive correlation between serum egg white-specific IgG4 levels and the proportion of IgG4-stained areas in the small intestine suggests a role for IgG4 in the disease pathophysiology.

Our knowledge of the pathophysiology of eosinophilic esophagitis is constantly evolving. There is significant association between eosinophilic esophagitis and atopy; however, multiple studies have refuted the role of IgE in its pathogenesis. Instead, new data have demonstrated an elevated IgG4 level in patients with eosinophilic esophagitis. We review the current understanding of eosinophilic esophagitis pathogenesis and highlight the increasing evidence for the role of IgG4.

Allergic diseases, such as IgE-mediated food allergy, asthma, and allergic rhinitis, are relevant health problems worldwide and show an increasing prevalence. Therapies for food allergies are food avoidance and the prompt administration of intramuscular epinephrine in anaphylaxis occurring after accidental exposure. However, allergen immunotherapy (AIT) is being investigated as a new potential tool for treating severe food allergies. Effective oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) induce desensitization and restore immune tolerance to the causal allergen. While immediate side effects are well known, the long-term effects of food AIT are still underestimated. In this regard, eosinophilic gastrointestinal disorders (EGIDs), mainly eosinophilic esophagitis, have been reported as putative complications of OIT for food allergy and sublingual immunotherapy (SLIT) for allergic asthma and rhinitis. Fortunately, these complications are usually reversible and the patient recovers after AIT discontinuation. This review summarizes current knowledge on the possible causative link between eosinophilic gastrointestinal disorders and AIT, highlighting recent evidence and controversies.

Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that occurs in both children and adults. Previous studies of affected tissue from pediatric cohorts have identified prominent signatures of eosinophilia and type 2 inflammation. However, the details of the immune response in adults with EoE are still being elucidated. To determine whether EoE in adults shares inflammatory profiles with those observed in children, we performed RNA sequencing of paired human esophageal biopsies and blood samples from adults with EoE or gastroesophageal reflux disease. Unbiased analysis of differentially expressed genes in tissue revealed a strong IFN signature that was significantly enriched in EoE patients as compared with patients with gastroesophageal reflux disease. Both type I and type II IFN-responsive genes were upregulated in adult biopsies, but not in blood. A similar increase in expression of IFN gene sets was observed in pediatric EoE biopsies as compared with non-EoE samples, and in public pediatric and adult RNA-sequencing data. Finally, we found that human peripheral CD4⁺ T cells from children with EoE produce IFN-γ upon activation with EoE-causal allergens. Together, this work identifies a conserved IFN signature in pediatric and adult EoE, highlighting a role for non-type 2 inflammatory networks in the disease process in humans.

IgE to α-Gal is a cause of mammalian meat allergy and has been linked to tick bites in North America, Australia, and Eurasia. Reports from the developing world indicate that α-Gal sensitization is prevalent but has been little investigated.

We sought evidence for the cause(s) of α-Gal sensitization and lack of reported meat allergy among children in less developed settings in Ecuador and Kenya.

IgE to α-Gal and total IgE were assessed in children from Ecuador (n = 599) and Kenya (n = 254) and compared with children with (n = 42) and without known (n = 63) mammalian meat allergy from the southeastern United States. Information on diet, potential risk factors, and helminth infections was available for children from Ecuador. IgG₄ to α-Gal and antibodies to regionally representative parasites were assessed in a subset of children.

In Ecuador (32%) and Kenya (54%), α-Gal specific IgE was prevalent, but levels were lower than in children with meat allergy from the United States. Sensitization was associated with rural living, antibody markers of Ascaris exposure, and total IgE, but not active infections with Ascaris or Trichuris species. In Ecuador, 87.5% reported consuming beef at least once per week, including 83.9% of those who had α-Gal specific IgE. Levels of α-Gal specific IgG₄ were not high in Ecuador, but were greater than in children from the United States.

These results suggest that in areas of the developing world with endemic parasitism, α-Gal sensitization is (1) common, (2) associated with Ascaris exposure, and (3) distinguished by a low percentage of specific/total IgE compared with individuals with meat allergy in the United States.

Food antigens are clearly implicated in the induction and persistence of eosinophilic oesophagitis. Dietary elimination to identify triggers is tedious and expensive. Alternatives that can mitigate cost and improve patient quality of life during this process are needed.

To test the hypothesis that antibodies against foods that trigger eosinophilic oesophagitis are secreted into the oesophageal lumen where they can be collected by oesophageal brushings.

We evaluated food-specific immune responses within brushings in 68 patients undergoing endoscopy (12 controls, 13 resolved eosinophilic oesophagitis and 43 active eosinophilic oesophagitis). Seventeen participants identified their trigger foods via food elimination diets. Immunoglobulin A and immunoglobulin G4 antibodies against the four most common eosinophilic oesophagitis food triggers were measured using the ImmunoCAP assay in the oesophageal brushings. Food-specific antibody values were compared between active eosinophilic oesophagitis, resolved eosinophilic oesophagitis and controls.

Patients with active eosinophilic oesophagitis (>15 eosinophils/hpf) demonstrated increased immunoglobulin A and immunoglobulin G4 levels to common eosinophilic oesophagitis triggers compared to controls (327 ± 380 vs 150 ± 130 for immunoglobulin A, and 1534 ± 3346 vs 178 ± 123 for immunoglobulin G4, P < 0.003). Specific trigger foods were associated with elevated immunoglobulin A and immunoglobulin G4 responses compared to foods that did not trigger oesophageal eosinophilia (733 ± 469 vs 142 ± 64, P < 0.001 immunoglobulin A and 2620 ± 3228 vs 526 ± 1050, P < 0.001 immunoglobulin G4).

Food-specific antibodies are easily collected along the oesophageal lumen of eosinophilic oesophagitis patients. Further studies are needed to validate our preliminary findings to determine whether these antibodies can be used to guide elimination diet therapy.

The mammalian meat allergy known as the "α-Gal syndrome" relates to IgE specific for galactose-α-1,3-galactose (α-Gal), an oligosaccharide that is present in cells and tissues of nonprimate mammals. The recognition of delayed reactions to food derived from mammals in patients with IgE to α-Gal and also the association with tick bites have been increasing worldwide. In 2018, the National Institute of Allergy and Infectious Diseases, Division of Allergy, Immunology and Transplantation, sponsored a workshop on this emerging tick-related disease. International experts from the fields of tick biology, allergy, immunology, infectious disease, and dermatology discussed the current state of our understanding of this emerging medical condition. The participants provided suggestions for specific research priorities and for the development of resources to advance our knowledge of the mechanisms, diagnosis, management, and prevention of this allergic disease. This publication is a summary of the workshop and the panel's recommendations are presented herein.

Recent advances in rare disease research are accelerated by the work of consortia that have been supported by the National Institutes of Health. Development of such consortia rely on multidisciplinary relationships and engagement with patient advocacy groups, as well as the National Institutes of Health and industry and academic partners. In this rostrum we present the development of such a process that focuses on eosinophilic gastrointestinal diseases. Principal investigators, patient advocacy groups, research assistants, and trainees work together to perform natural history studies that promote clinical trial readiness tools, conduct clinical trials, train a new generation of investigators, and perform innovative pilot studies.

Eosinophilic esophagitis is an immune-allergic pathology of multifactorial etiology (genetic and environmental) that affects both pediatric and adult patients. Its symptoms, which include heartburn, regurgitation, and esophageal stenosis (with dysphagia being more frequent in eosinophilic esophagitis in young adults and children), are similar to those of gastroesophageal reflux disease, causing delays in diagnosis and treatment. Although endoscopic findings such as furrows, esophageal mucosa trachealization, and whitish exudates may suggest its presence, this diagnosis should be confirmed histologically based on the presence of more than 15 eosinophils per high-power field and the exclusion of other causes of eosinophilia (parasitic infections, hypereosinophilic syndrome, inflammatory bowel disease, among others) for which treatment could be initiated. Currently, the 3 "D"s ("Drugs, Diet, and Dilation") are considered the fundamental components of treatment. The first 2 components, which involve the use of proton pump inhibitors, corticosteroids, immunosuppressants and empirical diets or guided food elimination based on allergy tests, are more useful in the initial phases, whereas endoscopic dilation is reserved for esophageal strictures. Herein, the most important aspects of eosinophilic esophagitis pathophysiology will be reviewed, in addition to evidence for the various treatments.