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. 2025 Apr 14;55(10):916–927. doi: 10.1111/cea.70055

Circulating Food Allergen‐Specific Antibodies, Beyond IgG4, Are Elevated in Eosinophilic Esophagitis

Manal Bel Imam 1, Sayuri Iwasaki 1, Sophieke Lems 1, Lacin Cevhertas 1, Patrick Westermann 1, Lotte Bach Larsen 2, Nina Aagaard Poulsen 2, Mübeccel Akdis 1, Philipp Schreiner 3, Andrea Kreienbühl 4, Alex Straumann 4, Alain M Schoepfer 5, Luc Biedermann 4, Willem van de Veen 1,✉; Swiss EoE Cohort Study Group
PMCID: PMC12515539  PMID: 40230181

ABSTRACT

Introduction

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition with an incompletely understood immuno‐pathogenesis involving a T2 response. EoE is triggered by food allergens although, unlike IgE‐mediated allergies, it exhibits high IgG4 levels in oesophageal biopsies and in circulation. We investigated whether other antibody isotypes specific for food allergens are elevated in EoE and vary with disease activity.

Methods

Plasma samples from patients with active EoE (n = 51), inactive EoE (n = 82) and non‐EoE controls (n = 14) were analysed for food‐specific IgG and IgA subclasses against casein, whey, wheat, egg and individual cow's milk allergens by ELISA. α‐lactalbumin (Bos d 4)‐ and β‐lactoglobulin (Bos d 5)‐specific B cells were measured by flow cytometry in a subset of patients.

Results

Food allergen‐specific antibodies in the plasma varied across EoE subgroups and non‐EoE controls. Elevated IgG4 in EoE patients confirmed a strong antibody response to food allergens, including casein, wheat and egg. αS1‐casein (Bos d 9)‐specific IgG, IgG2, IgG4, IgA1 and IgA2 differed between EoE and non‐EoE controls and between active and inactive EoE. β‐casein (Bos d 11, A1 variant) measurements showed higher levels of specific IgG2 and IgG4 in both EoE groups, whereas whey‐derived allergens showed opposing responses: Bos d 4 responses favoured IgG4, and Bos d 5 responses were elevated across multiple IgG and IgA subclasses in EoE. Allergen‐specific B cells could not be isolated from the circulation.

Conclusion

Our findings reveal distinct antibody profiles in EoE plasma, with elevated IgG and IgA subclasses beyond IgG4, highlighting a complex immune response to food allergens. Differential antibody responses support their clinical relevance in dietary management strategies, while the absence of allergen‐specific B cells in circulation likely restricts antibody production to the inflamed oesophagus. Future research should explore whether these antibody profiles can guide personalised treatment and novel therapeutic targets in EoE.

Keywords: allergen‐specific antibodies, eosinophilic esophagitis, humoural response

Elevated IgG and IgA subclasses to food allergens in eosinophilic esophagitis (EoE) highlight a complex immune response involving antibody production, underscoring the significance of dietary triggers like cow's milk in disease management and potential for personalised therapies.

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Summary.

  • EoE patients show elevated food allergen‐specific IgG and IgA subclasses beyond IgG4.

  • Elevated antibody responses target individual cow's milk allergens, particularly casein and whey proteins.

  • Circulating allergen‐specific B cells are absent, suggesting localised antibody production in oesophageal tissue.

1. Introduction

Eosinophilic esophagitis (EoE) is a chronic, immune‐mediated oesophageal disorder characterised by a predominant eosinophilic infiltration of the oesophageal tissue and symptoms of oesophageal dysfunction, leading to significant morbidity in both paediatric and adult populations [1, 2, 3]. Over recent decades, the incidence and prevalence of EoE have increased substantially, now affecting up to 1 in 1000 individuals in western countries [1, 4, 5]. Recent studies report prevalence rates ranging from 34.4 to 113 cases per 100,000 inhabitants, with higher rates observed in adults compared to children [6, 7]. EoE significantly impacts patients' quality of life and often leads to anxiety, dietary restrictions and repeated medical interventions [8, 9].

Leading symptoms in adult patients are dysphagia for solids, food impaction, heartburn and chest pain [10]. The diagnostic histological criterion is the presence of 15 or more eosinophils per high‐power field (eos/hpf) in oesophageal biopsies in conjunction with oesophageal dysfunction [11]. Additionally, endoscopic features such as oesophageal rings, linear furrows, white exudates, oedema and strictures are frequently observed, reflecting ongoing inflammation and tissue remodelling [11, 12]. The immuno‐pathogenesis of EoE is complex and involves a dysregulated immune response predominantly driven by Type 2 (T2) cytokines immune profile, with elevated levels of interleukin (IL)‐4, IL‐5 and IL‐13, which lead to oesophageal tissue damage, remodelling and subsequent symptoms [13, 14].

While the precise aetiology of EoE remains incompletely understood, the efficacy of dietary treatment with protein‐free amino acid formulas implicates food proteins as central triggers of the disease. Furthermore, empiric elimination diets that exclude common allergens such as cow's milk, wheat, eggs and soy have been shown to improve both clinical symptoms and histological findings, underscoring further the role of dietary antigens in EoE pathogenesis [15, 16, 17]. Among these, cow's milk is one of the most common triggers in EoE, with multiple studies demonstrating its high prevalence as a causative antigen in both paediatric and adult populations [18, 19, 20, 21, 22]. Emerging evidence also suggests that specific genetic variants of dietary proteins may influence their immunogenic potential and impact disease symptoms. For instance, genetic variants of β‐casein, a major cow's milk protein, have been ascribed potential health implications, although this remains a subject of ongoing debate [23]. The genetic variant A1 has been linked to adverse effects, including digestive discomfort, which are reportedly absent with the A2 variant [24]. While such associations have primarily been explored in the context of general digestive health, their relevance to EoE remains unexplored but merits consideration given the central role of milk proteins in EoE dietary triggers.

Despite its similarities with classic food allergies, EoE does not follow the typical immunoglobulin E (IgE)‐mediated type I hypersensitivity reaction. Clinical trials using anti‐IgE therapies, such as omalizumab, have not demonstrated significant improvements in EoE symptoms, suggesting that IgE is not a primary driver of the disease [25, 26]. Moreover, unlike food allergies, where symptoms occur immediately after food intake, EoE symptoms typically develop over time and do not involve anaphylactic responses. Managing EoE presents significant clinical challenges due to the need for ongoing dietary management, repeated endoscopies to monitor disease activity, and the limited efficacy of current pharmacologic treatments, which include proton pump inhibitors (PPIs) and topical corticosteroids [27, 28]. These challenges underscore the need for non‐invasive diagnostic tools and a deeper understanding of the disease's underlying immune mechanisms. Identifying reliable biomarkers could facilitate earlier diagnosis, improved disease monitoring and the development of targeted therapies. Emerging therapies for EoE, particularly cytokine‐targeting agents such as interleukin inhibitors, have shown promising results. Dupilumab, an IL‐4/IL‐13 blocking antibody, is now approved for EoE, effectively reducing inflammation, improving symptoms and enhancing histologic outcomes [29, 30, 31, 32]. This marks a significant advancement towards targeted treatments that address the underlying immune mechanisms in EoE, offering new options for patients unresponsive to conventional therapies.

To further refine diagnostic and therapeutic approaches, it is essential to investigate the immune mechanisms underlying EoE, including the role of the humoral immune response. Serological studies have primarily focused on measuring total and food allergen‐specific IgE and IgG4 levels in EoE patients [33, 34, 35, 36]. Systemic and local specific IgE antibodies are not typically elevated in EoE patients [37, 38]. In contrast, IgG4 levels are significantly increased in EoE, suggesting a potential role for IgG4‐mediated immune responses in the disease [34, 35, 39]. In the context of allergic disease, IgG4 is typically associated with regulatory immune responses and immune tolerance rather than promoting inflammation [40, 41]. However, the exact role of IgG4 in EoE remains unclear, as its elevation may reflect immune dysregulation rather than a protective or tolerogenic function. Whether EoE pathogenesis involves a broader array of antibody isotypes remains unanswered, underscoring the need for further investigation into their potential roles.

While serological studies have shown potential involvement of the humoral immune response in EoE, only a limited number of studies have examined the contribution that B cells have in this context. These studies revealed the presence of activated B cells in the mucosa of EoE patients following allergen exposure [42, 43]. The exact role of these cells has yet to be determined.

This study seeks to clarify whether specific antibody isotypes against a range of selected common food allergens, including subclasses beyond IgG4, are elevated in patients with EoE and explore whether these elevations vary based on disease activity (active vs. inactive EoE). We hypothesise that specific antibody isotypes beyond IgG4, such as IgG1‐3 and IgA, are not only elevated in EoE but also vary significantly between active and inactive EoE patients, reflecting distinct immune profiles within the disease spectrum.

2. Materials and Methods

Heparinized blood samples from adult EoE patients (n = 133) and non‐EoE controls (n = 14) were used in this study. EoE patients were recruited at the EoE Clinics of the University Hospital Zurich (USZ) with informed consent obtained from all participants and were part of the Swiss EoE Cohort Study (SEECS), a multicentric prospective database study (BASEC Number PB_2016‐01962) that has been actively recruiting patients in Switzerland since 2016 [44]. The study was approved by the local ethics committee (EKNZ 2015‐388). Demographical characteristics of the study cohort are shown in (Table 1).

TABLE 1.

Demographical characteristics of the study cohort.

Groups Peak inflammation (eos/hpf) N Age (years) Sex Allergy
Mean ± SD Range M F Allergic Aeroallergen Food allergen Other
Active EoE ≥ 15 51 40.0 ± 12.4 20–73 41 10 41 37 16 1
Inactive EoE < 15 82 46.4 ± 12.3 25–80 59 23 67 63 23 4
Non‐EoE controls NA 14 38.9 ± 16.9 25–73 11 3 NA NA NA NA
Total 147 111 36 108 100 39 5
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Abbreviations: eos/hpf, eosinophils per high power field; F, female; M, male; N, number of samples; SD, standard deviation.

Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and stored at −80° until further processing. Casein, whey, wheat and egg powder preparations were used to extract whole allergens and individual cow's milk allergens (αS1‐casein/Bos d 9, α‐lactalbumin/Bos d 4 and β‐lactoglobulin/Bos d 5, β‐casein variants/Bos d 11) were provided in purified form by collaborators. Table 2 oulines the food allergens confirmed to be present in casein, whey, wheat and egg powders by SDS‐PAGE. Antibodies against these allergen extracts and purified proteins were measured in plasma using indirect enzyme‐linked immunosorbent assay (ELISA) (IgG and IgA subclasses) and ImmunoCAP (IgE). In a subset of subjects with high antibody levels, the presence of allergen‐specific B cells was assessed by flow cytometry. Class‐switched B cells were isolated from PBMCs, immortalised and expanded under optimal conditions. Immortalised B cells were stained with biotinylated Bos d 4, Bos d 5 and Bos d 11, sorted and then cultured and analysed for IgG specificity using ELISA.

TABLE 2.

Major individual food allergens confirmed to be present in casein, whey, wheat and egg powders by SDS‐PAGE.

Allergen Presence of major allergens confirmed with SDS‐PAGE
Origin Protein powder
Cow's milk Casein Bos d 8, Bos d 9, Bos d 10, Bos d 11
Whey Bos d 4, Bos d 5, Bos d 6
Wheat Wheat Tri a 12, Tri a 17, Tri a 28, Tri a 37
Egg Egg Gal d 2, Gal d 3, Gal d 4, Gal d 5
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A detailed description of the methods can be found in the Supporting Information.

3. Results

3.1. Food‐Specific Antibodies Are Elevated in EoE Patients Compared to Controls and Correlate With Each Other

To evaluate allergen‐specific antibody responses, total IgG and specific IgG4 against casein, whey, wheat and egg extracts were measured in plasma from 147 participants across three groups: active EoE (n = 51), inactive EoE (n = 82) and non‐EoE controls (n = 14) (Figure 1).

FIGURE 1.

FIGURE 1

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Food extract‐specific IgG and IgG4. (A) Specific IgG and IgG4 levels against casein, whey, wheat and egg extracts in EoE patients and healthy controls. Statistical significance was calculated using the Kruskal‐Wallis test and the Dunn's multiple comparisons test. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, and ****p ≤ 0.0001. (B) Correlation between the food‐extract specific IgG and IgG4 measurements. Both point colour and size represent correlation strength: Red indicates stronger negative correlations, whereas blue indicates stronger positive correlations, with larger points corresponding to stronger correlations. The numerical value inside each point represents the p value. S, specific.

Significant differences were observed in casein‐specific IgG levels, with both EoE groups showing higher levels compared to controls, whereas casein‐specific IgG4 levels did not vary significantly between groups. Wheat and egg‐specific IgG and IgG4 also differed significantly across groups: IgG levels were significantly elevated in both EoE subgroups compared to controls, and IgG4 levels were higher in active EoE compared to controls. Egg‐specific IgG4 measurements further revealed a significant difference between active and inactive EoE, whereas whey‐specific IgG and IgG4 did not differ significantly among the groups.

Correlation analysis revealed relationships among antibody levels. Specifically, whey‐ and wheat‐specific IgG levels showed a non‐significant negative correlation with casein‐specific IgG, and egg‐specific IgG demonstrated a significant negative correlation with casein‐specific IgG (r = −0.22, p = 0.04). IgG4 levels followed a similar trend, although correlations were not statistically significant.

Given the recognition of cow's milk as the most common trigger for EoE and the significant differences in antibody levels in our casein measurements, we additionally measured Bos d 8‐specific IgE in a subset of participants—71 EoE patients (35 active EoE, 36 inactive EoE) and 15 non‐EoE controls. Due to the limited sensitivity of ELISA for detecting specific IgE levels in plasma, we employed IgE ImmunoCAP; however, only 3 EoE patient samples tested positive for Bos d 8‐specific IgE (Table S5) with levels ≥ 0.10 kilounits/liter (kU/L).

To further investigate the role of cow's milk allergens, we decided to focus specifically on antibody subclasses reactive to the cow's milk casein and whey allergens (Figure 2). The casein allergen Bos d 9 exhibited broadly elevated antibody levels in EoE patients. Particularly, specific IgG, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 levels were significantly higher in the active EoE subgroup compared to controls. In the inactive EoE subgroup, all specific antibodies except IgG1 and IgG3 were also elevated relative to controls.

FIGURE 2.

FIGURE 2

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Individual casein‐derived allergen‐specific antibodies in EoE patients and non‐EoE controls. (A) Bos d 9 total specific IgG, specific IgG1‐4 and specific IgA1‐2. (B) Bos d 11/A1 β‐casein variant‐specific IgG, specific IgG1‐4 and specific IgA1 levels. (C, D) Total specific IgG and specific IgG4 were measured against Bos d 11/A2 and I β‐casein variants. Statistical significance was calculated using the Kruskal–Wallis test and the Dunn's multiple comparisons test. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 and ****p ≤ 0.0001. S, specific.

The response to Bos d 11 (A1 genetic variant) showed a slightly different pattern: IgG2, IgG4 and IgA1 levels were elevated in both active and inactive EoE subgroups, whereas total IgG was increased only in active EoE. Other β‐caseins, for which only total specific IgG and specific IgG4 were measured given their molecular similarity, followed a similar pattern to the A1 variant.

Among the whey‐derived allergens, Bos d 4 induced an IgG4‐skewed response in active EoE, while Bos d 5 showed significant differences in most antibody isotypes between EoE patients and controls, except for IgG3 and IgA2 (Figure 3).

FIGURE 3.

FIGURE 3

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Individual whey‐derived allergen‐specific antibodies in EoE patients and non‐EoE controls. (A) Bos d 4 and (B) Bos d 5 total specific IgG, specific IgG1‐4 and specific IgA1‐2. Statistical significance was calculated using the Kruskal–Wallis test and the Dunn's multiple comparisons test. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 and ****p ≤ 0.0001. S, specific. [Correction added on 19 September 2025, after first online publication: The Figure 3 caption has been corrected.]

3.2. Specific Antibody Levels Varied Across Different Cow's Milk Allergens

Antibodies against casein and whey‐derived allergens were assessed to determine differential antibody responses among the groups. To further explore whether antibody responses to different cow's milk proteins were correlated, we compared the individual measurements in each study subject. Comparisons of IgG and IgA subclass levels against individual cow's milk allergens did not show clear clustering by disease group (Figure 4). The data reveal substantial individual variation in antibody responses across the allergens, without distinct clustering by disease group. Both active and inactive EoE subgroups show increased antibody levels for certain allergens compared to controls, although this increase does not yield a clear separation among the groups.

FIGURE 4.

FIGURE 4

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Heatmaps of individual cow's milk protein‐specific antibodies of (A) the IgG subclasses and (B) of the IgA subclasses. [Correction added on 19 September 2025, after first online publication: The Figure 4 legend has been corrected.]

3.3. Food Allergen‐Specific B Cells Are Not Found in the Circulation of EoE Patients

To investigate whether allergen‐specific memory B cells were present in circulation, we attempted to isolate Bos d 4‐, Bos d 5‐, Bos d 9‐ and Bos d 11‐specific B cells from 9 individuals (6 EoE patients, 3 non‐EoE controls) that showed high levels of total specific IgG and specific IgG4 to these allergens in our serological ELISA measurements. Cells double positive for Allergen‐PE and Allergen‐AF647, supposedly allergen‐specific B cells, were successfully isolated from all samples stained with Bos d 4 and Bos d 5 (Figures 5 and 6, Table S6), but not for other allergens (data not shown). These cells were expanded and sorted again with the same method. However, we could not detect any allergen‐positive cells after expansion. This may indicate that allergen‐specific B cells are predominantly localised in oesophageal tissue rather than in circulation.

FIGURE 5.

FIGURE 5

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Method used to isolate and expand allergen‐specific B cells. Class‐switched B cells (CD19+IgD−IgM−) were isolated and immortalised as described by Kwakkenbos et al. Cells were expanded in IMDM and stimulated with IL‐21 and CD40L‐L cells at 37°C and 5% CO2. Allergen‐specific B cells were isolated after being stained with allergen‐PE and allergen‐AF647 and expanded again. Specificity was confirmed by flow cytometry and ELISA on the supernatant of cell cultures.

FIGURE 6.

FIGURE 6

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Isolation of Bos d 4‐ and Bos d 5‐specific B cells. (A) Flow cytometry gating strategy for live B cells. (B) Representative flow cytometry plots showing the isolation of Bos d 4 and Bos d 5‐specific B cells before and after expansion. Staining with Strep‐AF647 and Strep‐PE was used as a negative control.

To assess the specificity of allergen‐specific B cells isolated in the first stage, we performed ELISA on the supernatant of cultures where at least 200,000 cells were present. Total IgG was present in the supernatant of each B cell clone, but no specific IgG could be detected.

4. Discussion

Our study offers new insights into the immunological profile of EoE, with a focus on food allergen‐specific antibodies targeting major cow's milk proteins. To our knowledge, this is the first systematic evaluation of a broad range of antibody isotypes and subclasses against foods and individual cow's milk proteins in the plasma of EoE patients. Notably, we found elevated levels not only of IgG4 but also of other IgG subclasses (IgG1, IgG2 and IgG3) and IgA subclasses (IgA1 and IgA2). This discovery simultaneously supports and challenges previous research, which has primarily centred on increased circulating IgG4 in adult and paediatric EoE patients [34, 35, 36, 39]. Specifically, EoE patients exhibited a broader humoral immune response to food allergens, including individual cow's milk allergens. Not only did the EoE patients differ from non‐EoE controls, but EoE subgroups also displayed significantly distinct responses in egg‐specific IgG4 levels, underscoring the need to expand antibody assessments beyond cow's milk allergens. Our findings suggest that additional antibody isotypes may play a role in the mechanisms underlying EoE, indicating that EoE pathogenesis might be more complex than previously thought.

The fact that we observed elevated IgG and IgA levels, in addition to IgG4, raises the possibility of immune dysregulation rather than a simple tolerogenic or protective function typically associated with IgG4. It was proposed that IgG4 could be a biomarker for EoE due to its tolerogenic role [34, 35], yet the elevation of IgG4 does not fit the typical immune tolerance model seen in other allergic conditions [39]. Our findings challenge this perspective by showing that IgG4 elevation in EoE might not exclusively indicate tolerance. Instead, the increase across multiple antibody subclasses could point to a broader dysregulation in humoral responses, suggesting that the immune system in EoE patients is responding to food antigens in a complex and potentially non‐tolerogenic manner.

EoE complexity is further highlighted by the ineffectiveness of allergy test‐driven diets in treating EoE, likely because sensitisation does not always result in symptoms or pathological outcomes. Since IgE does not appear to play a role in the onset of EoE symptoms, it is not surprising that IgE testing fails to benefit patients as it does not lead to symptomatic improvement, nor does it reduce eosinophil counts [26, 45, 46]. Additionally, anti‐IgE treatments such as omalizumab have shown limited efficacy in treating EoE symptoms [25, 26]. However, some food allergens, particularly cow's milk, have been identified as triggers in EoE following a diet. Specifically, elimination diets, which involve removing potential food triggers and reintroducing them individually, can help identify the culprit allergen by measuring peak eosinophil counts in oesophageal tissue after each reintroduction [18, 47, 48, 49]. Studies in children have shown that cow's milk elimination leads to remission, with 50%–65% of patients achieving histologic remission [16, 18, 19, 50, 51]. Our results showed that egg extract also stimulated an IgG4‐mediated immune response, suggesting that egg might be a more significant trigger in EoE than assumed, aligning with a recent study proposing that a history of egg allergy increases the risk of EoE [52]. While EoE is not a classical food allergy and patients do not typically experience anaphylaxis, its link to food allergy is strong.

Further supporting the complex relationship between food allergens and EoE, a food‐induced response (FIRE) syndrome was recently described in both paediatric and adult EoE patients [53, 54, 55]. FIRE is a newly identified syndrome that involves an immediate discomfort after the ingestion of specific foods. Although this discovery reduces the distance between EoE and food allergies, it is not clear whether this is a characteristic of EoE or rather a consequence of a more complex interrelation of EoE and concomitant conditions. Further investigations should be performed to understand the mechanisms underlying this syndrome. Additionally, it would be valuable to perform serological studies on these EoE patients and elucidate if they display a different humoral profile.

Despite our study demonstrating the presence of food allergen‐specific antibodies in the circulation of EoE patients, we could not isolate any allergen‐specific B cells. The methodology used was well established and gave positive results in previous investigations, mainly performed in allergic individuals [40, 56]. Our hypothesis is that allergen‐specific antibodies found in the circulation are produced locally in the oesophagus of EoE patients, and this would align with previous findings that reported the presence of B lymphocytes and plasma cells in the EoE tissue [42, 43, 57]. Although the role of lymphocytes has often been overshadowed by eosinophils in relation to EoE, recent investigations have identified EoE‐like diseases, including a form known as lymphocytic esophagitis [58]. Lymphocytic esophagitis is characterised by lymphocytic infiltration of the oesophagus in the absence of eosinophils and is now considered a spectrum of the more common classical EoE. It is therefore likely that B cells play a role in the disease, although it is not clear whether as bystanders or by actively contributing to the pathogenesis.

Our study has some limitations. First, while we included a substantial number of EoE patients, our control group was relatively small, and this imbalance in sample sizes may limit the statistical power. Moreover, these findings cannot be generalised to paediatric patients, as only adults are included in the study. While we aimed to gain insights into the humoural immune response independent of the patient characteristics, the use of certain treatments as well as the lack of comprehensive allergy testing data for each patient represent a limitation. Further studies should investigate whether specific food triggers correlate with distinct antibody profiles. Likewise, according to our rather cross‐sectional design lacking longitudinal sampling points over time, we cannot exclude that, in a given patient, the plasma antibody profile might substantially vary over time even under a stable therapeutic regimen and/or disease activity.

In conclusion, our findings reveal a broad food‐elicited humoral immune response in EoE, which challenges the prevailing focus on IgG4 as a solitary marker of disease. By highlighting the presence of multiple antibody isotypes against cow's milk allergens and suggesting local antibody production, our study lays the groundwork for future investigations into the immunopathogenesis of EoE.

Author Contributions

M.B. performed the experiments, analysed the data and wrote the manuscript. S.I. and S.L. performed experiments and analysed data. L.C., P.W., L.B.L. and N.A.P. performed experiments. M.A. supervised the study. P.S., A.K., A.S., A.M.S. and L.B. were involved in patient recruitment. A.M.S. provided logistic support and funding. W.V. conceptualised and supervised the study, acquired funding and edited the manuscript. All authors have been involved in revising the manuscript and have given final approval of the version to be published.

Conflicts of Interest

M.A. has received research grants from the Swiss National Science Foundation (310,030_201,053/1), European Union (EU CURE, EU Syn‐Air‐G), is the Co‐Chair for EAACI Scientific Program, is on the Advisory Boards of Stanford University Sean Parker Asthma Allergy Center (CA, USA), LEO Foundation Skin Immunology Research Center Copenhagen, Denmark. P.S. received fees for consulting and grants from Falk Pharma, Takeda, Sanofi, AbbVie, Janssen‐Cilag, Ferring, Pfizer, Galapagos and Lilly. A.S. has consultant contracts with Astra Zeneca, BMS‐Receptos, Calypso, EsoCap, Falk Pharma, GSK, Pfizer, Sanofi‐Regeneron and Shire. A.M.S. has received speaker fees from Abbvie, BMS, Dr. Falk Pharma, GSK, Pfizer, Sanofi‐Regeneron, none of which are relevant for this work. L.B. declares fees for advisory from AbbVie, Amgen, BMS, Falk, Janssen, Pfizer, Lilly, Takeda, Sanofi, Esocap and speaker fees for Takeda, Sanofi, Abbvie, Lilly, Falk, BMS, Pfizer none of which are relevant for this work. W.V. has consultant contracts with Mabylon A.G. and received research grants from the Promedica Stiftung, the Swiss EoE Foundation and Novartis Research Foundation.

Supporting information

Table S1. Assay conditions used for the detection of specific IgG, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 by ELISA.

Table S2. Overview of ELISA conditions measuring specific IgG, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 against casein, whey, wheat and egg extracts and individual cow’s milk allergens (Bos d 9, Bos d 11, Bos d 4, Bos d 5).

Table S3. Flow cytometry‐staining panel used for the isolation of B cells from immortalised pools.

Table S4. Flow cytometry‐staining panel used for the isolation of allergen‐specific B cells.

Table S5. Bos d 8‐specific IgE levels in EoE patients measured by ImmunoCAP.

Table S6. Number and percentage of isolated food allergen‐specific B cells per sample.

Figure S1. SDS‐PAGE under reducing (R) and non‐reducing (NR) conditions of wheat, whey, casein and egg extracts. The bands were compared to the molecular weight of major individual allergens in each extract to confirm their presence.

CEA-55-916-s001.docx (657.7KB, docx)

Acknowledgements

Corporate Authorship of the Swiss EoE Cohort Study Group (SEECS): Patrick Aepli, Luc Biedermann, Ruggero Biral, Carine Blanchard, Lorenzo Botteselle, Simon Buetikofer, Emanuel Burri, Joachim Diebold, Annika Eckhold, Annett Franke, Michèle Frei, Thomas Greuter, Chantal Hasler, Wolfram Jochum, Tanja Kilchmann, Seraina Koller, Andrea Kreienbühl, Fritz Murray, Peter Netzer, Gabrielle Reichhart, Elodie Ristorcelli, Gerhard Rogler, Jean‐Benoit Rossel, Ekaterina Safroneeva, Catherine Saner, Christoph Schlag, Jon‐Duri Senn, Alain M. Schoepfer, Philipp Schreiner, Christine Sempoux, Dagmar Simon, Hans‐Uwe Simon, Alex Straumann, Sven Trelle, Achim Weber, Niels Willi and Marcel Zwahlen. We thank Dr. Els Van Hoffen of NIZO Food Research for providing the purified αS1‐casein. Patrick Aepli, Ruggero Biral, Carine Blanchard, Lorenzo Botteselle, Simon Buetikofer, Emanuel Burri, Joachim Diebold, Annika Eckhold, Annett Franke, Michèle Frei, Thomas Greuter, Chantal Hasler, Wolfram Jochum, Tanja Kilchmann, Seraina Koller, Fritz Murray, Peter Netzer, Gabrielle Reichhart, Elodie Ristorcelli, Gerhard Rogler, Jean‐Benoit Rossel, Ekaterina Safroneeva, Catherine Saner, Christoph Schlag, Jon‐Duri Senn, Christine Sempoux, Dagmar Simon, Hans‐Uwe Simon, Sven Trelle, Achim Weber, Niels Willi, Marcel Zwahlen. Open access publishing facilitated by Universitat Zurich, as part of the Wiley ‐ Universitat Zurich agreement via the Consortium Of Swiss Academic Libraries. [Correction added on 17 June 2025, after first online publication: CSAL 2025 funding statement has been added.]

Funding: This study was supported by the Promedica Stiftung (Switzerland) (grant no. 1515/M to W. van de Veen), the Swiss National Science Foundation (grant no. 32003B_204751/1 to A. M. Schoepfer) and the EoE Foundation (Switzerland) (to W. van de Veen).

See Acknowledgments section for all members of Swiss EoE Cohort Study Group.

Contributor Information

Willem van de Veen, Email: willem.vandeveen@siaf.uzh.ch.

Swiss EoE Cohort Study Group:

Patrick Aepli, Ruggero Biral, Carine Blanchard, Lorenzo Botteselle, Simon Buetikofer, Emanuel Burri, Joachim Diebold, Annika Eckhold, Annett Franke, Michèle Frei, Thomas Greuter, Chantal Hasler, Wolfram Jochum, Tanja Kilchmann, Seraina Koller, Fritz Murray, Peter Netzer, Gabrielle Reichhart, Elodie Ristorcelli, Gerhard Rogler, Jean‐Benoit Rossel, Ekaterina Safroneeva, Catherine Saner, Christoph Schlag, Jon‐Duri Senn, Christine Sempoux, Dagmar Simon, Hans‐Uwe Simon, Sven Trelle, Achim Weber, Niels Willi, and Marcel Zwahlen

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1. Assay conditions used for the detection of specific IgG, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 by ELISA.

Table S2. Overview of ELISA conditions measuring specific IgG, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 against casein, whey, wheat and egg extracts and individual cow’s milk allergens (Bos d 9, Bos d 11, Bos d 4, Bos d 5).

Table S3. Flow cytometry‐staining panel used for the isolation of B cells from immortalised pools.

Table S4. Flow cytometry‐staining panel used for the isolation of allergen‐specific B cells.

Table S5. Bos d 8‐specific IgE levels in EoE patients measured by ImmunoCAP.

Table S6. Number and percentage of isolated food allergen‐specific B cells per sample.

Figure S1. SDS‐PAGE under reducing (R) and non‐reducing (NR) conditions of wheat, whey, casein and egg extracts. The bands were compared to the molecular weight of major individual allergens in each extract to confirm their presence.

CEA-55-916-s001.docx (657.7KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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