Skip to main content

Advertisement

SpringerLink
Log in

Food-Specific IgG4 Is Elevated Throughout the Upper Gastrointestinal Tract in Eosinophilic Esophagitis

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Food-specific immunoglobulin G4 (FS-IgG4) is associated with eosinophilic esophagitis (EoE); however, it is not clear whether production is limited to the esophagus.

Aims

To assess FS-IgG4 levels in the upper gastrointestinal tract and plasma and compare these with endoscopic disease severity, tissue eosinophil counts, and patient-reported symptoms.

Methods

We examined prospectively banked plasma, throat swabs, and upper gastrointestinal biopsies (esophagus, gastric antrum, and duodenum) from control (n = 15), active EoE (n = 24), and inactive EoE (n = 8) subjects undergoing upper endoscopy. Patient-reported symptoms were assessed using the EoE symptom activity index (EEsAI). Endoscopic findings were evaluated using the EoE endoscopic reference score (EREFS). Peak eosinophils per high-power field (eos/hpf) were assessed from esophageal biopsies. Biopsy homogenates and throat swabs were normalized for protein content and assessed for FS-IgG4 to milk, wheat, and egg.

Results

Median FS-IgG4 for milk and wheat was significantly increased in the plasma, throat swabs, esophagus, stomach, and duodenum of active EoE subjects compared to controls. No significant differences for milk- or wheat-IgG4 were observed between active and inactive EoE subjects. Among the gastrointestinal sites sampled, FS-IgG4 levels were highest in the esophagus. Esophageal FS-IgG4 for all foods correlated significantly across all sites sampled (r ≥ 0.59, p < 0.05). Among subjects with EoE, esophageal FS-IgG4 correlated significantly with peak eos/hpf (milk and wheat) and total EREFS (milk). EEsAI scores and esophageal FS-IgG4 levels did not correlate.

Conclusions

Milk and wheat FS-IgG4 levels are elevated in plasma and throughout the upper gastrointestinal tract in EoE subjects and correlate with endoscopic findings and esophageal eosinophilia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AMS:

Avoidance, modification, and slow eating

BCA:

Bicinchoninic acid assay

CI:

Confidence interval

CTAB:

Cetrimonium bromide

EEsAI:

Eosinophilic esophagitis symptom activity index

EGID:

Eosinophilic gastrointestinal disease

EoD:

Eosinophilic duodenitis

EoE:

Eosinophilic esophagitis

EoG:

Eosinophilic gastritis

eos/hpf:

Eosinophils per high-power field

EREFS:

Endoscopic reference score

FS-IgG4:

Food-specific immunoglobulin G4

GERD:

Gastroesophageal reflux disease

GI:

Gastrointestinal

H&E:

Hematoxylin and eosin

IBS:

Irritable bowel syndrome

PPI:

Proton pump inhibitor

Q1:

Quartile 1

Q3:

Quartile 3

VDQ:

Visual dysphagia question

yrs:

Years

References

  1. Muir A, Falk GW. Eosinophilic Esophagitis: A Review. JAMA. 2021;326(13):1310–1318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. O’Shea KM, Aceves SS, Dellon ES et al. Pathophysiology of Eosinophilic Esophagitis. Gastroenterology. 2018;154(2):333–345.

    Article  CAS  PubMed  Google Scholar 

  3. Arias A, Gonzalez-Cervera J, Tenias JM, Lucendo AJ. Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis. Gastroenterology. 2014;146(7):1639–1648.

    Article  PubMed  Google Scholar 

  4. Clayton F, Fang JC, Gleich GJ et al. Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology. 2014;147(3):602–609.

    Article  CAS  PubMed  Google Scholar 

  5. Loizou D, Enav B, Komlodi-Pasztor E et al. A pilot study of omalizumab in eosinophilic esophagitis. PLoS One. 2015;10(3):e0113483.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Simon D, Cianferoni A, Spergel JM et al. Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity. Allergy. 2016;71(5):611–620.

    Article  CAS  PubMed  Google Scholar 

  7. Wright BL, Kulis M, Guo R et al. Food-specific IgG(4) is associated with eosinophilic esophagitis. J Allergy Clin Immunol. 2016;138(4):1190–1192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dellon ES, Guo R, McGee SJ et al. A Novel Allergen-Specific Immune Signature-Directed Approach to Dietary Elimination in Eosinophilic Esophagitis. Clin Transl Gastroenterol. 2019;10(12):e00099.

    Article  PubMed  PubMed Central  Google Scholar 

  9. McGowan EC, Medernach J, Keshavarz B, et al. Food antigen consumption and disease activity affect food-specific IgG4 levels in patients with eosinophilic esophagitis (EoE). Clin Exp Allergy. 2022.

  10. Schuyler AJ, Wilson JM, Tripathi A et al. Specific IgG(4) antibodies to cow’s milk proteins in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol. 2018;142(1):139–148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dilollo J, Rodriguez-Lopez EM, Wilkey L, Martin EK, Spergel JM, Hill DA. Peripheral markers of allergen-specific immune activation predict clinical allergy in eosinophilic esophagitis. Allergy. 2021;76(11):3470–3478.

    Article  CAS  PubMed  Google Scholar 

  12. Tordesillas L, Berin MC. Mechanisms of Oral Tolerance. Clin Rev Allergy Immunol. 2018;55(2):107–117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pyne AL, Hazel MW, Uchida AM et al. Oesophageal secretions reveal local food-specific antibody responses in eosinophilic oesophagitis. Aliment Pharmacol Ther. 2022;56(9):1328–1336.

    Article  CAS  PubMed  Google Scholar 

  14. Rosenberg CE, Mingler MK, Caldwell JM et al. Esophageal IgG4 levels correlate with histopathologic and transcriptomic features in eosinophilic esophagitis. Allergy. 2018;73(9):1892–1901.

    Article  CAS  PubMed  Google Scholar 

  15. Pope AE, Stanzione N, Naini BV et al. Esophageal IgG4: Clinical, Endoscopic, and Histologic Correlations in Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr. 2019;68(5):689–694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zukerberg L, Mahadevan K, Selig M, Deshpande V. Oesophageal intrasquamous IgG4 deposits: an adjunctive marker to distinguish eosinophilic oesophagitis from reflux oesophagitis. Histopathology. 2016;68(7):968–976.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Peterson K, Lin E, Saffari H et al. Food-specific antibodies in oesophageal secretions: association with trigger foods in eosinophilic oesophagitis. Aliment Pharmacol Ther. 2020;52(6):997–1007.

    CAS  PubMed  Google Scholar 

  18. Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. Gut. 2013;62(4):489–495.

    Article  PubMed  Google Scholar 

  19. Dellon ES, Liacouras CA, Molina-Infante J et al. Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference. Gastroenterology. 2018;155(4):1022–1033.

    Article  PubMed  Google Scholar 

  20. Schoepfer AM, Straumann A, Panczak R et al. Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis. Gastroenterology. 2014;147(6):1255–1266.

    Article  PubMed  Google Scholar 

  21. Safroneeva E, Pan Z, King E et al. Long-Lasting Dissociation of Esophageal Eosinophilia and Symptoms After Dilation in Adults With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2022;20(4):766–775.

    Article  CAS  PubMed  Google Scholar 

  22. Liacouras CA, Furuta GT, Hirano I et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128(1):3–20.

    Article  PubMed  Google Scholar 

  23. Zhan T, Ali A, Choi JG et al. Model to Determine the Optimal Dietary Elimination Strategy for Treatment of Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2018;16(11):1730–1737.

    Article  PubMed  Google Scholar 

  24. Hiramoto B, Zalewski A, Gregory D et al. Low Prevalence of Extraesophageal Gastrointestinal Pathology in Patients with Eosinophilic Esophagitis. Dig Dis Sci. 2022;67(7):3080–3088.

    Article  PubMed  Google Scholar 

  25. Quinn L, Nguyen B, Menard-Katcher C, Spencer L. IgG4+ cells are increased in the gastrointestinal tissue of pediatric patients with active eosinophilic gastritis and duodenitis and decrease in remission. Dig Liver Dis. 2023;55(1):53–60.

    Article  CAS  PubMed  Google Scholar 

  26. Kosaka S, Tanaka F, Nakata A et al. Gastrointestinal IgG4 Deposition Is a New Histopathological Feature of Eosinophilic Gastroenteritis. Dig Dis Sci. 2022;67(8):3639–3648.

    Article  CAS  PubMed  Google Scholar 

  27. Letner D, Farris A, Khalili H, Garber J. Pollen-food allergy syndrome is a common allergic comorbidity in adults with eosinophilic esophagitis. Dis Esophagus. 2018;31(2):15.

    Article  Google Scholar 

  28. Mahdavinia M, Bishehsari F, Hayat W, Elhassan A, Tobin MC, Ditto AM. Association of eosinophilic esophagitis and food pollen allergy syndrome. Ann Allergy Asthma Immunol. 2017;118(1):116–117.

    Article  PubMed  Google Scholar 

  29. Schroeder S, Ochkur SI, Shim KP et al. Throat-derived eosinophil peroxidase is not a reliable biomarker of pediatric eosinophilic esophagitis. J Allergy Clin Immunol Pract. 2017;5(6):1804–1805.

    Article  PubMed  Google Scholar 

  30. Saffari H, Baer K, Boynton KK, Gleich GJ, Peterson KA. Pharyngeal mucosa brushing does not correlate with disease activity in patients with eosinophilic esophagitis. J Allergy Clin Immunol Pract. 2017;5(5):1455–1456.

    Article  PubMed  Google Scholar 

  31. Smeekens JM, Baloh C, Lim N et al. Peanut-Specific IgG4 and IgA in Saliva Are Modulated by Peanut Oral Immunotherapy. J Allergy Clin Immunol Pract. 2022;10(12):3270–3275.

    Article  CAS  PubMed  Google Scholar 

  32. Wright BL, Fernandez-Becker NQ, Kambham N et al. Gastrointestinal Eosinophil Responses in a Longitudinal, Randomized Trial of Peanut Oral Immunotherapy. Clin Gastroenterol Hepatol. 2021;19(6):1151–1159.

    Article  CAS  PubMed  Google Scholar 

  33. Ravi A, Marietta EV, Alexander JA et al. Mucosal penetration and clearance of gluten and milk antigens in eosinophilic oesophagitis. Aliment Pharmacol Ther. 2021;53(3):410–417.

    CAS  PubMed  Google Scholar 

  34. Ohsaki A, Venturelli N, Buccigrosso TM et al. Maternal IgG immune complexes induce food allergen-specific tolerance in offspring. J Exp Med. 2018;215(1):91–113.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to thank the patients at Mayo Clinic Arizona who participated in this study. We appreciate the assistance of Sara Farmer in the Mayo Clinic Survey Research Center for her assistance with the electronic questionnaires and database. We would also like to thank the members of the esophageal disease group (Marcelo Vela, MD, Francisco Ramirez, MD, and David Fleischer, MD), the allied health staff in the endoscopy suite, and the pathology research core and biorepository staff who assisted with specimen collection, storage and requisition. We acknowledge the support of clinical research coordinators Shannan Avelar and Rachel Kendrick. We thank Ekaterina Safroneeva, PhD for allowing us to use the EEsAI PRO and Evan Dellon, MD, MPH for his aid in interpreting the EEsAI scores.

Funding

This work was supported by the Arizona Biomedical Research Consortium (ADHS18-198880), Donald R. Levin Family Foundation, Mayo Clinic Foundation, and Phoenix Children's Hospital Foundation. M.Y.M. is a member of the Immunology Graduate Program and is supported by the Mayo Clinic Graduate School of Biomedical Sciences. B.L.W. also reports funding from NIH (L30 AI147030) and the Consortium of Eosinophilic Gastrointestinal Disease Researchers U54AI117804 (CEGIR), which is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR). CEGIR is also supported by patient advocacy groups, including American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Diseases (CURED), and Eosinophilic Family Coalition (EFC). As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (DMCC) (U2CTR002818).

Author information

Authors and Affiliations

  1. Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA

    Mia Y. Masuda, William E. LeSuer, Arina Putikova, Jessica B. Gibson, Grace C. Pyon, Temeka D. Simmons, Alfred D. Doyle & Benjamin L. Wright

  2. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Mia Y. Masuda

  3. Mayo Clinic Arizona, Scottsdale, AZ, USA

    Mia Y. Masuda

  4. Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA

    Jennifer L. Horsley-Silva

  5. Division of Biomedical Statistics and Biomedical Informatics, Department of Health Sciences Research, Mayo Clinic Arizona, Scottsdale, AZ, USA

    Matthew R. Buras

  6. Section of Allergy and Immunology, Division of Pulmonology, Phoenix Children’s Hospital, Phoenix, AZ, USA

    Benjamin L. Wright

Authors
  1. Mia Y. Masuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William E. LeSuer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jennifer L. Horsley-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arina Putikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthew R. Buras
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jessica B. Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Grace C. Pyon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Temeka D. Simmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alfred D. Doyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Benjamin L. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BLW designed the study. TS recruited the subjects. JLH collected the human specimens. MYM, WEL, AP, JGB, and GCP performed the data collection. MYM, ADD, and BLW analyzed the data and wrote the initial draft of the manuscript. MRB performed the statistical analysis. All authors have reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Benjamin L. Wright.

Ethics declarations

Conflicts of interest

None to report.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 266 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Masuda, M.Y., LeSuer, W.E., Horsley-Silva, J.L. et al. Food-Specific IgG4 Is Elevated Throughout the Upper Gastrointestinal Tract in Eosinophilic Esophagitis. Dig Dis Sci 68, 2406–2413 (2023). https://doi.org/10.1007/s10620-023-07924-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-023-07924-2

Keywords

Search

Navigation