Immunoglobulin G4 in eosinophilic esophagitis: Immune complex formation and correlation with disease activity

• Published in: Allergy (Copenhagen) Vol. 78; no. 12; pp. 3193 - 3203
• Main Authors: Medernach, Jonathan G., Li, Rung‐Chi, Zhao, Xiao‐Yu, Yin, Bocheng, Noonan, Emily A., Etter, Elaine F., Raghavan, Shyam S., Borish, Larry C., Wilson, Jeffrey M., Barnes, Barrett H., Platts‐Mills, Thomas A. E., Ewald, Sarah E., Sauer, Bryan G., McGowan, Emily C.
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.12.2023
• Subjects: Adult; adults; Allergens; Animals; Antigen-Antibody Complex; Antigen-antibody complexes; Antigens; Autoimmune diseases; Biopsy; Bos; Calpain; Cattle; Cell activation; Cow's milk; digestive tract mucosa; disease progression; eosinophilic esophagitis; Eosinophilic Esophagitis - pathology; Esophageal diseases; Esophagitis; Esophagus; Female; fluorescent antibody technique; Food; Food allergies; Humans; hypersensitivity; Immunofluorescence; Immunoglobulin G; Immunoglobulin G4; Immunoglobulins; Immunoprecipitation; Leukocytes (eosinophilic); Localization; Mass spectrometry; Mass spectroscopy; milk; Milk Proteins; pathophysiology; precipitin tests; Protein interaction; Proteins; proteome; Proteomes; Remission; Remission (Medicine); Scientific imaging; immunoglobulin G4; eosinophilic esophagitis
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.15826

Background 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. Methods 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. Results 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. Conclusion 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. We assessed the co‐localization of IgG4 and cow's milk proteins in paired active disease and remission esophageal biopsy samples from EoE patients. IgG4‐milk co‐localization was higher in the active EoE group compared to paired remission samples. Using a novel technique, autoSTOMP, IgG4‐enriched areas were found to contain a high abundance of eosinophil‐associated proteins and food peptides.Abbreviations: autoSTOMP, automated Spatially Targeted Optical MicroProteomics; CAPN14, calpain 14; CMP, cow’s milk protein; EoE, eosinophilic esophagitis; EPX, eosinophil peroxidase; IgG4, immunoglobulin G4; PRG, proteoglycan; RNASE3, ribonuclease A family member 3.