Esophageal IgG4 levels correlate with histopathologic and transcriptomic features in eosinophilic esophagitis

• Published in: Allergy (Copenhagen) Vol. 73; no. 9; pp. 1892 - 1901
• Main Authors: Rosenberg, C. E., Mingler, M. K., Caldwell, J. M., Collins, M. H., Fulkerson, P. C., Morris, D. W., Mukkada, V. A., Putnam, P. E., Shoda, T., Wen, T., Rothenberg, M. E.
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.09.2018
• Subjects: Allergies; Autoimmune diseases; Biopsy; Blood diseases; Case-Control Studies; Child; Child, Preschool; Enzyme-linked immunosorbent assay; eosinophilic esophagitis; Eosinophilic Esophagitis - diagnosis; Eosinophilic Esophagitis - etiology; eosinophilic oesophagitis; Esophageal diseases; Esophageal Mucosa - immunology; Esophageal Mucosa - metabolism; Esophageal Mucosa - pathology; Esophagitis; Esophagus; Esophagus - immunology; Esophagus - metabolism; Esophagus - pathology; Female; Gastrointestinal diseases; Gene Expression; Histocytochemistry; histology; Humans; IgG4; Immunoglobulin A; Immunoglobulin E; Immunoglobulin G; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Isotypes - immunology; Immunoglobulin M; Interleukin 1; Interleukin 10; Interleukin 13; Interleukin 4; Leukocytes; Leukocytes (eosinophilic); Lysates; Male; pediatric; Pediatrics; Proteins; Transcription; Transcriptome; Transforming growth factor-b1; IgG4; eosinophilic oesophagitis; histology; transcriptome; eosinophilic esophagitis; pediatric
• DOI: 10.1111/all.13486
• ISSN: 0105-4538; 1398-9995

Background Recent data associate eosinophilic esophagitis (EoE) with IgG4 rather than IgE, but its significance and function have not been determined. Our aims were to measure esophageal IgG4 levels and to determine functional correlations as assessed by histologic and transcriptome analyses. Methods This case‐control study included pediatric subjects with EoE (≥15 eosinophils/HPF) and non‐EoE controls. Protein lysates were analyzed for IgA, IgM, and IgG1‐IgG4 using the Luminex 100 system; IgE was quantified by ELISA. Esophageal biopsies were scored using the EoE histology scoring system. Transcripts were probed by the EoE diagnostic panel, designed to examine the expression of 96 esophageal transcripts. Results Esophageal IgG subclasses, IgA, and IgM, but not IgE, were increased in subjects with EoE relative to controls. The greatest change between groups was seen in IgG4 (4.2 mg/g protein [interquartile range: 1.0‐13.1 mg/g protein] vs 0.2 mg/g protein [0.1‐0.9]; P < .0001). Tissue IgG4 levels correlated with esophageal eosinophil counts (P = .0006); histologic grade (P = .0011) and stage (P = .0112) scores; and IL4, IL10, IL13, but not TGFB1, expression and had strong associations with a subset of the EoE transcriptome. Esophageal IgG4 transcript expression was increased and correlated with IgG4 protein levels and IL10 expression. Conclusion These findings extend prior studies on IgG4 in adult EoE to the pediatric population and provide deeper understanding of the potential significance and regulation of IgG4, demonstrating that IgG4 is a relevant feature of the disease; is closely related to esophageal eosinophil levels, type 2 immunity and T regulatory cytokines; and is likely produced locally. Esophageal IgG4 levels are increased in patients with EoE compared with control individuals and strongly correlate with esophageal eosinophil numbers and multiple features of histologic grade and stage scores. Esophageal IgG4 protein levels correlate with multiple components of the disease as assessed by transcriptome profiling, including IL4, IL13 and IL10 mRNA expression levels. IgG4 heavy chain mRNA expression is proportional to IgG4 protein levels and IL10 mRNA expression levels in the esophagus of patients with EoE.