IgG4 is closely associated with eosinophilic esophagitis

What this study means

Rosenberg et al.’s study (1) confirms the presence of abundant IgG4 in eosinophilic esophagitis (EoE) and has added important novel findings: that the abundant IgG4 is also present in pediatric EoE patients, that IgG4 content correlates with the degree of disease activity as measured by both eosinophil counts and by other histologic findings, and that IgG4 content also correlates with many, but not all, of the EoE mRNA markers. Of particular note is the correlation with IL-10, which induces expression of IgG4 rather than IgE (2). Together, these findings show that IgG4 is closely associated with EoE. This is an important confirmation and extension of the prior work. In contrast, relatively modest and variable IgG4 associations are seen in many other allergic and inflammatory diseases.

What IgG4 means in the context of EoE

Unlike classical IgE-mediated allergies like asthma, EoE does not respond to omalizumab, an anti-IgE monoclonal antibody (3). The lack of an IgE effect could be because IgG4 and other non-IgE antibodies function as blocking antibodies inhibiting IgE mast cell or basophil activation (4), as well as by binding mast cell FcGRIIb receptors (5). There is no evidence for IgG4 in the direct pathogenesis of EoE. There is instead compelling evidence in a mouse model (6) and some evidence in humans (7) that Th2 lymphocytes might be crucial in the development of EoE.

Future directions

While we (3) and others (8) have demonstrated IgG4 specific to the usual EoE trigger foods, we have found that the food specificity of serum IgG4 antibodies is a relatively poor predictor of which food(s) trigger EoE in a particular patient (unpublished observations). It remains unclear whether the food specificity of local/locally produced IgG4 will better predict the trigger foods.

The authors, correctly in my view, favor that the IgG4 is largely made locally. A detailed understanding of the immune response in the subepithelial stroma, where nearly all the local IgG4 plasma cells reside (3), will be needed to fully understand this disease. While this site is relatively inaccessible, new biopsy techniques allow biopsy of deeper tissue; and early studies have been done (9). I agree with the authors that the IgG4 and the associated IL-10 noted here, as well as the occasional induction of EoE by oral immunotherapy (10), suggest that EoE is not solely an allergy, but also, in part, an immunoregulatory immune response. The presence of regulatory B cells as well as TGF-beta-related induced regulatory T cells are both highly likely to be present in this tissue site.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aoe.2018.09.05). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rosenberg CE, Mingler MK, Caldwell JM, et al. Esophageal IgG4 levels correlate with histopathologic and transcriptomic features in eosinophilic esophagitis. Allergy 2018;73:1892-901. [Crossref] [PubMed]
2. Jeannin P, Lecoanet S, Delneste Y, et al. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol 1998;160:3555-61. [PubMed]
3. Clayton F, Fang JC, Gleich GJ, et al. Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology 2014;147:602-9. [Crossref] [PubMed]
4. Dodev TS, Bowen H, Shamji MH, et al. Inhibition of allergen-dependent IgE activity by antibodies of the same specificity but different class. Allergy 2015;70:720-4. [Crossref] [PubMed]
5. Burton OT, Tamayo JM, Stranks AJ, et al. Allergen-specific IgG antibody signaling through FcγRIIb promotes food tolerance. J Allergy Clin Immunol 2018;141:189-201.e3. [Crossref] [PubMed]
6. Mishra A, Schlotman J, Wang M, et al. Critical role for adaptive T cell immunity in experimental eosinophilic esophagitis in mice. J Leukoc Biol 2007;81:916-24. [Crossref] [PubMed]
7. Mitson-Salazar A, Yin Y, Wansley DL, et al. Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function. J Allergy Clin Immunol 2016;137:907-18.e9. [Crossref] [PubMed]
8. Wright BL, Kulis M, Guo R, et al. Food-specific IgG4 is associated with eosinophilic esophagitis. J Allergy Clin Immunol 2016;138:1190-2.e3. [Crossref] [PubMed]
9. Schoepfer AM, Simko A, Bussmann C, et al. Eosinophilic Esophagitis: Relationship of Subepithelial Eosinophilic Inflammation With Epithelial Histology, Endoscopy, Blood Eosinophils, and Symptoms. Am J Gastroenterol 2018;113:348-57. [Crossref] [PubMed]
10. Lucendo AJ, Arias A, Tenias JM. Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2014;113:624-9. [Crossref] [PubMed]