Eosinophilic esophagitis (EoE) is a T-helper type 2 (Th2) mediated disease characterized by an eosinophilic dominant esophageal inflammatory response that is thought to promote esophageal remodeling and reduced esophageal caliber leading to vomiting, dysphagia, chest pain, food impaction and decreased health-related quality of life (1). The cellular and molecular processes that underlie the pathophysiology of EoE are not yet fully understood, however a combination of environmental and genetic factors interwoven with host immunity is thought to drive the clinical manifestations of disease (2-5).
The demonstration of histologic and clinical improvement following elemental and elimination diets has led to the concept that food allergens and IgE are important contributors to the pathogenesis of EoE (6-10). This is further supported by the demonstration that EoE individuals have increased incidence of IgE-mediated food sensitization and levels of food specific IgE (11-13). However, elimination of foods based upon skin prick testing (SPT) or elevated serum IgE levels and anti-IgE therapy (omalizumab) have had limited success (14-17).
Recent clinical datasets have revealed a link between IgG4 and pediatric and adult EoE (17-19). Notably, investigators have demonstrated increased levels of serum IgG4 and esophageal IgG4+ plasma cells (PCs) in EoE patients compared to control individuals. Assessment of cow’s milk protein specific IgG4 antibodies in a pediatric EoE cohort has revealed serum IgG4/IgE ratios to be >10,000 in EoE patients and, following adjustment for age and milk consumption, high titers of IgG4 to CM protein strongly correlated with EoE with an odds ratio of >20 (19). IgG4 is considered to be an anti-inflammatory antibody as it possesses a short hinge and low Fab arm flexibility, can undergo a process termed “Fab arm exchange” which precludes cross-linking of identical antigens, and has a low affinity for the Fc gamma activating receptors (20,21). So the link between elevated levels of IgG4 and EoE was somewhat surprising and led to the speculation that EoE may be an IgG4-associated disease. However, how IgG4 contributes to EoE pathogenesis remains unclear.
A recent case-control study by Rosenberg et al., published in the journal Allergy, examined the role of IgG4 in pediatric patients with EoE (22). The authors revealed a relationship between immunoglobulin levels, in particularly IgG4, and histologic and transcriptomic profiles of esophageal biopsy samples from EoE (n=17) and control (n=19) pediatric patients. Moreover, the authors observed increased levels of IgM, IgA, IgG1, IgG2, IgG3 and IgG4 in esophageal tissue of patients with EoE compared to controls. Most striking, the esophageal IgG4 levels in EoE patients were 22-fold higher than that observed in control individuals. No significant differences in esophageal IgE levels were observed in patients with EoE compared to control individuals.
To analyze of the relationship between IgG4 levels and EoE severity the authors employed the validated EoE histology scoring system (EoEHSS) (23). Rosenberg and colleagues revealed that levels of IgG4 in esophageal tissue correlated with mean histologic grade and stage in pediatric EoE. Notably, the strongest correlation was with basal zone hyperplasia (BZH) and esophageal eosinophilia. Transcriptional analyses of cytokine levels revealed a correlation between esophageal interleukin (IL)-4, IL-10 and IL-13 mRNA levels and IgG4, but there was no association with transforming growth factor beta (TGF-β). IL-4 and IL-13 are known Th2 cytokines that induce B-cell class switching promoting production of IgE and IgG4 (24,25). On the other hand, IL-10 which is produced at high levels by regulatory T cells (Treg) as well as eosinophils and enhances production of IgG4 as opposed to IgE (26-28). Comparison of esophageal IgG4 levels with gene expression in EoE using the EoE Diagnostic panel, a panel of 96 EoE genes (29), revealed a significant correlation with 62 genes that are involved in the biological processes including epithelial barrier, cell adhesion, inflammation, ion channels, chemokines/cytokines as well as proliferation. It would be interesting to know whether the observed increased levels of other immunoglobulins were associated with EoE severity and transcriptome profile to determine whether this was specifically related to IgG4 or a general phenomenon related to increased inflammatory disease. Despite this, the positive correlation with the inflammatory pathways and observed histologic link suggests that IgG4 may play a pro-inflammatory role contributing to the ongoing inflammation and esophageal epithelial remodeling in EoE.
Recently there has been a number of studies evaluating esophageal immunoglobulin levels in EoE patients (17-19). In an adult EoE cohort, investigators reported increased IgG4 levels in esophageal tissue samples from patients with EoE compared to controls, however, levels of IgM, IgA, IgG1, IgG2, IgG3 were not different between groups. Mohammad and colleagues reported increased IgG4+-plasma cells (PC) in a pediatric EoE cohort compared with age- and sex-matched controls (18). Notably, IgG4+-PC levels did not correlate with esophageal eosinophilia or therapeutic outcomes. Similarly, Schuler et al. (19) reported high sera CM-specific IgG4 in a pediatric EoE cohort compared to controls. However, they did not observe any relationship between CM-specific IgG4 levels and disease remission following CM elimination diet (19). Rosenberg and colleagues did not observe significant differences in esophageal IgE levels in EoE compared with controls. This would be in contrast to previous reports demonstrating heightened levels of IgE and IgE-PCs in esophageal biopsy samples in EoE compared with controls (12,13,19,30). In a randomized, double-blind, placebo-controlled trial of adults with EoE given an antibody against IgE (omalizumab) investigators reported that treatment with anti-IgE (omalizumab) did not alter symptoms or esophageal eos/HPF compared with placebo treatment (17) suggesting that EoE may not be an IgE-mediated disease process. It is important to note that Rosenberg et al. report that the ratio of IgG4 to IgE was 10:1 in control subjects and was 224:1 in patients with EoE. Consistent with this, Schuyler et al., observed a similar increase in the CM-specific sIgG4/sIgE ratio in pediatric patients with EoE (19). The discrepancies between these studies related to IgG4 and IgE association with disease severity and therapeutic outcomes maybe reflective of differential roles for IgG4 between pediatric and adult EoE or a differential contribution during the natural history of disease where IgE-mediated processes are involved in the initial disease course and then transition to primarily IgG4-associated disease.
There were some limitations with this study. Firstly, the authors only analyzed n=17 non-EoE controls and n=19 EoE individuals and the small sample size is underpowered to evaluate the relationship between different treatment modalities impacts on IgG4 levels. Furthermore, EoE individuals were selected without regard to atopic status, treatment status and it was not specified whether patients underwent or undergoing PPI trial which could impact the immunological and histologic outcome measurements. Furthermore, there was no exploration of the food sensitization status of those individuals in the control group. A future case-control study evaluating the levels of esophageal immunoglobulins in the setting of food sensitization could be of value. Furthermore, all the patients were of Caucasian descent which may influence the generalizability of these findings to broader populations.
Despite these limitations, the study by Rosenberg and colleagues adds further weight to the emerging concept of a role for IgG4 in EoE. However, there are many unanswered questions including (I) whether heightened IgG4 levels is just an epiphenomenon in EoE patients related to the elevated CD4+ Th2 and eosinophilic response or whether IgG4 directly contributes to disease pathogenesis or (II) what is the predictive value of IgG4/IgE ratio to EoE disease state and responsiveness to treatment modalities? Questions that will only be fully answered by additional clinical studies in both pediatric and adult EoE cohorts.
Funding: This work was supported by NIH R01 AI073553, R01 DK090119, Department of Defense W81XWH-15-1-0517 and Food Allergy Research Education (FARE).
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: O’Shea K, Hogan SP. IgG4 in eosinophilic esophagitis: perpetrator, accomplice or bystander? Ann Esophagus 2018;1:14.