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Annals of Clinical & Laboratory Science 39:99-107 (2009)
© 2009 Association of Clinical Scientists

Increased Esophageal Regulatory T Cells and Eosinophil Characteristics in Children with Eosinophilic Esophagitis and Gastroesophageal Reflux Disease

Usa Tantibhaedhyangkul1,3, Nina Tatevian2, Mark A. Gilger1, Angela M. Major2 and Carla M. Davis1
1 Departments of Pediatrics and 2 Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA; 3 Phramongkutklao Hospital, Phramongkutklao College of Medicine, Bangkok, Thailand

Address correspondence to Carla M. Davis, M.D., Dept. of Pediatrics, Texas Children’s Hospital, 6621 Fannin St. (FC330.01), Houston, TX 77030-2399, USA; e-mail cmdavis{at}texaschildrenshospital.org; tel 832 824 1319; fax 832 825 1260.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Eosinophilic esophagitis (EE) and gastroesophageal reflux disease (GERD) have similar clinical presentations. The immunoregulatory mechanisms involved in both diseases are not clearly defined. We studied cellular inflammation in pediatric patients with EE and GERD compared to normal controls (NC). Pathology records were reviewed of 10 EE, 8 GERD, and 10 NC children who were seen at Texas Children’s Hospital in the past 3 yr. FOXP3, CD4, CD8, CD25, eotaxin-3, and IL-5 immunohistochemical stains were performed on formalin-fixed, paraffin-embedded esophageal tissue sections and assessed by a blinded observer. The numbers of FOXP3+, CD25+, and CD8+ cells were significantly increased in both EE and GERD compared with NC. No significant differences in the numbers of FOXP3+, CD4+, CD8+, and CD25+ cells were detected between the patients with EE and GERD. Eotaxin-3+ was found in mature epithelial cells and IL-5 was detected in esophageal intravascular space in all 3 groups. Eosinophil degranulation and microabscesses were significantly increased in EE compared to GERD. IL-5 was detected in vessels of the affected esophageal area and eotaxin-3 is produced locally by mature epithelial cells. Increased numbers of esophageal FOXP3+ regulatory T cells, and CD8+ T cells in both EE and GERD suggest that a negative feedback mechanism may regulate the inflammatory response.

Keywords: regulatory T cells, eosinophilic esophagitis, gastroesophageal reflux disease, IL-5, eotaxin-3


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Eosinophilic esophagitis (EE) is an inflammatory disease characterized by accumulation of eosinophils in the esophagus with absence of a known non-atopic cause of eosinophilia [1–3]. EE is being increasingly reported in children and adults [4,5], but the etiology of EE is poorly understood. Food or aeroallergen hypersensitivity is involved in ~50% of EE cases. Children with EE have symptoms that include abdominal pain, nausea, vomiting, regurgitation, dysphagia, heart burn, and poor eating with failure to thrive [1,6,7]. The clinical presentation of EE is similar to gastroesophageal reflux disease (GERD), but the pathogenesis of each disease is thought to differ. While EE is usually triggered by food or pollen allergens, the eosinophilic inflammation observed in GERD is induced by gastric acid. Five to 10% of pediatric patients with reflux symptoms unresponsive to acid blockade have EE [1,6]. There is eosinophilic infiltration of the esophagus in both EE and GERD but GERD typically has less intense eosinophilic inflammation. The tissue eosinophil numbers that differentiate EE from GERD are not clearly defined, but may lie between 15 and 20–24 cells/ high power field (hpf) [1,2,5,7–11]. The severity of eosinophilia in the esophagus correlates negatively with the response to conventional GERD therapy [1,12,13]. Esophageal eosinophil numbers higher than 23 cells/hpf correlate with poor responsiveness to anti-GERD treatment [1,12].

CD4+CD25+FOXP3+ regulatory T cells (Tregs) are a subtype of T cells that express the IL- 2 receptor alpha chain (CD25high) and the transcriptional regulator (FOXP3). Tregs are important in the immunoregulatory suppression of T cell proliferation and function [14–16]. Abnormal function and/or number of Tregs can lead to inflammatory diseases. Natural Tregs develop in the thymus prior to antigen exposure and adaptive Tregs are generated in peripheral lymphoid tissues from naïve CD4+FOXP3– cells after antigen exposure. A recent study identified a human CD8+ Tregs subset (CD8+CD25+FOXP3+) that inhibits T cell activation [17]. Murine CD25–/lowFOXP3+ cells have equal potency to the CD25highFOXP3+ population in in-vitro suppression assays [18]. Hence, FOXP3 expression is considered more important than CD25 for the regulatory phenotype [19]. FOXP3 expression in T cells is now accepted as the gold standard for defining Tregs [20]. Tregs directly or indirectly suppress effector cells of allergic inflammation, such as eosinophils [21].

Eotaxin-3 and IL-5 are important in eosinophil regulation. Eotaxin-3 is a critical tissue recruitment factor for eosinophils and IL-5 is most specific to the eosinophil linage and regulates eosinophil proliferation, release from bone marrow into the peripheral circulation, maturation, activation, and survival [22]. Anti-IL-5 therapeutic agents may have a role in controlling EE symptoms and disease severity and may become important in the future as a treatment of EE. An open-label phase I/II safety and efficacy study showed that anti-IL-5 antibody therapy was associated with marked decrease of eosinophilia in peripheral blood and esophageal tissue in patients with EE [22].

This study was designed to characterize cellular inflammation in pediatric patients with EE and GERD in comparison to normal controls (NC). Tissue eosinophil characteristics were determined and mucosal Tregs, CD25+ cells, CD4+, and CD8+ T cells were examined. Tissue eotaxin-3 and IL-5 were also determined in EE and GERD patients in comparison to NC subjects.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The study was approved by the Institutional Review Board of Baylor College of Medicine and Affiliated Hospitals. Patients were identified based on review of the pathology records at Texas Children’s Hospital from January 2004 to April 2007. The 10 most recently diagnosed EE, GERD, and NC patients who met the enrollment criteria were included. All available esophageal biopsy tissue on the histology slides, ranging from 3–19 hpf, was assessed by a blinded observer. The median numbers of hpf for the assessment of FOXP3+, CD4+, and CD8+ cells were not statistically different among the 3 groups. EE was histologically defined by a peak intra-epithelial eosinophil count in the esophagus >24 cells/hpf. GERD patients were included if the peak intra-epithelial eosinophil count was <15 cells/hpf and clinical symptoms were improved with anti-reflux therapy. Patients with peak intra-epithelial eosinophil counts from 15 to 24 cells/hpf were excluded from the study. The NC group included patients with normal biopsy specimens after endoscopy for diagnostic purposes. Patients with other esophageal pathologic diagnoses were excluded. EE, GERD, and NC patients who had been treated with corticosteroids or mast cell stabilizers within 4 wk before endoscopy and biopsy were also excluded.

Clinical information.  Charts were reviewed for symptoms upon clinical presentation, duration of symptoms, age, sex, endoscopic findings, biopsy site (proximal, mid, or distal) and food-specific IgE testing. The positive specific IgE tests for cow’s milk and egg allergy were defined by accepted 95% positive predictive values [23]. The skin prick test or specific IgE test data from outside allergy clinics were also reviewed.

Histologic evaluation.  Esophageal biopsy specimens were fixed in 10% formalin, embedded in paraffin, and sectioned at 3 µm thickness. Eosinophils were counted, eosinophil degranulation was graded, and eosinophilic microabscesses were detected by a blinded pathologist on the H&E-stained sections. Eosinophil degranulation was graded as 0 (no degranulation), + (<10% eosinophils with degranulation), ++ (10–50% eosinophils with degranulation), and +++ (>50% eosinophils with degranulation). Eosinophilic microabscesses were defined as aggregates of ≥4 eosinophils.

Immunohistochemistry analysis.  Antigen retrieval was performed by citrate (CD8, CD25, IL-5), pepsin (eotaxin-3), EDTA (FOXP3), or decloaker (CD4) prior to immunohistochemical staining to improve antigen detection. Sections were incubated for 1 hr at room temperature with mouse monoclonal antibodies (mAbs) directed against CD4 (1:50, clone 4B12, Novocastra); CD8 (1:50, clone C8/144B, Dako- Cytomation); CD25 (1:200, clone 4C9, Novocastra); FOXP3 (1:100, clone 236A/E7, Abcam); or IL-5 (1:300, clone 9906, R&D Systems); sections were incubated overnight at 4°C with eotaxin-3 mAb (1:50, clone 115002, R&D Systems). A secondary mouse antibody (DakoCytomation) was used. The immunohistochemical signal was detected with streptavidin-conjugated horseradish peroxidase and aminoethylcabazole. Except for eotaxin-3 staining, enzyme activity was detected with diaminobenzidine as substrate. Sections were counterstained with hematoxylin. The CD4+, CD8+, CD25+, and FOXP3+ cells were counted and the presence of IL-5 and eotaxin-3 was assessed in every field of the intra-epithelial areas of each slide.

Statistical analyses.  The Kruskal-Wallis test was used for all patient and control group comparisons and the Mann- Whitney U test was used to compare 2 groups at a time. Data were expressed as medians with 25% to 75% interquartile ranges. Categorical data were analyzed by Chi-square test to compare the groups. Correlations were assessed with Spearman’s rho test (r >0.3). Statistical significance was defined as p <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical information, demographic data, and allergy testing.  A total of 30 children were studied. Two patients were excluded after enrollment. One was excluded because the peak intra-epithelial esophageal eosinophil count, reviewed by a blinded pathologist, was 24 cells/hpf; another patient was excluded because of inadequate tissue in the biopsy specimen. There were 10 patients with EE (7 males), 8 patients with GERD (7 males), and 10 NC (4 males). The gender distribution was not statistically different among the groups but there was a male predominance in both EE and GERD. The median age at time of biopsy with 25%–75% interquartile range and clinical presenting symptoms for each group are shown in Table 1Go. The age at time of biopsy and presenting symptoms were not significantly different among the groups, but the failure to thrive was present in 30% of EE while absent in the other groups. The duration of symptoms at time of biopsy was not significantly different between EE and GERD groups (median duration and 25–75 interquartile in EE group = 1.0 and 0.2–2.0 yr; GERD group = 0.7 and 0.1–1.0 yr respectively).


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  		Table 1. Clinical features of the eosinophilic esophagitis (EE), gastroesophageal reflux disease (GERD), and normal control (NC) groups.
 
In the EE group, there was a higher proportion of Caucasian ethnicity (50% Caucasian, 20% African, 20% Hispanic, and 10% unknown). The GERD group also had a predominance of Caucasian ethnicity (75% Caucasian, 12.5% Asian, 12.5% unknown) The NC group was 44% Caucasian, 22% Hispanic, and 44% unknown. In the EE group, 6 of 10 patients had previous specific IgE or skin prick tests. Five of these 6 EE patients were allergic to at least one food. The 5 most common food allergies were cow’s milk (33.3%), egg (33.3%), wheat (33.3%), soy (16.7%), and peanut (16.7%).

Endoscopic findings.  In the EE group, abnormalities were found in 3 of 10 patients, including moderate esophagitis with linear furrowing, mucosal exudate with loss of vascularity, and very irregular esophageal mucosa with erythema and nodularity. Two of 8 GERD patients were found to have abnormalities, including mild edema of the distal esophageal mucosa and slight creasing of the esophagus. No abnormal esophageal endoscopic findings were seen in the NC group.

Histopathologic findings.  A total of 196 slides from 28 esophageal biopsy specimens were analyzed by H&E and immunohistochemical staining. In the EE group, 5 specimens were from the proximal esophagus and 2 from the mid-esophagus; 3 specimens were unspecified. Elongation of vascular papillae and basal cell hyperplasia were present in all specimens. In the GERD group, 2 specimens were from the distal esophagus and the others were unspecified. The papillary vascular elongation was seen in 7 specimens and basal cell hyperplasia in 5. The NC biopsy specimens did not show any histologic alterations. The medians and 25%–75% interquartile ranges of the peak eosinophil counts for all groups are listed in Table 2Go.


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  		Table 2. Medians of the peak eosinophil counts/hpf and numbers of subjects with eosinophil degranulation and eosinophilic microabscesses in the intra-epithelial layer of the esophagus.
 
Eighty percent of the EE esophageal biopsy specimens had eosinophilic microabscesses and none were detected in the GERD and NC groups. The number of patients with eosinophilic microabscesses was significantly increased in the EE group compared with the GERD (p = 0.001) and NC groups (p = 0.001). All 10 EE and 2 of 8 GERD patients had eosinophil degranulation; none was detected in NC patients. Eosinophil degranulation was significantly increased in EE (p = 0.002 vs GERD and p <0.001 vs NC, respectively). The EE patients had variable degrees of eosinophil degranulation, 7 showed moderate (++) to intense (+++) degranulation and the other 3 showed mild (+) degranulation. Two of 8 GERD patients had mild (+) to moderate (++) eosinophil degranulation. None of the 10 NC subjects had eosinophil degranulation.

Esophageal CD4+, CD8+, CD25+, and FOXP3+ cells.  In the EE group, many CD4+, CD8+, and FOXP3+ cells were found in the intraepithelial layer, but only a few CD25+ cells were demonstrated (Fig. 1Go). The median counts of CD4+, CD8+, CD25+, and FOXP3+ cells/hpf and the 25%–75% interquartiles are shown in Table 3Go. The median number of esophageal CD8+ cells/hpf was higher than that of CD4+ cells. The numbers of CD8+, CD25+, and FOXP3+ cells/hpf were significantly increased in EE compared to NC (p <0.01). The number of CD4+ cell/hpf was marginally different between the EE and NC groups (p =0.05). The median numbers of CD4+ and CD8+ cells/hpf were ~6-fold higher in the EE group compared to the NC group. The median numbers of CD4+, CD8+, CD25+, and FOXP3+ cells/hpf were not significantly different between the EE and GERD groups. However, the median numbers of CD4+, CD8+, and FOXP3+ cells/hpf in the EE group tended to be higher than in the GERD group. The CD4/CD8 ratios were not significantly different among the 3 groups. There were no significant correlations between peak eosinophil counts and CD4+, CD8+, and FOXP3+ cells/hpf in each group. However, peak eosinophil counts were correlated inversely with the CD4/CD8 ratio in the EE group (r = –0.8, p=0.04); such correlation was not found in the GERD and NC groups.


Figure 1
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  		Fig 1. FOXP3+, CD8+, CD4+, and CD25+ cells in the intra-epithelial layer of esophagus in EE (A-D) and GERD (E-H). The numbers of FOXP3+, CD8+, and CD25+ cells were significantly increased in both EE and GERD groups compared with NC. No significant differences of the numbers of FOXP3+, CD4+, CD8+, or CD25+ cells were detected between EE and GERD groups. The magnification is 400x in all photomicrographs.

 

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  		Table 3. Median numbers (and interquartile ranges) of various cell types/hpf by immunohistochemical staining.
 
In the GERD group, some CD8+, few CD4+ and FOXP3+, and scarce CD25+ cells/hpf were found in the intra-epithelial area of the esophagus (Fig. 1Go). The median number of esophageal CD8+ cells/hpf was higher than that of CD4+ cells. The median counts of CD8+, FOXP3+, and CD25+ cells/hpf were significantly higher in GERD than in NC (p <0.01 for CD8+ and FOXP3+ cells; p <0.05 for CD25+ cells). The median number of CD8+ cells/hpf was 4-fold increased in GERD compared to the NC group. The CD4+ cell number/ hpf was not significantly different in the GERD and NC groups.

In the NC group, small numbers of CD4+ and CD8+ cells were found in the intra-epithelial layer. The median esophageal CD8+ cell number/hpf was higher than that of CD4+ cells, consistent with a previous report [5]. The CD25+ and FOXP3+ cells were scarce in all intraepithelial areas and vascular pappillae of the slides (Table 3Go).

Esophageal eotaxin-3 and IL-5 detection.  To determine eotaxin-3 and TH2 cytokine production from T cells in esophageal tissue, staining was performed for eotaxin-3 positive cells and IL-5. Eotaxin-3 expression was evident in mature squamous epithelial cells in all groups but not in immature cells of the proliferative layer. The site of positive eotaxin-3 staining in EE and GERD groups in comparison to H&E staining is shown in Fig. 2Go. There were rare eotaxin-3 positive cells in the lamina propria and lymphoid follicles of all groups. IL-5 was noted in the intravascular lumen in all groups (Fig. 3Go). Extravasation of IL-5 into the intercellular space was present in the EE group, but not in the GERD or NC groups.


Figure 2
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  		Fig 2. The site of eotaxin-3 positive staining (brown) of esophageal biopsy specimens in EE (A), GERD (C) and NC (E) compared to H&E staining of the same specimens (B, D and F), respectively (magnification 200x). The eotaxin-3 positive cells are found in mature squamous epithelial cells in all 3 groups.

 

Figure 3
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  		Fig 3. IL-5 positive staining in the intravascular space in EE (A, B), NC (C), and GERD (D). Extravasation of IL-5 to intercellular space was detected in the EE group (B). The magnification is 400x in all photomicrographs.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this investigation of the cellular inflammatory characteristics of EE, an increase in FOXP3+ Tregs, CD8+, and CD25+ cells was observed in both EE and GERD, which are diseases with similar clinical presentations. The symptoms of these diseases are similar [6,7,9] and there is a male predominance in both EE and GERD [1,24], which was also seen in our cohorts. Both CD4+ and CD8+ T regulatory cells have been identified. CD8+ Tregs have different mechanisms of immune suppression and are observed in different diseases compared to CD4+CD25+ Tregs. In fact, in some cases they work together to mediate immunosuppression [25]. FOXP3 represents a more specific marker for Tregs than currently used cell-surface molecules such as CD25 to discriminate between Tregs and activated effector cells [19,20,26]. Using FOXP3 expression, we showed that the number of esophageal mucosal Tregs is significantly higher in both EE and GERD than in NC. Our data differ from reports that describe the occurrence of Tregs in allergic diseases [27,28]. It has been observed that children who outgrew cow’s milk allergy had higher frequencies of circulating CD4+CD25+ Tregs compared to children who had clinically active allergy [28,29]. CD4CD25high Tregs were decreased in bronchoalveolar lavage fluid of asthmatic children compared to values in children with cough or control subjects [27]. Although an increase in Tregs has been associated with decreased manifestations of allergic disease, there are also conflicting reports. Our data corroborate these latter findings, indicating a production of Tregs in response to allergic disease.

In this study, CD8+ cells were significantly higher in EE and GERD than in NC. Two previous studies have demonstrated an increase of these cells in EE compared with NC [4,5]. We suggest that the increase of Tregs and CD8+ T cells in EE and GERD may be a negative feedback mechanism to regulate the inflammatory response to external stimuli or allergen exposures. However, cell suppression assays for Treg function via IL-10 and TGF-β will be necessary to demonstrate the activity of these cells in situ. The increase of Tregs in EE suggests that lack of immunoregulation may not be a significant factor in EE pathogenesis. Intraepithelial CD4+ T cells were 6-fold higher in number in EE vs the NC group. There were marginally different numbers of CD4+ T cells in the EE and NC groups, yet no difference was detected between the EE and GERD groups. Our data are similar to a previous study demonstrating increased CD4+ T cells in EE compared to NC with no difference detected between EE and GERD [5]. Allergic responses are controlled by TH2 cytokines[30], which are predominant in allergic diseases [31]. The immunopathogenesis of EE is associated with atopy and that of GERD is associated with inflammation from tissue damage by gastric acid. Since there was no significant difference in CD4+ T cell numbers between EE and GERD, we suggest that other common factors may be involved in the immunopathogenesis of EE and GERD. The tissue inflammation present in EE may facilitate damage by gastric acid and induce recruitment of CD4+ T cells. On the other hand, anti-ulcer medications that increase the risk of food allergy [32] may promote the increase of CD4+ T cells in both diseases. Such data argue against the routine use of acid suppression therapy in children with EE or GERD. Although both CD4+ and CD8+ T cells could be contributory, our findings imply that the esophageal CD8+ T cells may have a more predominant role than CD4+ T cells in the esophageal inflammation of both EE and GERD.

We identified a significant increase of eosinophilic microabscesses and eosinophil degranulation that differentiates EE from GERD. Using aggregates of ≥4 eosinophils to define eosinophilic microabscesses, we showed a significant difference between EE and GERD. This corroborates previous reports [33–35]. Although we found eosinophil degranulation in both EE and GERD, the level of degranulation was significantly higher in EE than GERD. Since intraepithelial eosinophil counts between 15–24 cells/hpf may not clearly differentiate EE from GERD, eosinophilic degranulation and microabscess may be helpful to define the diseases. The presence of eosinophil degranulation and microabscesses are important in the distinction betwen EE and GERD.

The localization of cytokine IL-5 and chemokine eotaxin-3 in esophageal tissues of EE and GERD by immunohistochemistry may give further insight to the different pathogenesis of these diseases. Eotaxin-3 has been identified as the single most dysregulated gene in the esophagus of EE patients, and an eotaxin-3 gene single nucleotide polymorphism has been associated with disease susceptibility [3]. Eotaxin-3 expression has been reported to be either increased [2,36] or unchanged [8] in EE compared to NC. Although the immunohistochemical staining techniques do not quantitate the amount of eotaxin-3, we detected the eotaxin-3 positive cells in mature intra-epithelial cells. This corroborates a previous study [37] that demonstrated the expression of eotaxin-3 mRNA in epithelial cells. The location of eotaxin-3 mRNA was usually close to the proliferative region (basal layer) of the esophagus of EE patients. However, we observed the eotaxin-3 positive cells in the mature epithelial layer, with absence of these cells in the proliferative layer of all EE patients. It is conceivable that young epithelial cells in the esophagus express eotaxin-3 mRNA and produce eotaxin-3 protein that is then accumulated in the mature layer.

IL-5 is a specific eosinophil differentiation and survival factor generated by T-helper cells, eosinophils, and mast cells [3]. Intestinal eosinophils of EE patients and NC subjects also expressed IL-5 [38]. However plasma levels of IL-5 are in the normal range in eosinophilic gastroenteritis and in half of EE patients [22,39]. In our study, the IL-5+ cells were not clearly demonstrated as seen in previous literature by immunofluorescence [38]. We detected IL-5 in the intravascular space of esophageal tissue in all 3 groups and found extravasation of IL-5 into the intercellular space in the EE group. These findings suggest that IL-5 is secreted into the circulation and transferred to the affected esophageal tissue in an endocrine fashion. IL-5 had a larger presence in the intercellular space in EE compared to GERD in this study.

We conclude that eosinophil degranulation, eosinophilic microabscesses, and peak eosinophil counts are important in the differentiation between EE and GERD. We describe the presence of IL-5 in the affected esophageal area in vessels and the presence of eotaxin-3 in mature epithelial cells. The numbers of esophageal FOXP3+ Tregs and CD8+ T cells were significantly increased in both EE and GERD. Although CD4+ and CD8+ T cells both have roles in the pathogenesis, esophageal CD8+ T cells are predominant in EE and GERD. Our findings suggest that the increase of Tregs and CD8+ T cells in EE may be a negative feedback mechanism to regulate the inflammatory response to external stimuli or allergen exposures.


   Acknowledgments
 
The authors thank Dr. E. O’Brian Smith for statistical help, Dr. Milton J Finegold for valuable suggestions, and Drs. William T Shearer and Javier Chinen for critical reviews of the manuscript.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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