Elevated Tryptase in EoE Is an Independent Phenomenon Associated with Extra-Esophageal Symptoms.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic disease characterized histologically by > 15 eosinophils per high-power field (eos/hpf). Esophageal mucosal mast cells have been implicated in EoE pathogenesis. The association of atopy with EoE has been established but has not been correlated with levels of serum tryptase. The lack of concurrent atopy in some patients suggests the possibility that atopy may either be the related subtype of EoE or may be a sign of comorbidities. No study has looked at whether patients present with different phenotypes/comorbid disease when they have evidence of elevated serum tryptase. We hypothesized that these patients differ with respect to presentation and comorbidities with more refractory GI disease. AIMS: To examine whether elevations of serum tryptase associate with different, more severe clinical presentations in EoE patients which may be explained via mast cell activation. MATERIALS AND METHODS: Retrospective chart review identified 72 patients with EoE with results for serum tryptase between 2015 and 2016. Patients were classified as TryptaseHI (tryptase > 10.9 µg/l) and TryptaseLO (< 10.9 µg/l). Clinical characteristics and treatment response were compared using univariate analysis and multivariate regression between the groups. RESULTS: Out of 72 patients, 12 were tested as TryptaseHI (16.7%, 95% CI 8.1-25.3%). TryptaseHI was associated frequently with asthma (P = 0.0003), urticaria (P = 0.002), arthralgia (P = 0.005), sinusitis (P = 0.03), nausea/vomiting (P = 0.046), and eosinophilic gastrointestinal disease (P = 0.001). Asthma and arthralgia were found to be significantly associated with TryptaseHI (P = 0.0013, P = 0.0098, respectively). Mucosal eosinophil counts and tryptase levels were not correlated (R2 0.095, P = 0.77). Tryptase did not resolve with resolution of esophageal eosinophilia. CONCLUSIONS: We found that EoE patients with elevated tryptase levels more commonly presented with asthma, urticaria, arthralgia, nausea/vomiting, sinusitis, and more distal eosinophilia. This indicates that atopy in EoE patients warrants further exploration. The lack of correlation between histologic remission and reduction of serum tryptase levels post-treatment suggests that mast cell activation may be an independent, yet associated disease. More study into this unique association is warranted.

Noncanonical NF-κB signaling and the essential kinase NIK modulate crucial features associated with eosinophilic esophagitis pathogenesis.

Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus driven by T cell and eosinophil responses to dietary allergens, resulting in chronic mucosal inflammation. Few spontaneous animal models of esophageal eosinophilia exist, with most studies relying on artificial sensitization procedures. NF-κB-inducing kinase (NIK; MAP3K14) is a key signaling molecule of the noncanonical NF-κB (NFKB1) pathway, an alternative signaling cascade producing chemokines involved in lymphoid stroma development and leukocyte trafficking. Nik-/- mice have been shown to develop a hypereosinophilic syndrome in peripheral blood and major filtering organs; however, the gastrointestinal mucosa of these mice has not been well characterized. We show that Nik-/- mice develop significant, localized eosinophilic esophagitis that mimics human EoE, including features such as severe eosinophil accumulation, degranulation, mucosal thickening, fibrosis and basal cell hyperplasia. The remainder of the GI tract, including the caudal stomach, small intestine and colon, in mice with active EoE are unaffected, also similar to human patients. Gene expression patterns in esophageal tissue of Nik-/- mice mimics human EoE, with thymic stromal lymphopoetin (TSLP) in particular also elevated at the protein level. In gene expression data sets from human biopsy specimens, we further show that many genes associated with noncanonical NF-κB signaling are significantly dysregulated in EoE patients, most notably a paradoxical upregulation of NIK itself with concurrent upregulation of powerful protein-level destabilizers of NIK. These findings suggest that Nik-/- mice could be useful as a spontaneous model of specific features of EoE and highlight a novel role for noncanonical NF-κB signaling in human patients.

MMPs-2 and -14 Are Elevated in Eosinophilic Esophagitis and Reduced Following Topical Corticosteroid Therapy.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a chronic, antigen-mediated disease in children and adults associated with substantial esophageal remodeling and fibrosis. The expression of the remodeling-associated matrix metalloproteinases (MMPs) has not been previously detailed in EoE. METHODS: MMP-2 and -14 expression and cellular localization were assessed using real-time quantitative polymerase chain reaction and immunohistochemistry/immunofluorescence in EoE fibroblasts, active and inactive pediatric EoE biopsies, and nondiseased control biopsies. The effect of transforming growth factor (TGF)-ß1 treatment on MMP-2 expression in cultured esophageal epithelial (HET1A) cells was analyzed. RESULTS: MMP-2 and -14 mRNA were expressed in EoE fibroblasts and biopsies. Proliferating epithelial cells produced MMP-14 more abundantly in EoE than in controls (P < 0.001) and the degree of epithelial MMP-14 expression correlated positively with basal zone hyperplasia (r = 0.65, P = 0.002). EoE lamina propria had higher numbers of MMP-2- and -14-positive cells (906 ±â€Š167 and 701 ±â€Š93 cells/mm²) as compared with controls (258 ±â€Š93 cells/mm², P < 0.01 and 232 ±â€Š54 cells/mm², P < 0.01), and MMP-14 expression correlated with the severity of fibrosis. Following therapy with topical corticosteroids, MMP-14 and -2 were significantly diminished (P < 0.01). TGF-ß1 increased the expression and secretion of MMP-2 from esophageal epithelial HET1A cells. CONCLUSIONS: MMP-2 and -14 are elevated in pediatric patients with EoE and significantly decrease following topical corticosteroid therapy. TGF-ß1 increases MMP-2 in esophageal epithelial cells. This alludes to previously unappreciated role for MMPs in EoE-associated esophageal remodeling and a potential positive feedback loop via TGF-ß1.

Tryptase staining of mast cells may differentiate eosinophilic esophagitis from gastroesophageal reflux disease.

OBJECTIVES: Mast cells may contribute to the pathogenesis of eosinophilic esophagitis (EoE), but their role in diagnosis is unknown. Our aim was to determine whether tryptase staining of esophageal mast cells differentiates EoE from gastroesophageal reflux disease (GERD) and has utility for diagnosis of EoE. METHODS: We performed a case-control study comparing patients with EoE, defined by consensus guidelines, to GERD patients with eosinophils on esophageal biopsy. Immunohistochemistry was performed with mast cell tryptase. The density (mast cells/mm2) and intensity (0-4 scale) of mast cell staining was compared between groups after masking the diagnosis. Receiver operating characteristic (ROC) curves were constructed, and the area under the curve (AUC) was calculated to assess mast cell staining as both a stand-alone diagnostic test and an adjunctive assay with eosinophil counts. RESULTS: Fifty-four EoE (mean age 24 years; 69% male; mean 146 eosinophils per high-power field (eos/hpf)) and 55 GERD (mean age 34 years; 60% male; mean 20 eos/hpf) patients were analyzed. The maximum epithelial tryptase density was higher in EoE than in GERD (162±87 mast cells/mm2 vs. 67±54; P<0.001). Mast cells were diffusely distributed throughout the biopsy in more EoE than GERD patients (41 vs. 7%; P<0.001). Tryptase density and eosinophil count were only weakly correlated (R2=0.09; P=0.002). The AUC was 0.84 for tryptase staining alone, and 0.96 for the combination of mast cells and eosinophils. CONCLUSIONS: Patients with EoE have higher levels of tryptase-positive mast cells compared with GERD patients, improving the diagnostic value of biopsies beyond eosinophil counts alone. Mast cell tryptase may have utility as a diagnostic assay for EoE.