Background Eosinophilic esophagitis (EoE) is a clinicopathologic entity of increasing worldwide prevalence. IL-5 is essential for eosinophil trafficking and anti-IL-5 therapy decreases esophageal eosinophilia. EoE is associated with a prominent mast cell infiltration. Objective We investigated whether anti-IL-5 (mepolizumab) treatment reduced esophageal mast cell accumulation in pediatric EoE biopsy specimens from a previous randomized anti-IL-5 trial. Methods A sub-analysis was completed for children treated with 0.55, 2.5, or 10mg/kg of mepolizumab monthly for 12 weeks followed by no treatment until week 24. Quantitative immunochemistry was used to assess eosinophils, tryptase-positive mast cells, IL-9+ cells, and mast cell-eosinophil couplets prior to and following treatment. Results 43 patient biopsies had adequate tissue for paired analysis. 40% of subjects responded to anti-IL-5 (defined as <15 eosinophils per hpf following mepolizumab therapy) and 77% of all subjects had decreased numbers of mast cells following anti-IL-5. In responders, epithelial mast cells decreased from 62 to 19 per hpf (p<0.001), were significantly lower than in non-responders following therapy (p<0.05), and correlated with eosinophil numbers (r=0.75, p<0.0001). Mast cells and eosinophils were found in couplets prior to therapy and these were significantly decreased only in responders following anti-IL-5 (p<0.001). Esophageal eosinophils comprised the majority of cells that made the mast cell growth factor IL-9. IL-9+ cells decreased from 102 to 71 per hpf (p<0.001) following anti-IL-5. Conclusions Pediatric EoE patients had significantly fewer mast cells, IL-9+ cells, and mast cell-eosinophil couplets in the esophageal epithelium following anti-IL-5 therapy. Since eosinophils were one source of IL-9, they may support esophageal mastocytosis.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Background Eosinophilic esophagitis (EoE) is a chronic Th2 inflammatory disease characterized by tissue remodeling that leads to esophageal strictures and food impactions. Effects of therapy on long term remodeling in pediatric eosinophil-associated diseases has not been previously described. Objective To understand the long term control of esophageal remodeling in EoE Methods We assessed endoscopic and histologic remodeling and TGFβ1 expression in esophageal biopsies from children (n=32) with EoE treated with topical corticosteroids (TCS) over 10 years (mean=4.5). We utilized standardized EoE scoring tools to gauge endoscopic and symptom features. Results 738 biopsies from 246 endoscopic procedures were evaluated over 10 years. 486 biopsies had adequate lamina propria (LP) for evaluation of subepithelial remodeling. The severity of epithelial esophageal eosinophilia correlated with epithelial remodeling (basal zone hyperplasia, desquamation, and dilated intercellular spaces) (p<0.0001), LP eosinophilia (p<0.0001), and fibrosis (p<0.0001). Sixteen subjects were initial responders (<15 eosinophils per hpf) to TCS. Responders and non-responders spent 54% and 97% of their total disease duration with active EoE (p<0.001) and 23% and 53% (p<0.02) with maximal fibrosis scores, respectively. Responders had lower endoscopy scores during their disease duration (p=0.013). Having <15 eosinophils per hpf at any time correlated with lower fibrosis and endoscopic severity. TGFβ1 positive cells decreased in responders at the first biopsy but this was not sustained. Symptoms did not correlate with other disease features. Conclusions Children with EoE have substantial esophageal remodeling which associates with inflammation and that can improve in a sustainable manner with TCS. Although endoscopic features correspond to histologic features, symptoms did not correlate with inflammation or fibrosis.