Bose Paroma, Zhang Wenwu, Mehrpouya-Bahrami Pegah, Collins Katrina, Zhao Jennifer, Cannon Anthony M, Albright Eric, Idrees Muhammad T, Perkins Anthony, Gupta Sandeep K, Hon Emily C, Kaplan Mark H
Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, IN, USA.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Dis Esophagus. 2025 Jan 7;38(1). doi: 10.1093/dote/doae071.
Proton pump inhibitors (PPIs) are one of the standards of care of eosinophilic esophagitis (EoE) treatment, though PPI response rates are variable ranging from 23 to 63% in pediatric studies. We sought to determine if expression of select genes in esophageal mucosa can predict PPI responsiveness in EoE. Children with a new diagnosis of EoE (15 or more eosinophils/hpf on esophageal biopsy) were prospectively treated with 8 weeks of PPI therapy before follow-up esophagogastroduodenoscopy (EGD). Children with <15 eosinophils/hpf on follow-up were classified as having PPI-Responsive EoE (PPI-R) and ≥ 15 eosinophils/hpf as PPI-Nonresponsive EoE (PPI-NR). Using the Nanostring nCounter Analysis System, mRNA expression of a custom panel of genes was measured in esophageal biopsies. Immunohistochemical staining of biopsies was performed. Among children with EoE, 32% (8/25) had PPI-R EoE. ATP12A, ATP4A, tryptase-beta 2 (TPSB2), CLC and IL13 had higher expression in PPI-NR EoE compared to PPI-R EoE or controls. Immunohistochemical staining of ATP12A was higher among PPI-R EoE and PPI-NR EoE, compared to non-EoE controls. In this study, PPI-NR EoE had significantly higher baseline gene expression of mast cell, cytokine, proton pump, and eosinophil genes compared to PPI-R EoE. PPIs may be involved in an inflammatory cascade of mast cell activation that stimulates IL-13 release, which upregulates ATP12A and ATP4A that leads to eosinophil recruitment. Histologic PPI failure may occur when increased gene expression of these components is high and cannot be overcome pharmacologically, especially in the case of proton pump genes.
质子泵抑制剂（PPIs）是嗜酸性食管炎（EoE）治疗的标准护理方法之一，尽管在儿科研究中，PPI的有效率有所不同，在23%至63%之间。我们试图确定食管黏膜中特定基因的表达是否能预测EoE对PPI的反应性。新诊断为EoE（食管活检每高倍视野有15个或更多嗜酸性粒细胞）的儿童在进行随访食管胃十二指肠镜检查（EGD）之前，接受了为期8周的PPI治疗。随访时每高倍视野嗜酸性粒细胞少于15个的儿童被归类为PPI反应性EoE（PPI-R），每高倍视野嗜酸性粒细胞≥15个的儿童被归类为PPI无反应性EoE（PPI-NR）。使用Nanostring nCounter分析系统，在食管活检组织中检测一组定制基因的mRNA表达。对活检组织进行免疫组织化学染色。在患有EoE的儿童中，32%（8/25）患有PPI-R EoE。与PPI-R EoE或对照组相比，ATP12A、ATP4A、类胰蛋白酶β2（TPSB2）、CLC和IL13在PPI-NR EoE中的表达更高。与非EoE对照组相比，PPI-R EoE和PPI-NR EoE中ATP12A的免疫组织化学染色更高。在本研究中，与PPI-R EoE相比，PPI-NR EoE的肥大细胞、细胞因子、质子泵和嗜酸性粒细胞基因的基线基因表达显著更高。PPI可能参与了肥大细胞激活的炎症级联反应，刺激IL-13释放，进而上调ATP12A和ATP4A，导致嗜酸性粒细胞募集。当这些成分的基因表达增加且无法通过药物克服时，可能会出现组织学上的PPI治疗失败，尤其是在质子泵基因的情况下。
