PSMB8 and HLA-A Stratify Therapy Response in Eosinophilic Esophagitis

Abstract Background and Objective Proton-pump inhibitors (PPI) serve as an effective first-line therapy for Eosinophilic Esophagitis (EoE). However, in the clinical routine, approximately 50% of patients are refractory to PPI treatment but the underlying biological mechanisms driving the variability in PPI response remain unclear, with no reliable predictive markers for treatment outcomes. Therefore, this study was designed to explore the differences in esophageal immunologic transcriptome between PPI-non-responders (PPI-NR) and PPI-responders (PPI-R) patients to elucidate the molecular mechanisms and identify potential biomarkers that could predict therapeutic outcomes. Method Pediatric EoE patients who were treated with PPI-therapy were enrolled at University Hospital Erlangen and subsequently classified as PPI-NR or PPI-R. The pre-treatment esophagus biopsy and clinical information from all participants were collected to analyze transcriptome expression profiles. We performed differential expression analysis between PPI-NR and PPI-R patients and conducted enrichment analysis and protein-protein interaction network analysis. The hub genes revealed through these analyses were further validated via immunohistochemistry. Results Differential expression analysis revealed that the immunological transcriptomic profile partially differed between PPI-NR and PPI-R groups as 12 DEGs were upregulated and 1 downregulated. Enrichment analysis highlighted a strong association of these DEGs with antigen processing and presentation functions. The protein-protein interaction network analysis identified HLA-A and PSMB8 as key hub genes differing between PPI-NR and PPI-R groups, and immunohistochemistry validation showed a significant higher expression levels in the PPI-NR group (HLA-A: p<0.05, PSMB8: p<0.01). Additionally, the ROC curve analysis of HLA-A and PSMB8 demonstrate a highly predictive value in differentiating between PPI-NR and PPI-R patient. Conclusion PPI-NR patients exhibited a more pronounced dysregulation of immunological gene expression compared to PPI-R patients. The two key hub genes PSMB8 and HLA-A are potential biomarkers for predicting PPI responsiveness in pediatric EoE patients.