Cellular and molecular profiling of collagenous gastritis implicates pathogenic CD4⁺ T cells

Collagenous gastritis (CG) is a rare disease characterized by thick bands of subepithelial collagen within the stomach that presents with symptoms ranging from anemia to vomiting. Its etiology is poorly understood, and currently, there are no well-defined effective treatment options. We collected gastric and duodenal biopsies from seven patients with CG and several matched controls. Flow cytometry, histopathology, and single-cell RNA-seq (scRNA-seq) and T cell receptor (TCR)-sequencing were performed on samples to understand immune mechanisms underlying CG. Patients with CG had reduced parietal cells and enhance expression of collagen genes by fibroblasts. We identified a population of activated/exhausted lymphocytes, with increased CD4:CD8 ratios and decreased tissue-resident T cells in patients with CG compared to controls. We identified potential therapeutic targets, including integrin α4 expression (ITGA4), indicative of mucosal homing. Preventing activated T cells from entering the gastric mucosa through blockade of integrin α4 may be a useful therapeutic target for patients with CG.