Celiac disease (CeD) is a T-cell-mediated autoimmune-like disorder driven by gluten-specific CD4+ T cells that promote a TH1 inflammatory response in the intestinal mucosa, together with cytotoxic intraepithelial CD8+ lymphocytes that mediate epithelial destruction. CeD is also marked by a robust intestinal B cell response, including expansion of mucosal plasma cells and production of antibodies against deamidated gluten peptides and transglutaminase 2, implicating B cells as antigen-presenting cells for gluten-reactive CD4+ T cells. Despite substantial evidence from in vitro assays and murine models supporting a role for B cells in CeD pathogenesis, the transcriptional program of intestinal B cells associated with lesion formation remains largely unexplored in human tissue.
To address this gap, we used single-cell RNA sequencing to characterize intestinal B cells heterogeneity in a longitudinal cohort of fifty CeD patients with active disease, sampled at baseline, 3 months, and 1 year after starting a gluten-free diet. Latent factor analysis (fastTopics) identified nine B cell transcriptional programs. One, defined by high expression of FCRL4, ITGAX, SOX5, and SIGLEC6, marked a subset whose signature overlapped with inflammation-associated B cell programs described in other autoimmune settings. This B cell population was more abundant in patients with more severe villous atrophy, assessed by the villous height-to-crypt depth (VH:CD) ratio, and this association held up in two independent analyses (padj<0.001 for both). Spatial transcriptomic profiling (Xenium) of the same lesions is helping define this population's tissue niche and its spatial relationship to T cells and epithelial damage. Together, these findings nominate this B cell state as a previously unrecognized contributor to tissue damage in celiac disease, and a candidate mechanistic link to inflammatory pathology across autoimmune disease more broadly.