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<p>The immune–epithelial–stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4<sup>+</sup> T cells, intraepithelial lymphocytes, CD8<sup>+</sup> and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune–epithelial ‘scar’. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell–B cell interactions. Receptor–ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.</p>

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Immune–epithelial–stromal networks define the cellular ecosystem of the small intestine in celiac disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月6日

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  • Michael E. B. FitzPatrick,
  • Agne Antanaviciute,
  • Melanie Dunstan,
  • Karolina Künnapuu,
  • Dominik Trzupek,
  • Nicholas M. Provine,
  • Kyla Dooley,
  • Jia-Yuan Zhang,
  • Sophie L. Irwin,
  • Lucy C. Garner,
  • Jane I. Pernes,
  • Ricardo C. Ferreira,
  • Sarah C. Sasson,
  • Dominik Aschenbrenner,
  • Devika Agarwal,
  • Astor Rodrigues,
  • Lucy Howarth,
  • Oliver Brain,
  • Darren Ruane,
  • Elizabeth Soilleux,
  • Sarah A. Teichmann,
  • Calliope A. Dendrou,
  • Alison Simmons,
  • Holm H. Uhlig,
  • John A. Todd,
  • Paul Klenerman

摘要

The immune–epithelial–stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4+ T cells, intraepithelial lymphocytes, CD8+ and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune–epithelial ‘scar’. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell–B cell interactions. Receptor–ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.