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<p>Secretory IgA (SIgA) is critical for maintaining the intestinal barrier. A dysregulated B-cell compartment and altered Ig secretion have been well documented in Crohn’s disease (CD) patients, although their origin is unknown. To unravel the role of mucosal humoral immunity in CD pathogenesis, we in-depth phenotype colonic plasma cell (PC) differentiation in CD at the single-cell level, linked to ex vivo functional characterization and experimental mouse models with a congenital mitochondrial defect or under glucose-free high-protein dietary intervention. Here, we demonstrate that despite expanded colonic B cells, CD patients in remission present significantly diminished mucosal dimeric IgA and fecal SIgA. Colonic plasmablasts and immature CD19<sup>+</sup>CD45<sup>+</sup> PCs are increased at the expense of the mature CD19<sup>-</sup>CD45<sup>-</sup> phenotype. Accordingly, CD-derived ex vivo differentiated PCs display impaired maturation into dimeric IgA-secreting PCs. In this study, patient-derived data from colonic RNA-seq, spatial single-cell proteomics, and plasma metabolomics are combined with data from both mouse models and highlight the crucial role of mitochondrial oxidative phosphorylation in colonic IgA<sup>+</sup>-PC differentiation, suggesting promising directions for future therapeutic strategies.</p>

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Colonic spatial single-cell proteomics and murine models link mitochondrial dysfunction to dimeric IgA-secreting plasma cell deficiency in Crohn’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • Annika Raschdorf,
  • Larissa Nogueira de Almeida,
  • Philipp Solbach,
  • Martha M. Kirstein,
  • Jens U. Marquardt,
  • Franziska Schmelter,
  • Ulrich L. Günther,
  • Heidi Schlichting,
  • Maren Hicken,
  • Lea Christiansen,
  • Miriam Wiestler,
  • Hauke C. Tews,
  • Dominik Bettenworth,
  • Alexander Katalinic,
  • Martina Oberländer,
  • Ruth Deck,
  • Holger Sültmann,
  • Nikolas von Bubnoff,
  • Tobias Hutzenlaub,
  • Peter Jülg,
  • Dominik Burziwoda,
  • Matthias Peipp,
  • Thomas Valerius,
  • Mohab Ragab,
  • Thorben Sauer,
  • Timo Gemoll,
  • Marc Ehlers,
  • Philip Rosenstiel,
  • Rudolf A. Manz,
  • Axel Künstner,
  • Hauke Busch,
  • Christian Sina,
  • Stefanie Derer

摘要

Secretory IgA (SIgA) is critical for maintaining the intestinal barrier. A dysregulated B-cell compartment and altered Ig secretion have been well documented in Crohn’s disease (CD) patients, although their origin is unknown. To unravel the role of mucosal humoral immunity in CD pathogenesis, we in-depth phenotype colonic plasma cell (PC) differentiation in CD at the single-cell level, linked to ex vivo functional characterization and experimental mouse models with a congenital mitochondrial defect or under glucose-free high-protein dietary intervention. Here, we demonstrate that despite expanded colonic B cells, CD patients in remission present significantly diminished mucosal dimeric IgA and fecal SIgA. Colonic plasmablasts and immature CD19+CD45+ PCs are increased at the expense of the mature CD19-CD45- phenotype. Accordingly, CD-derived ex vivo differentiated PCs display impaired maturation into dimeric IgA-secreting PCs. In this study, patient-derived data from colonic RNA-seq, spatial single-cell proteomics, and plasma metabolomics are combined with data from both mouse models and highlight the crucial role of mitochondrial oxidative phosphorylation in colonic IgA+-PC differentiation, suggesting promising directions for future therapeutic strategies.