Colonic spatial single-cell proteomics and murine models link mitochondrial dysfunction to dimeric IgA-secreting plasma cell deficiency in Crohn’s disease
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.
Authors
- Matthias Peipp (ORCID: https://orcid.org/0000-0002-5088-3804)
- Hauke Christian Tews (ORCID: https://orcid.org/0009-0001-1068-2151)
- Martina Oberländer
- Dominik Burziwoda
- Rudolf A. Manz (ORCID: https://orcid.org/0000-0003-1263-7693)
- Peter Jülg
- Philipp Solbach (ORCID: https://orcid.org/0000-0003-2708-3611)
- Larissa N. Almeida (ORCID: https://orcid.org/0000-0003-2974-433X)
- Annika Raschdorf
- Franziska Schmelter (ORCID: https://orcid.org/0009-0009-0649-675X)
- Martha M. Kirstein (ORCID: https://orcid.org/0000-0001-9415-4083)
- Alexander Katalinic (ORCID: https://orcid.org/0000-0003-0490-1554)
- Heidi Schlichting
- Thomas Valerius (ORCID: https://orcid.org/0000-0001-9181-8067)
- Tobias Hutzenlaub (ORCID: https://orcid.org/0000-0001-6554-0604)
- Dominik Bettenworth (ORCID: https://orcid.org/0000-0002-1435-4825)
- Timo Gemoll
- Jens U. Marquardt (ORCID: https://orcid.org/0000-0002-8314-2682)
- Ruth Deck
- Maren Hicken
- Miriam Wiestler
- Stefanie Derer
- Marc Ehlers
- Mohab Ragab
- Christian Sina
- Axel Künstner
- Philip Rosenstiel
- Hauke Busch
- Ulrich L. Günther
- Nikolas von Bubnoff
- Holger Sültmann
- Lea Christiansen
- Thorben Sauer
Institutions
- University of Münster (DE)
- TUM Klinikum (DE)
- University Hospital Regensburg (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Medizinische Hochschule Hannover (DE)
- Universitäres Kinderwunschzentrum Lübeck (DE)
- University Hospital Schleswig-Holstein (DE)
- Technical University of Applied Sciences Lübeck (DE)
- German Center for Lung Research (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-12
- DOI
- https://doi.org/10.1038/s41467-026-69069-w
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00