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

## TL;DR

This study shows that mitochondrial dysfunction in Crohn’s disease patients leads to reduced dimeric IgA production by plasma cells in the colon.

## Contribution

The study links mitochondrial dysfunction to impaired IgA-secreting plasma cell differentiation in Crohn’s disease using single-cell proteomics and mouse models.

## Key findings

- CD patients in remission have significantly reduced mucosal dimeric IgA and fecal SIgA.
- CD-derived plasma cells show impaired maturation into dimeric IgA-secreting cells.
- Mitochondrial oxidative phosphorylation is crucial for colonic IgA+-PC differentiation.

## Abstract

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.

Crohn’s disease is associated with disturbances in the B-cell compartment and secreted antibodies. Here, the authors reveal impaired colonic dimeric IgA responses in patients with Crohn’s disease and verify this phenotype in murine models, demonstrating that mitochondrial dysfunction drives defective mucosal humoral immunity.