Mucosal deficiency of mitochondria-driven humoral immunity is linked to 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 phenotyped colonic plasma cell (PC) differentiation in CD at the single-cell level, linked to ex vivo functional characterization and experimental mouse models. Despite expanded colonic B cells, CD patients in remission presented significantly diminished mucosal dimeric IgA and fecal SIgA. Colonic plasmablasts and immature CD19 ⁺ CD45 ⁺ PCs were increased at the expense of the mature CD19 ^- CD45 ^- phenotype. Accordingly, CD-derived ex vivo differentiated PCs displayed impaired maturation into IgA-secreting PCs. Patient-derived data from colonic RNA-seq, spatial single-cell proteomics, and NMR-metabolomics were combined with data from two mouse models and highlighted the crucial role of mitochondria function in colonic IgA ⁺ -PC differentiation, suggesting promising directions for future therapeutic strategies.