DOP030 Mucosal deficiency of mitochondria-driven humoral immunity is linked to Crohn’s Disease
Authors: Raschdorf A , Nogueira de Almeida L , Solbach P , Kirstein M M , Schmelter F , Schlichting H , Hicken M , Christiansen L , Wiestler M , Tews H C , Bettenworth D ,   CRC. Outlive-Consortium, Ragab M , Ibrahim S M , Hirose M , Sauer T , Gemoll T , Ehlers M , Manz R A , Künstner A , Busch H , Marquardt J U , Sina C , Derer S 
Published: January 2025

Abstract

Background
Secretory IgA (sIgA) is critical for the maintenance of the mucosal barrier function, preventing bacterial translocation and reducing the risk of chronic inflammation. Several decades of research have revealed a dysregulation of the B-cell compartment in inflammatory bowel disease (IBD) of yet unknown origin1,2. While increased serum levels of (auto)antibodies against S. cerevisiae or the intestinal M-cell expressed FimH receptor glycoprotein 2 (GP2) are observed in patients with Crohn’s disease (CD)3, some studies indicated an impaired generation of intestinal immunoglobulin-secreting plasma cells (PCs)4. To unravel the role of mucosal humoral immunity in CD pathogenesis, we aimed to provide an in-depth characterisation of colonic PC differentiation in patients with CD.

Methods
In-depth phenotyping of patients with CD in remission and non-IBD controls (hospitalised normals) was performed using multi-omics analyses (spatial single-cell proteomics, proteomics, metabolomics, and transcriptomics) of plasma or colon biopsy samples. Colonic switched memory B cells (sMBCs) were sorted from lamina propria mononuclear cells (LPMNCs) by magnetic-activated cell sorting and ex vivo differentiated into PCs. The impact of mitochondrial function on colonic PC maturation was studied in mitochondrial respiratory chain complex V-deficient ATP8 mutant mice and mice that underwent nutritional intervention.

Results
Despite a hyperactive colonic B-cell compartment, patients with CD displayed significantly diminished mucosal dimeric IgA (dIgA) and fecal IgA compared to non-IBD controls. Polymeric immunoglobulin receptor (PIGR) expression did not differ, excluding a defective epithelial transcytosis of dIgA. Spatial single-cell proteomics uncovered that colonic plasmablasts and immature CD19+CD45+ PCs were increased at the expense of the fully mature CD19-CD45- phenotype. Consistently, PCs generated ex vivo from CD-derived sMBCs revealed impaired capacity to differentiate into IgA-secreting PCs. Metabolic phenotyping indicated a colonic mitochondrial dysfunction in patients with CD that was also reflected in colonic PCs by increased expression of the cell-surface NADase CD38 in concert with decreased expression of mitochondrially encoded transcripts. Of note, splenic PCs isolated from ATP8 mutant mice displayed a hyperproliferative and low-differentiated phenotype, while colonic IgA-secreting PCs were reduced. Conversely, feeding mice an isocaloric glucose-free, high-protein diet, which promotes mitochondrial activity, increased colonic IgA levels.

Conclusion
In summary, this study links mitochondrial dysfunction to impaired PC differentiation in patients with CD, resulting in reduced levels of sIgA and thereby compromised mucosal barrier integrity.

References
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2. Uzzan M, Martin JC, Mesin L, et al. Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nat Med. 2022;28(4):766-779. doi:10.1038/s41591-022-01680-y.
3. Derer S, Brethack AK, Pietsch C, et al. Inflammatory bowel disease-associated GP2 autoantibodies inhibit mucosal immune response to adherent-invasive bacteria. Inflamm Bowel Dis. 2020;26(12):1856-1868. doi:10.1093/ibd/izaa069.
4. MacDermott RP, Nash GS, Bertovich MJ, et al. Altered patterns of secretion of monomeric IgA and IgA subclass 1 by intestinal mononuclear cells in inflammatory bowel disease. Gastroenterology. 1986;91:379-85. doi:10.1016/0016-5085(86)90572-x.