Mucosal deficiency of mitochondria-driven humoral immunity is linked to Crohn’s Disease Article Swipe

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Annika Raschdorf , Larissa N. Almeida , Philipp Solbach , Martha M. Kirstein , Jens U. Marquardt , Franziska Schmelter , Ulrich Günther , Heidi Schlichting , Maren Hicken , Lea Christiansen , Miriam Wiestler , Hauke Christian Tews , Dominik Bettenworth , OUTLIVE-CRC consortium , Mohab Ragab , Thorben Sauer , Timo Gemoll , Marc Ehlers , Philip Rosenstiel , Rudolf A. Manz , Axel Künstner , Hauke Busch , Christian Sina , Stefanie Derer ·

YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.21203/rs.3.rs-6463867/v1

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.

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Crohn's disease Immunity Humoral immunity Immunology Mitochondrion Disease Medicine Immune system Biology Internal medicine Genetics

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Type: preprint
Language: en
Landing Page: https://doi.org/10.21203/rs.3.rs-6463867/v1
PDF: https://www.researchsquare.com/article/rs-6463867/latest.pdf
OA Status: gold
Related Works: 10
OpenAlex ID: https://openalex.org/W4409712191

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DOI: https://doi.org/10.21203/rs.3.rs-6463867/v1

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Title: Mucosal deficiency of mitochondria-driven humoral immunity is linked to Crohn’s Disease

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Type: preprint

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Language: en

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Publication year: 2025

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Publication date: 2025-04-23

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Authors: Annika Raschdorf, Larissa N. Almeida, Philipp Solbach, Martha M. Kirstein, Jens U. Marquardt, Franziska Schmelter, Ulrich Günther, Heidi Schlichting, Maren Hicken, Lea Christiansen, Miriam Wiestler, Hauke Christian Tews, Dominik Bettenworth, OUTLIVE-CRC consortium, Mohab Ragab, Thorben Sauer, Timo Gemoll, Marc Ehlers, Philip Rosenstiel, Rudolf A. Manz, Axel Künstner, Hauke Busch, Christian Sina, Stefanie Derer

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Landing page: https://doi.org/10.21203/rs.3.rs-6463867/v1

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PDF URL: https://www.researchsquare.com/article/rs-6463867/latest.pdf

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Concepts: Crohn's disease, Immunity, Humoral immunity, Immunology, Mitochondrion, Disease, Medicine, Immune system, Biology, Internal medicine, Genetics

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countries_distinct_count	2
institutions_distinct_count	24
sustainable_development_goals[0].id	https://metadata.un.org/sdg/3
sustainable_development_goals[0].score	0.5899999737739563
sustainable_development_goals[0].display_name	Good health and well-being
citation_normalized_percentile.value	0.16040063
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	True