2025/09/08 by Emma Erlich, Quazim A. Alayo, A‐Young Kim +13 · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · #IL-33, ST2, and ILC Pathways #Inflammatory Bowel Disease #Microscopic Colitis
paper · pdf · doi:10.1038/s41590-025-02263-y
openalex publication_date 2025/09/08 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/27
Crohn’s disease pathology is modeled in TNFΔARE+/− mice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LTα3, is produced by B cells, but has received scarce attention because LTα also partners with LTβ to generate membrane-tethered LTαβ2 that promotes tertiary lymphoid tissue—another feature of Crohn’s disease. We hypothesized that B cell-derived LTαβ2 would critically affect ileitis in TNFΔARE+/− mice. However, whereas deleting LTβ in B cells was essential for tertiary lymphoid tissue, disease pathology was minimally affected. By contrast, loss of B cell-derived LTα increased intestinal permeability, shrunk the pool of IgA+ ileal plasma cells, elevated cytokines and prompted weight loss, including loss of muscle mass—a systemic feature of Crohn’s disease. Neutralizing antibodies to LTα3 strongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LTαβ2 and LTα3 have distinct roles in ileitis, with the role of LTα3 unexpectedly protective through counterbalancing TNF. Erlich et al. show that soluble LTα and membrane-bound LTα1β2 lymphotoxins expressed by B cells play distinct roles to attenuate the pathology observed in ileitis.