BAFF Blockade Attenuates B Cell MALT Formation in Conditional Nlrc5 ‐Deficient Mice With Helicobacter felis Infection

ABSTRACT Helicobacter infection is a key cause of gastric B cell mucosa–associated lymphoid tissue (MALT) lymphoma. This study examined the role of B cell–activating factor (BAFF), a major driver of B cell proliferation and many B cell disorders, in this malignancy using a model in which conditional knockout mice for NOD‐like receptor family CARD domain‐containing 5 ( Nlrc5 ) are infected with Helicobacter felis . Gastric BAFF production was significantly increased in H. felis –infected Nlrc5 mø‐KO mice compared to wild‐type. Blocking BAFF signalling, before or after the onset of Helicobacter ‐induced gastritis, significantly reduced MALT development, with fewer gastric B cell follicles and reduced gland hyperplasia. BAFF blockade also reshaped the immune cell landscape in the stomach, resulting in fewer CD4 + T cells, Tregs, macrophages and dendritic cells. Using a cell culture model, we identified the protein‐coding BAFF transcripts that are upregulated in NLRC5‐deficient macrophages stimulated with either H. felis or the NLRC5 agonist, lipopolysaccharide. Among the upregulated variants, TNFSF13B (BAFF)‐206 acts as a transcription factor and is reported to enhance BAFF production in autoimmune diseases and cancer. Altogether, these findings implicate the NLRC5–BAFF signalling axis in Helicobacter ‐induced B cell MALT lymphoma, highlighting BAFF inhibition as a potential therapeutic approach.