Distinct roles for B cell-derived LTα3 and LTα1β2 in TNF-mediated ileitis.

Crohn's disease pathology is modeled in TNF mice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LTα, is produced by B cells, but has received scarce attention because LTα also partners with LTβ to generate membrane-tethered LTαβ that promotes tertiary lymphoid tissue-another feature of Crohn's disease. We hypothesized that B cell-derived LTαβ would critically affect ileitis in TNF 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 LTα strongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LTαβ and LTα have distinct roles in ileitis, with the role of LTα unexpectedly protective through counterbalancing TNF.