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<p>Crohn’s disease pathology is modeled in TNF<sup>ΔARE+/−</sup> mice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LTα<sub>3</sub>, is produced by B cells, but has received scarce attention because LTα also partners with LTβ to generate membrane-tethered LTαβ<sub>2</sub> that promotes tertiary lymphoid tissue—another feature of Crohn’s disease. We hypothesized that B cell-derived LTαβ<sub>2</sub> would critically affect ileitis in TNF<sup>ΔARE+/−</sup> 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<sup>+</sup> 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<sub>3</sub> strongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LTαβ<sub>2</sub> and LTα<sub>3</sub> have distinct roles in ileitis, with the role of LTα<sub>3</sub> unexpectedly protective through counterbalancing TNF.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月8日

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  • Emma C. Erlich,
  • Quazim A. Alayo,
  • Ayoung Kim,
  • Jichang Han,
  • Rachel L. Mintz,
  • Christopher G. Huckstep,
  • Heather S. Ruiz,
  • Rachael L. Field,
  • Taylor J. Dunning,
  • Leila S. Saleh,
  • Mark H. Hoofnagle,
  • Alexei V. Tumanov,
  • Farshid Guilak,
  • Jonathan R. Brestoff,
  • Rafael S. Czepielewski,
  • Gwendalyn J. Randolph

摘要

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.