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
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引用次数: 0
Abstract
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.
期刊介绍:
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