Erlich Emma C, Alayo Quazim A, Kim Ayoung, Han Jichang, Mintz Rachel L, Huckstep Christopher G, Ruiz Heather S, Field Rachael L, Dunning Taylor J, Saleh Leila S, Hoofnagle Mark H, Tumanov Alexei V, Guilak Farshid, Brestoff Jonathan R, Czepielewski Rafael S, Randolph Gwendalyn J
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Division of Biological and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
Nat Immunol. 2025 Sep 8. doi: 10.1038/s41590-025-02263-y.
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.
克罗恩病的病理过程在肿瘤坏死因子（TNF）过表达的小鼠中建模，TNF通过TNF受体驱动疾病发展。TNF受体的另一种配体，可溶性淋巴毒素α（LTα），由B细胞产生，但很少受到关注，因为LTα也与淋巴毒素β（LTβ）结合形成膜结合的LTαβ，后者促进三级淋巴组织形成——这是克罗恩病的另一个特征。我们推测B细胞来源的LTαβ对TNF小鼠的回肠炎有关键影响。然而，虽然在B细胞中删除LTβ对三级淋巴组织形成至关重要，但疾病病理受到的影响最小。相比之下，B细胞来源的LTα缺失会增加肠道通透性，减少回肠IgA浆细胞池，升高细胞因子水平并导致体重减轻，包括肌肉量减少——这是克罗恩病的一个全身特征。针对LTα的中和抗体强烈增强了TNF的恶病质样效应。因此，B细胞产生的LTαβ和LTα在回肠炎中具有不同作用，其中LTα的作用出人意料地具有保护作用，可通过抵消TNF来实现。
