华盛顿大学医学院Gwendalyn J. Randolph课题组取得一项新突破。他们研究出B细胞来源的LTα₃和LTα1β₂在TNF介导的回肠炎中的不同作用。这一研究成果于2025年9月8日发表在国际顶尖学术期刊《自然—免疫学》上。

研究团队假设B细胞来源的LTαβ₂会严重影响TNF^ΔARE+/-老鼠的回肠炎。

然而，在B细胞是三级淋巴组织所必需的，对疾病病理影响最小。相比之下，B细胞源性LTα增加了肠通透性，缩小了IgA⁺回肠浆细胞池，细胞因子升高，并促使体重减轻，包括细胞质量的减少——这是克罗恩病的系统性特征。LTα3中和抗体强烈增强了TNF的恶病质样作用。由此可见，B细胞产生的LTαβ₂和LTα₃在回肠炎中具有不同的作用，其中LTα₃通过平衡TNF发挥意想不到的保护作用。

据了解，克罗恩病病理模型见TNF^ΔARE+/-过量产生肿瘤坏死因子（TNF）的小鼠通过TNF受体驱动疾病。TNF受体的另一种配体，可溶性LTα₃，是B细胞产生的，因为LTα也与LTβ一起产生膜系住的LTαβ₂，促进三级淋巴组织-克罗恩病的另一个特征。

附：英文原文

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

Author: 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.

Issue&Volume: 2025-09-08

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 Bcells, 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 Bcell-derived LTαβ2 would critically affect ileitis in TNFΔARE+/ mice. However, whereas deleting LTβ in Bcells was essential for tertiary lymphoid tissue, disease pathology was minimally affected. By contrast, loss of Bcell-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, Bcell-produced LTαβ2 and LTα3 have distinct roles in ileitis, with the role of LTα3 unexpectedly protective through counterbalancing TNF.

DOI: 10.1038/s41590-025-02263-y

Source: https://www.nature.com/articles/s41590-025-02263-y