英国约翰雷德克里夫医院Paul Klenerman课题组报道了免疫-上皮-基质网络定义了腹腔疾病小肠的细胞生态系统。这一研究成果于2025年5月6日发表在国际顶尖学术期刊《自然—免疫学》上。

为了解决这个问题，研究组进行了单细胞转录组学(RNA测序；86,442个免疫细胞、实质细胞和上皮细胞；35名参与者)和空间转录组学（20名参与者）对CD肠道活检样本进行了研究。

本研究表明，在CD中，上皮细胞群向祖细胞状态转移，伴有干扰素驱动的转录反应，并扰乱分泌和肠内分泌细胞群。粘膜T细胞在调节性和滤泡辅助细胞样CD4⁺ T细胞、上皮内淋巴细胞、CD8⁺和γδ T细胞亚群中表现出数量和功能上的变化，T细胞抗原受体谱歪斜。尽管进行了治疗，粘膜变化仍可检测到，这代表了持续的免疫上皮“疤痕”。空间转录组学定义了传统组织学评分中捕获的转录利基，包括包含T细胞- B细胞相互作用的CD特异性淋巴细胞聚集体。结合疾病易感性基因表达的受体-配体空间分析确定了趋化因子和形态因子信号改变的网络，并为CD的预防和治疗提供了潜在的治疗靶点。

据悉，乳糜泻（CD）肠道损伤背后的免疫-上皮-基质相互作用尚不完全清楚。

附：英文原文

Title: Immune–epithelial–stromal networks define the cellular ecosystem of the small intestine in celiac disease

Author: FitzPatrick, Michael E. B., Antanaviciute, Agne, Dunstan, Melanie, Knnapuu, Karolina, Trzupek, Dominik, Provine, Nicholas M., Dooley, Kyla, Zhang, Jia-Yuan, Irwin, Sophie L., Garner, Lucy C., Pernes, Jane I., Ferreira, Ricardo C., Sasson, Sarah C., Aschenbrenner, Dominik, Agarwal, Devika, Rodrigues, Astor, Howarth, Lucy, Brain, Oliver, Ruane, Darren, Soilleux, Elizabeth, Teichmann, Sarah A., Dendrou, Calliope A., Simmons, Alison, Uhlig, Holm H., Todd, John A., Klenerman, Paul

Issue&Volume: 2025-05-06

Abstract: The immune–epithelial–stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4+ T cells, intraepithelial lymphocytes, CD8+ and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune–epithelial ‘scar’. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell–B cell interactions. Receptor–ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.

DOI: 10.1038/s41590-025-02146-2

Source: https://www.nature.com/articles/s41590-025-02146-2