具有淋巴瘤驱动体细胞突变的扩增T细胞克隆在难治性乳糜泻中积累

IF 15.8 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-05-14 DOI:10.1126/scitranslmed.adp6812

Mandeep Singh, Raymond H. Y. Louie, Jerome Samir, Matthew A. Field, Claire Milthorpe, Thiruni Adikari, Joseph Mackie, Ellise Roper, Megan Faulks, Katherine J. L. Jackson, Andrew Calcino, Melinda Y. Hardy, Piers Blombery, Timothy G. Amos, Ira W. Deveson, Helen Vander Wende, Stephen N. Floor, Scott A. Read, Dmitri Shek, Antoine Guerin, Cindy S. Ma, Stuart G. Tangye, Antonio Di Sabatino, Marco V. Lenti, Alessandra Pasini, Rachele Ciccocioppo, Golo Ahlenstiel, Dan Suan, Jason A. Tye-Din, Christopher C. Goodnow, Fabio Luciani

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引用次数: 0

摘要

尽管无麸质饮食，腹腔疾病患者的肠道炎症仍在继续。通过对十二指肠活检进行多组学单细胞分析，我们发现难治性乳糜泻2型（RCD2）患者的低级别恶性肿瘤伴淋巴瘤驱动突变是由表面cd3阴性（sCD3−）淋巴细胞组成的，这些淋巴细胞停滞在先天淋巴样细胞(ILC) -祖T细胞阶段，经历了广泛的TRA、TRB和TRD - TCR重组。在难治性乳糜泻1型（RCD1）患者（目前缺乏解释）中，我们在10名RCD1患者中的6名和一名最近诊断为活动性乳糜泻的患者中发现了sCD3+ T细胞淋巴瘤驱动突变。此外，突变T细胞形成大的TCRαβ克隆，并表现出炎症和细胞毒性分子谱。因此，淋巴瘤驱动突变的T细胞和sCD3 -祖细胞的积累可能导致慢性、无反应性乳糜泻。

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Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease

Intestinal inflammation continues in a subset of patients with celiac disease despite a gluten-free diet. Here, by applying multi-omic single-cell analysis to duodenal biopsies, we found that low-grade malignancies with lymphoma driver mutations in patients with refractory celiac disease type 2 (RCD2) are comprised by surface CD3-negative (sCD3⁻) lymphocytes stalled at an innate lymphoid cell (ILC)–progenitor T cell stage undergoing extensive TRA, TRB, and TRD TCR recombination. In people with refractory celiac disease type 1 (RCD1), a disease currently lacking explanation, we identified sCD3⁺ T cells with lymphoma driver mutations in 6 of 10 individuals with RCD1 and in one of the patients with active, recently diagnosed celiac disease. Furthermore, the mutant T cells formed large TCRαβ clones and displayed inflammatory and cytotoxic molecular profiles. Thus, accumulation of lymphoma driver–mutated T cells and sCD3⁻ progenitors may contribute to chronic, nonresponsive celiac disease.

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.