携带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。

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

作者信息

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

机构信息

Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.

School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Sydney, NSW 2052, Australia.

出版信息

Sci Transl Med. 2025 May 14;17(798):eadp6812. doi: 10.1126/scitranslmed.adp6812.

DOI:10.1126/scitranslmed.adp6812

PMID:40367192

Abstract

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 , , and 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.

摘要

尽管采用无麸质饮食，乳糜泻患者中的一部分人肠道炎症仍会持续。在此，通过对十二指肠活检样本进行多组学单细胞分析，我们发现，2型难治性乳糜泻（RCD2）患者中带有淋巴瘤驱动突变的低度恶性肿瘤由表面CD3阴性（sCD3）淋巴细胞构成，这些淋巴细胞停滞在一个先天性淋巴细胞（ILC）-祖T细胞阶段，正在经历广泛的、和TCR重组。在1型难治性乳糜泻（RCD1）患者中（这是一种目前尚无合理解释的疾病），我们在10名RCD1患者中的6名以及1名新近诊断出的活动性乳糜泻患者中鉴定出了带有淋巴瘤驱动突变的sCD3 T细胞。此外，突变T细胞形成了大的TCRαβ克隆，并呈现出炎症性和细胞毒性分子特征。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。