Mandeep Singh, Raymond HY Louie, Jerome Samir, Matthew Field, Claire Milthorpe Milthorpe, Thiruni Adikari, Joseph Mackie, Ellise Roper, Megan Faulks, Katherine JL Jackson, Andrew Calcino, Melinda Y Hardy, Piers Blombery, Timothy G Amos, Ira W Deveson, Scott A Read, Dmitry Shek, Antoine Guerin, Cindy S Ma, Stuart G Tangye, Antonio Di Sabatino, Marco 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
尽管采用了无麸质饮食，但一部分乳糜泻（CD）患者的肠道炎症仍在持续。在这里，通过对十二指肠活检组织进行多组学单细胞分析，我们发现难治性 CD 2 型（RCD2）患者体内存在淋巴瘤驱动基因突变的低度恶性肿瘤，其中包括表面 CD3 阴性（sCD3-）淋巴细胞，它们停滞在先天性淋巴细胞（ILC）-祖先 T 细胞阶段，正在经历广泛的 TCR 重组。在目前无法解释的难治性 CD 1 型（RCD1）患者中，我们发现在 10 个个体中的 6 个中，有淋巴瘤驱动突变的 sCD3+ T 细胞形成了显示炎症和细胞毒性分子特征的大型克隆，而在 4 个近期诊断的活跃 CD 病例中，有 1 个是单一的小型克隆。驱动基因突变的T细胞及其sCD3-祖细胞的积累可以解释慢性、非反应性自身免疫。
Expanded T cell clones with lymphoma driver somatic mutations in refractory celiac disease
Intestinal inflammation continues in a subset of celiac disease (CD) patients despite a gluten-free diet. Here, by applying multiomic single cell analysis to duodenal biopsies, we find low-grade malignancies with lymphoma driver mutations in refractory CD type 2 (RCD2) patients comprise surface CD3 negative (sCD3-) lymphocytes stalled at an innate lymphoid cell (ILC) - progenitor T cell stage undergoing extensive TCR recombination. In people with refractory CD type 1 (RCD1), who currently lack explanation, we discover sCD3+ T cells with lymphoma driver mutations forming large clones displaying inflammatory and cytotoxic molecular profiles in 6 of 10 individuals, and a single small clone in 1 of 4 active recently diagnosed CD cases. Accumulation of driver-mutated T cells and their sCD3- progenitors may explain chronic, non-responsive autoimmunity.
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