Science translational medicine · 2025
Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.