Expanded T cell clones with lymphoma driver somatic mutations in refractory celiac disease
Abstract 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 extensiveTCRrecombination. 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.One-Sentence Summary Treatment refractory autoimmunity in celiac disease may be explained by dysregulated T cells and progenitors that have acquired lymphoma-driver mutations..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 25. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Singh, Mandeep [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.03.17.24304320 |
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| PPN (Katalog-ID): |
XBI042973910 |
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| 520 | |a Abstract 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 extensiveTCRrecombination. 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.One-Sentence Summary Treatment refractory autoimmunity in celiac disease may be explained by dysregulated T cells and progenitors that have acquired lymphoma-driver mutations. | ||
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