Genome medicine · 2026
Multi-centered T cell repertoire profiling identifies alterations in the immune repertoire of individuals with inflammatory bowel disease across different disease stages.
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Mahdy Aya K H, ElAbd Hesham, Kokubun Érika Endo, Kriukova Valeriia, Pesesky Mitchell, May Damon H, Olbjørn Christine, Perminow Gøri, Bengtson May-Bente, Ricanek Petr, Andersen Svend, Detlie Trond Espen, Kristensen Vendel A, Moum Bjørn, Vatn Morten H, Jahnsen Jørgen, Bokemeyer Bernd, Hov Johannes Roksund, Halfvarson Jonas, Schreiber Stefan, Howie Bryan, Robins Harlan S, Høivik Marte Lie, Franke Andre, IBSEN-III study group
Аннотация
BACKGROUND: Inflammatory bowel disease (IBD) is an incurable immune-mediated inflammatory disease, affecting the gut with a high rate of primary- and secondary- loss-of-response to therapy. By investigating the T cell receptor repertoire of individuals with IBD, novel therapeutic and preventive strategies can be identified, and a better understanding of IBD can be obtained.
METHODS: To identify and validate T cell clonotypes implicated in the pathogenesis of IBD, we profiled the T cell receptor alpha (TRA) repertoire of three cohorts containing treatment-naive, treated individuals, and individuals living with the disease for >20 years, resulting in an exhaustive dataset containing the TRA repertoire of 1,732 individuals.
RESULTS: Using the generated datasets, we were able to replicate previous findings describing the expansion of Crohn's-associated invariant T (CAIT) cells in individuals with Crohn's disease (CD) in the three cohorts. Using a hypothesis-free statistical testing framework, we identified clonotypes that were associated with the disease at its different stages, e.g., at the time of diagnosis and decades post-diagnosis. By conducting a meta-analysis across the three cohorts, we were able to identify a set of clonotypes that were associated with the disease regardless of its stage. We validated our findings in a previously published independent test dataset from a German cohort, showing the robustness of the identified clonotypes.
CONCLUSIONS: The identified clonotypes are novel therapeutic targets to treat IBD, for example, through targeted depletion. By identifying antigens recognized by these T cells, a better understanding of the etiopathology of IBD, particularly CD, can be obtained.
METHODS: To identify and validate T cell clonotypes implicated in the pathogenesis of IBD, we profiled the T cell receptor alpha (TRA) repertoire of three cohorts containing treatment-naive, treated individuals, and individuals living with the disease for >20 years, resulting in an exhaustive dataset containing the TRA repertoire of 1,732 individuals.
RESULTS: Using the generated datasets, we were able to replicate previous findings describing the expansion of Crohn's-associated invariant T (CAIT) cells in individuals with Crohn's disease (CD) in the three cohorts. Using a hypothesis-free statistical testing framework, we identified clonotypes that were associated with the disease at its different stages, e.g., at the time of diagnosis and decades post-diagnosis. By conducting a meta-analysis across the three cohorts, we were able to identify a set of clonotypes that were associated with the disease regardless of its stage. We validated our findings in a previously published independent test dataset from a German cohort, showing the robustness of the identified clonotypes.
CONCLUSIONS: The identified clonotypes are novel therapeutic targets to treat IBD, for example, through targeted depletion. By identifying antigens recognized by these T cells, a better understanding of the etiopathology of IBD, particularly CD, can be obtained.