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| Item Type: | Article |
|---|---|
| Title: | Intergenic risk variant rs56258221 skews the fate of naive CD4(+) T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis |
| Creators Name: | Poch, T., Bahn, J., Casar, C., Krause, J., Evangelakos, I., Gilladi, H., Kunzmann, L.K., Laschtowitz, A., Iuso, N., Schäfer, A.M., Liebig, L.A., Steinmann, S., Sebode, M., Folseraas, T., Engesæter, L.K., Karlsen, T.H., Franke, A., Hubner, N., Schlein, C., Galun, E., Huber, S., Lohse, A.W., Gagliani, N., Schwinge, D. and Schramm, C. |
| Abstract: | Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4(+) T (CD4(+) T(N) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4(+) T(N) is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases. |
| Keywords: | Primary Sclerosing Cholangitis, Immune-Mediated Liver Disease, Genetic Polymorphism, CD4 T Cells, Naive T Cells, TH17 Cells, Regulatory T Cells, BACH2, MiR4464 |
| Source: | Cell Reports Medicine |
| ISSN: | 2666-3791 |
| Publisher: | Elsevier / Cell Press |
| Volume: | 5 |
| Number: | 7 |
| Page Range: | 101620 |
| Date: | 16 July 2024 |
| Official Publication: | https://doi.org/10.1016/j.xcrm.2024.101620 |
| PubMed: | View item in PubMed |
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