Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2
| العنوان: | Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2 |
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| المؤلفون: | Tina Nguyen, Anthony Lau, Julia Bier, Kristen C. Cooke, Helen Lenthall, Stephanie Ruiz-Diaz, Danielle T. Avery, Henry Brigden, David Zahra, William A Sewell, Luke Droney, Satoshi Okada, Takaki Asano, Hassan Abolhassani, Zahra Chavoshzadeh, Roshini S. Abraham, Nipunie Rajapakse, Eric W. Klee, Joseph A. Church, Andrew Williams, Melanie Wong, Christoph Burkhart, Gulbu Uzel, David R. Croucher, David E. James, Cindy S. Ma, Robert Brink, Stuart G. Tangye, Elissa K. Deenick |
| المصدر: | Journal of Experimental Medicine. 220 |
| بيانات النشر: | Rockefeller University Press, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Immunology, Immunology and Allergy |
| الوصف: | Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients’ immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies. |
| تدمد: | 1540-9538 0022-1007 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::94dc53e894f25928d46f491829022051 https://doi.org/10.1084/jem.20221020 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........94dc53e894f25928d46f491829022051 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15409538 00221007 |
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