| Autor: |
Maria Elena Maccari, Pascal Schneider, Cristian Roberto Smulski, Andrea Meinhardt, Fernando Pinto, Luis Ignacio Gonzalez-Granado, Catharina Schuetz, Mauricio Pablo Sica, Miriam Gross, Ilka Fuchs, Patrick Kury, Maximilian Heeg, Tatjana Vocat, Laure Willen, Caroline Thomas, Regina Hühn, Aude Magerus, Myriam Lorenz, Klaus Schwarz, Frederic Rieux-Laucat, Stephan Ehl, Anne Rensing-Ehl |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
The Journal of allergy and clinical immunology. |
| ISSN: |
1097-6825 |
| Popis: |
Fas ligand (FasL) is expressed by activated T cells and induces death in target cells upon binding to Fas. Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers. While most ALPS patients carry heterozygous FAS mutations, FASLG mutations are rare and usually biallelic. Only two heterozygous variants were reported, associated with an atypical clinical phenotype.Revisit the significance of heterozygous FASLG mutations as a cause of ALPS.Clinical features and biomarkers were analysed in 24 individuals with homozygous or heterozygous FASLG variants predicted to be deleterious. Cytotoxicity assays were performed with patient T cells and biochemical assays with recombinant FasL.Homozygous FASLG variants abrogated cytotoxicity and resulted in early-onset severe ALPS with elevated DNT, raised Vitamin B12 and usually no soluble FasL. In contrast, heterozygous variants impacted FasL function by reducing expression, impairing trimerization or preventing Fas-binding. However, they were not associated with elevated DNT and Vitamin B12 and did not affect FasL-mediated cytotoxicity. The dominant negative effects of previously published variants could not be confirmed. Even Y166C, causing loss of Fas-binding with a dominant-negative effect in biochemical assays, did not impair cellular cytotoxicity nor caused Vitamin B12 and DNT elevation.Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG.Based on current evidence, none of the reported heterozygous FASLG mutations can be claimed to cause an inborn error of immunity. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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