Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations - 04/05/23
Abstract |
Background |
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 2 heterozygous variants were reported, associated with an atypical clinical phenotype.
Objective |
We revisited the significance of heterozygous FASLG mutations as a cause of ALPS.
Methods |
Clinical features and biomarkers were analyzed 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.
Results |
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 affected FasL function by reducing expression, impairing trimerization, or preventing Fas binding. However, they were not associated with elevated DNT and vitamin B12, and they 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 or cause vitamin B12 and DNT elevation.
Conclusion |
Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG.
Le texte complet de cet article est disponible en PDF.Key words : Autoimmune lymphoproliferative syndrome, Fas ligand, Fas, inborn error of immunity, apoptosis
Abbreviations used : ALPS, BAFF, DNT, EGFP, FASLG, FasL, PE, SEC, sFasL, WT
Plan
| The first 2 authors contributed equally to this article, and both should be considered first author. The last 2 authors contributed equally to this article, and both should be considered senior author. |
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| This work was funded by the German Federal Ministry of Education and Research (grant BMBF-01-EO-0803 to the Center of Chronic Immunodeficiency and grant BMBF-01GM1111B to the PID-Net Initiative) and the Wilhelm Sander Stiftung (1-027-087-401). M.E.M. was supported by an EXCEL fellowship, Faculty of Medicine, University of Freiburg, funded by the Else-Kröner-Fresenius-Stiftung. P.S. is supported by the Swiss National Scientific Foundation (grants 31003A_176256 and 310030_205196). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 151 - N° 5
P. 1391 - mai 2023 Retour au numéro
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