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Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations

Maccari, Maria Elena ; Schneider, Pascal ; Smulski, Cristian Roberto ; Meinhardt, Andrea ; Pinto, Fernando ; Gonzalez-Granado, Luis Ignacio ; Schuetz, Catharina ; Sica, Mauricio Pablo ; Gross, Miriam ; Fuchs, Ilka ; Kury, Patrick ; Heeg, Maximilian ; Vocat, Tatjana ; Willen, Laure ; Thomas, Caroline ; Hühn, Regina ; Magerus, Aude ; Lorenz, Myriam ; Schwarz, Klaus ; Rieux-Laucat, Frederic ; Ehl, Stephan ; Rensing-Ehl, Anne

Journal of allergy and clinical immunology, 2023-05, Vol.151 (5), p.1391-1401.e7 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
Autor: Maccari, Maria Elena ; Schneider, Pascal ; Smulski, Cristian Roberto ; Meinhardt, Andrea ; Pinto, Fernando ; Gonzalez-Granado, Luis Ignacio ; Schuetz, Catharina ; Sica, Mauricio Pablo ; Gross, Miriam ; Fuchs, Ilka ; Kury, Patrick ; Heeg, Maximilian ; Vocat, Tatjana ; Willen, Laure ; Thomas, Caroline ; Hühn, Regina ; Magerus, Aude ; Lorenz, Myriam ; Schwarz, Klaus ; Rieux-Laucat, Frederic ; Ehl, Stephan ; Rensing-Ehl, Anne
Assuntos: apoptosis ; Apoptosis - genetics ; Autoimmune lymphoproliferative syndrome ; Autoimmune Lymphoproliferative Syndrome - genetics ; Biomarkers ; Fas ; Fas ligand ; Fas Ligand Protein - genetics ; fas Receptor - genetics ; Humans ; inborn error of immunity ; Mutation ; Vitamins
É parte de: Journal of allergy and clinical immunology, 2023-05, Vol.151 (5), p.1391-1401.e7
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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. We revisited the significance of heterozygous FASLG mutations as a cause of ALPS. 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. 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. Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations

United States: Elsevier Inc

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