Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations

Autores
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; Brieux Olivera, Amelia Carolina Marta; Ehl, Stephan; Rensing Ehl, Anne
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Maccari, Maria Elena. Albert Ludwigs University of Freiburg; Alemania
Fil: Schneider, Pascal. Universite de Lausanne; Suiza
Fil: Smulski, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina
Fil: Meinhardt, Andrea. University Hospital Giessen; Alemania
Fil: Pinto, Fernando. Royal Hospital for Children Glasgow; Reino Unido
Fil: Gonzalez Granado, Luis Ignacio. Universidad Complutense de Madrid; España
Fil: Schuetz, Catharina. University Hospital Carl Gustav Carus; Alemania
Fil: Sica, Mauricio Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Gerencia del área de Seguridad Nuclear y Ambiente. Instituto de Energía y Desarrollo Sustentable. Instituto de Energía y Desarrollo Sustentable - Sede Bariloche; Argentina
Fil: Gross, Miriam. Albert Ludwigs University of Freiburg; Alemania
Fil: Fuchs, Ilka. Albert Ludwigs University of Freiburg; Alemania
Fil: Kury, Patrick. Albert Ludwigs University of Freiburg; Alemania
Fil: Heeg, Maximilian. Albert Ludwigs University of Freiburg; Alemania
Fil: Vocat, Tatjana. Albert Ludwigs University of Freiburg; Alemania
Fil: Willen, Laure. Universite de Lausanne; Suiza
Fil: Thomas, Caroline. Universite de Nantes; Francia
Fil: Hühn, Regina. University Hospital Halle; Alemania
Fil: Magerus, Aude. Université Paris-Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases; Francia
Fil: Lorenz, Myriam. Universitat Ulm; Alemania
Fil: Schwarz, Klaus. Universitat Ulm; Alemania
Fil: Brieux Olivera, Amelia Carolina Marta. Université Paris-Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases; Francia
Fil: Ehl, Stephan. Albert Ludwigs University of Freiburg; Alemania
Fil: Rensing Ehl, Anne. Albert Ludwigs University of Freiburg; Alemania
Materia
APOPTOSIS
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME
FAS
FAS LIGAND
INBORN ERROR OF IMMUNITY
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/226006
Acceder
id CONICETDig_4815b4b50ca619b1df93c933d003116e
oai_identifier_str oai:ri.conicet.gov.ar:11336/226006
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutationsMaccari, Maria ElenaSchneider, PascalSmulski, Cristian RobertoMeinhardt, AndreaPinto, FernandoGonzalez Granado, Luis IgnacioSchuetz, CatharinaSica, Mauricio PabloGross, MiriamFuchs, IlkaKury, PatrickHeeg, MaximilianVocat, TatjanaWillen, LaureThomas, CarolineHühn, ReginaMagerus, AudeLorenz, MyriamSchwarz, KlausBrieux Olivera, Amelia Carolina MartaEhl, StephanRensing Ehl, AnneAPOPTOSISAUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROMEFASFAS LIGANDINBORN ERROR OF IMMUNITYhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: 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.Fil: Maccari, Maria Elena. Albert Ludwigs University of Freiburg; AlemaniaFil: Schneider, Pascal. Universite de Lausanne; SuizaFil: Smulski, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; ArgentinaFil: Meinhardt, Andrea. University Hospital Giessen; AlemaniaFil: Pinto, Fernando. Royal Hospital for Children Glasgow; Reino UnidoFil: Gonzalez Granado, Luis Ignacio. Universidad Complutense de Madrid; EspañaFil: Schuetz, Catharina. University Hospital Carl Gustav Carus; AlemaniaFil: Sica, Mauricio Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Gerencia del área de Seguridad Nuclear y Ambiente. Instituto de Energía y Desarrollo Sustentable. Instituto de Energía y Desarrollo Sustentable - Sede Bariloche; ArgentinaFil: Gross, Miriam. Albert Ludwigs University of Freiburg; AlemaniaFil: Fuchs, Ilka. Albert Ludwigs University of Freiburg; AlemaniaFil: Kury, Patrick. Albert Ludwigs University of Freiburg; AlemaniaFil: Heeg, Maximilian. Albert Ludwigs University of Freiburg; AlemaniaFil: Vocat, Tatjana. Albert Ludwigs University of Freiburg; AlemaniaFil: Willen, Laure. Universite de Lausanne; SuizaFil: Thomas, Caroline. Universite de Nantes; FranciaFil: Hühn, Regina. University Hospital Halle; AlemaniaFil: Magerus, Aude. Université Paris-Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases; FranciaFil: Lorenz, Myriam. Universitat Ulm; AlemaniaFil: Schwarz, Klaus. Universitat Ulm; AlemaniaFil: Brieux Olivera, Amelia Carolina Marta. Université Paris-Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases; FranciaFil: Ehl, Stephan. Albert Ludwigs University of Freiburg; AlemaniaFil: Rensing Ehl, Anne. Albert Ludwigs University of Freiburg; AlemaniaMosby-Elsevier2023-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/226006Maccari, Maria Elena; Schneider, Pascal; Smulski, Cristian Roberto; Meinhardt, Andrea; Pinto, Fernando; et al.; Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations; Mosby-Elsevier; Journal of Allergy and Clinical Immunology; 151; 5; 1-2023; 1391-14010091-67491085-8725CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.jacionline.org/article/S0091-6749(23)00001-5/info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jaci.2022.11.028info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:41:43Zoai:ri.conicet.gov.ar:11336/226006instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:41:43.914CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
title Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
spellingShingle Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
Maccari, Maria Elena
APOPTOSIS
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME
FAS
FAS LIGAND
INBORN ERROR OF IMMUNITY
title_short Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
title_full Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
title_fullStr Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
title_full_unstemmed Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
title_sort Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations
dc.creator.none.fl_str_mv 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
Brieux Olivera, Amelia Carolina Marta
Ehl, Stephan
Rensing Ehl, Anne
author Maccari, Maria Elena
author_facet 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
Brieux Olivera, Amelia Carolina Marta
Ehl, Stephan
Rensing Ehl, Anne
author_role author
author2 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
Brieux Olivera, Amelia Carolina Marta
Ehl, Stephan
Rensing Ehl, Anne
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv APOPTOSIS
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME
FAS
FAS LIGAND
INBORN ERROR OF IMMUNITY
topic APOPTOSIS
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME
FAS
FAS LIGAND
INBORN ERROR OF IMMUNITY
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Maccari, Maria Elena. Albert Ludwigs University of Freiburg; Alemania
Fil: Schneider, Pascal. Universite de Lausanne; Suiza
Fil: Smulski, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina
Fil: Meinhardt, Andrea. University Hospital Giessen; Alemania
Fil: Pinto, Fernando. Royal Hospital for Children Glasgow; Reino Unido
Fil: Gonzalez Granado, Luis Ignacio. Universidad Complutense de Madrid; España
Fil: Schuetz, Catharina. University Hospital Carl Gustav Carus; Alemania
Fil: Sica, Mauricio Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Gerencia del área de Seguridad Nuclear y Ambiente. Instituto de Energía y Desarrollo Sustentable. Instituto de Energía y Desarrollo Sustentable - Sede Bariloche; Argentina
Fil: Gross, Miriam. Albert Ludwigs University of Freiburg; Alemania
Fil: Fuchs, Ilka. Albert Ludwigs University of Freiburg; Alemania
Fil: Kury, Patrick. Albert Ludwigs University of Freiburg; Alemania
Fil: Heeg, Maximilian. Albert Ludwigs University of Freiburg; Alemania
Fil: Vocat, Tatjana. Albert Ludwigs University of Freiburg; Alemania
Fil: Willen, Laure. Universite de Lausanne; Suiza
Fil: Thomas, Caroline. Universite de Nantes; Francia
Fil: Hühn, Regina. University Hospital Halle; Alemania
Fil: Magerus, Aude. Université Paris-Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases; Francia
Fil: Lorenz, Myriam. Universitat Ulm; Alemania
Fil: Schwarz, Klaus. Universitat Ulm; Alemania
Fil: Brieux Olivera, Amelia Carolina Marta. Université Paris-Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases; Francia
Fil: Ehl, Stephan. Albert Ludwigs University of Freiburg; Alemania
Fil: Rensing Ehl, Anne. Albert Ludwigs University of Freiburg; Alemania
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/226006
Maccari, Maria Elena; Schneider, Pascal; Smulski, Cristian Roberto; Meinhardt, Andrea; Pinto, Fernando; et al.; Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations; Mosby-Elsevier; Journal of Allergy and Clinical Immunology; 151; 5; 1-2023; 1391-1401
0091-6749
1085-8725
CONICET Digital
CONICET
url http://hdl.handle.net/11336/226006
identifier_str_mv Maccari, Maria Elena; Schneider, Pascal; Smulski, Cristian Roberto; Meinhardt, Andrea; Pinto, Fernando; et al.; Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations; Mosby-Elsevier; Journal of Allergy and Clinical Immunology; 151; 5; 1-2023; 1391-1401
0091-6749
1085-8725
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.jacionline.org/article/S0091-6749(23)00001-5/
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jaci.2022.11.028
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Mosby-Elsevier
publisher.none.fl_str_mv Mosby-Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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