CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses

Autores
Block, Violeta; Sevdali, Eirini; Recher, Mike; Abolhassani, Hassan; Hammarstrom, Lennart; Smulski, Cristian Roberto; Baronio, Manuela; Plebani, Alessandro; Proietti, Michele; Speletas, Matthaios; Warnatz, Klaus; Voll, Reinhard E.; Lougaris, Vassilios; Schneider, Pascal; Eibel, Hermann
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Purpose: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding. Methods: In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt’s lymphoma cells and analyzed for their impacts on BAFFR function. Results: Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R. Conclusion: Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID.
Fil: Block, Violeta. Albert Ludwigs University of Freiburg; Alemania
Fil: Sevdali, Eirini. Albert Ludwigs University of Freiburg; Alemania
Fil: Recher, Mike. Universitat Basel; Suiza
Fil: Abolhassani, Hassan. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia. Research Center For Immunodeficiencies; Irán
Fil: Hammarstrom, Lennart. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia
Fil: Smulski, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Albert Ludwigs University of Freiburg; Alemania
Fil: Baronio, Manuela. Università Degli Studi Di Brescia; Italia
Fil: Plebani, Alessandro. Università Degli Studi Di Brescia; Italia
Fil: Proietti, Michele. Albert Ludwigs University of Freiburg; Alemania
Fil: Speletas, Matthaios. University of Thessaly; Grecia
Fil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; Alemania
Fil: Voll, Reinhard E.. Albert Ludwigs University of Freiburg; Alemania
Fil: Lougaris, Vassilios. Università Degli Studi Di Brescia; Italia
Fil: Schneider, Pascal. Universite de Lausanne; Suiza
Fil: Eibel, Hermann. Albert Ludwigs University of Freiburg; Alemania
Materia
BAFF
BAFFR
CVID
NF-KB2
PI3K
SNVS
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:11336/218163
Acceder
id CONICETDig_c0ba252dc6751e7f906fa8b6bb1ed394
oai_identifier_str oai:ri.conicet.gov.ar:11336/218163
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling ResponsesBlock, VioletaSevdali, EiriniRecher, MikeAbolhassani, HassanHammarstrom, LennartSmulski, Cristian RobertoBaronio, ManuelaPlebani, AlessandroProietti, MicheleSpeletas, MatthaiosWarnatz, KlausVoll, Reinhard E.Lougaris, VassiliosSchneider, PascalEibel, HermannBAFFBAFFRCVIDNF-KB2PI3KSNVShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Purpose: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding. Methods: In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt’s lymphoma cells and analyzed for their impacts on BAFFR function. Results: Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R. Conclusion: Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID.Fil: Block, Violeta. Albert Ludwigs University of Freiburg; AlemaniaFil: Sevdali, Eirini. Albert Ludwigs University of Freiburg; AlemaniaFil: Recher, Mike. Universitat Basel; SuizaFil: Abolhassani, Hassan. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia. Research Center For Immunodeficiencies; IránFil: Hammarstrom, Lennart. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Smulski, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Albert Ludwigs University of Freiburg; AlemaniaFil: Baronio, Manuela. Università Degli Studi Di Brescia; ItaliaFil: Plebani, Alessandro. Università Degli Studi Di Brescia; ItaliaFil: Proietti, Michele. Albert Ludwigs University of Freiburg; AlemaniaFil: Speletas, Matthaios. University of Thessaly; GreciaFil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; AlemaniaFil: Voll, Reinhard E.. Albert Ludwigs University of Freiburg; AlemaniaFil: Lougaris, Vassilios. Università Degli Studi Di Brescia; ItaliaFil: Schneider, Pascal. Universite de Lausanne; SuizaFil: Eibel, Hermann. Albert Ludwigs University of Freiburg; AlemaniaSpringer/Plenum Publishers2022-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/218163Block, Violeta; Sevdali, Eirini; Recher, Mike; Abolhassani, Hassan; Hammarstrom, Lennart; et al.; CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses; Springer/Plenum Publishers; Journal of Clinical Immunology; 43; 2; 10-2022; 391-4050271-9142CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1007/s10875-022-01378-3info:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007/s10875-022-01378-3info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:37:42Zoai:ri.conicet.gov.ar:11336/218163instacron: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 10:37:42.918CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
title CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
spellingShingle CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
Block, Violeta
BAFF
BAFFR
CVID
NF-KB2
PI3K
SNVS
title_short CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
title_full CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
title_fullStr CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
title_full_unstemmed CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
title_sort CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
dc.creator.none.fl_str_mv Block, Violeta
Sevdali, Eirini
Recher, Mike
Abolhassani, Hassan
Hammarstrom, Lennart
Smulski, Cristian Roberto
Baronio, Manuela
Plebani, Alessandro
Proietti, Michele
Speletas, Matthaios
Warnatz, Klaus
Voll, Reinhard E.
Lougaris, Vassilios
Schneider, Pascal
Eibel, Hermann
author Block, Violeta
author_facet Block, Violeta
Sevdali, Eirini
Recher, Mike
Abolhassani, Hassan
Hammarstrom, Lennart
Smulski, Cristian Roberto
Baronio, Manuela
Plebani, Alessandro
Proietti, Michele
Speletas, Matthaios
Warnatz, Klaus
Voll, Reinhard E.
Lougaris, Vassilios
Schneider, Pascal
Eibel, Hermann
author_role author
author2 Sevdali, Eirini
Recher, Mike
Abolhassani, Hassan
Hammarstrom, Lennart
Smulski, Cristian Roberto
Baronio, Manuela
Plebani, Alessandro
Proietti, Michele
Speletas, Matthaios
Warnatz, Klaus
Voll, Reinhard E.
Lougaris, Vassilios
Schneider, Pascal
Eibel, Hermann
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BAFF
BAFFR
CVID
NF-KB2
PI3K
SNVS
topic BAFF
BAFFR
CVID
NF-KB2
PI3K
SNVS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Purpose: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding. Methods: In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt’s lymphoma cells and analyzed for their impacts on BAFFR function. Results: Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R. Conclusion: Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID.
Fil: Block, Violeta. Albert Ludwigs University of Freiburg; Alemania
Fil: Sevdali, Eirini. Albert Ludwigs University of Freiburg; Alemania
Fil: Recher, Mike. Universitat Basel; Suiza
Fil: Abolhassani, Hassan. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia. Research Center For Immunodeficiencies; Irán
Fil: Hammarstrom, Lennart. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia
Fil: Smulski, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Albert Ludwigs University of Freiburg; Alemania
Fil: Baronio, Manuela. Università Degli Studi Di Brescia; Italia
Fil: Plebani, Alessandro. Università Degli Studi Di Brescia; Italia
Fil: Proietti, Michele. Albert Ludwigs University of Freiburg; Alemania
Fil: Speletas, Matthaios. University of Thessaly; Grecia
Fil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; Alemania
Fil: Voll, Reinhard E.. Albert Ludwigs University of Freiburg; Alemania
Fil: Lougaris, Vassilios. Università Degli Studi Di Brescia; Italia
Fil: Schneider, Pascal. Universite de Lausanne; Suiza
Fil: Eibel, Hermann. Albert Ludwigs University of Freiburg; Alemania
description Purpose: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding. Methods: In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt’s lymphoma cells and analyzed for their impacts on BAFFR function. Results: Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R. Conclusion: Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID.
publishDate 2022
dc.date.none.fl_str_mv 2022-10
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/11336/218163
Block, Violeta; Sevdali, Eirini; Recher, Mike; Abolhassani, Hassan; Hammarstrom, Lennart; et al.; CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses; Springer/Plenum Publishers; Journal of Clinical Immunology; 43; 2; 10-2022; 391-405
0271-9142
CONICET Digital
CONICET
url http://hdl.handle.net/11336/218163
identifier_str_mv Block, Violeta; Sevdali, Eirini; Recher, Mike; Abolhassani, Hassan; Hammarstrom, Lennart; et al.; CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses; Springer/Plenum Publishers; Journal of Clinical Immunology; 43; 2; 10-2022; 391-405
0271-9142
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1007/s10875-022-01378-3
info:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007/s10875-022-01378-3
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
dc.publisher.none.fl_str_mv Springer/Plenum Publishers
publisher.none.fl_str_mv Springer/Plenum Publishers
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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