Artículo
CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses
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
Fecha de publicación:
10/2022
Editorial:
Springer/Plenum Publishers
Revista:
Journal of Clinical Immunology
ISSN:
0271-9142
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(CCT - PATAGONIA NORTE)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - PATAGONIA NORTE
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - PATAGONIA NORTE
Citación
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
Compartir
Altmétricas