TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes

• Autores: Martinez Gallo, Monica; Radigan, Lin; Almejún, María Belén; Martınez Pomar, Natalia; Matamoros, Nuria; Cunningham Rundles, Charlotte
• Año de publicación: 2012
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Cvid; Taci; Hypogammaglobulinemia; Activation Induced Cytidine Deaminase
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Background: Mutations in the gene coding for the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) are found in 8% to 10% of subjects with common variable immunodeficiency (CVID). Although heterozygous mutations may coincide with immunodeficiency in a few families, most mutation-bearing relatives are not hypogammaglobulinemic. Thus, the role of TACI mutations in producing the immune defect remains unclear. Objective: This study examined the expression and function of TACI mutations in healthy heterozygous relatives. Methods: We examined the surface and intracellular expression of TACI protein in EBV-transformed B cells of patients and relatives with mutations in 7 families, binding of a proliferation-inducing ligand, and secretion of IgG and IgA by ligand-activated B cells. We tested whether Toll-like receptor 9 agonists increased TACI expression and whether an agonistic anti-TACI antibody could induce activation-induced cytidine deaminase mRNA in those with mutations. Results: Intracellular and extracellular TACI expression was defective for B cells of all subjects with mutations, including subjects with CVID and relatives. Although Toll-like receptor 9 triggering normally up-regulates B-cell TACI expression, this was defective for all subjects with mutations. Triggering TACI by an agonistic antibody showed loss of activation-induced cytidine deaminase mRNA induction in all mutation-bearing B cells. However, ligand-induced IgG and IgA production was normal for healthy relatives but not for subjects with CVID. Conclusion: Thus, B cells of relatives of subjects with CVID who have mutations in TACI but normal immune globulin levels still have detectable in vitro B-cell defects.
Fil: Martinez Gallo, Monica. Mount Sinai School of Medicine. Departament of Pediatrics; Estados Unidos. Mount Sinai School of Medicine. Immunology Institute; Estados Unidos. Hospital Universitari Vall d; España
Fil: Radigan, Lin. Mount Sinai School of Medicine. Departament of Medicine; Estados Unidos
Fil: Almejún, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Martınez Pomar, Natalia. Son Espases University Hospital. Servei d’ Immunologia; España
Fil: Matamoros, Nuria. Son Espases University Hospital. Servei d’ Immunologia; España
Fil: Cunningham Rundles, Charlotte. Mount Sinai School of Medicine. Departament of Medicine; Estados Unidos. Mount Sinai School of Medicine. Immunology Institute; Estados Unidos. Mount Sinai School of Medicine. Departament of Pediatrics; Estados Unidos