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

Abstract

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 proliferationinducing ligand, and secretion of IgG and IgA by ligandactivated 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; EspañaFil: Radigan, Lin. Mount Sinai School of Medicine. Departament of Medicine; Estados UnidosFil: Almejún, María Belén. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Servicio de Inmunolog ía y Reumatolog ía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mart ınez Pomar, Natalia. Son Espases University Hospital. Servei d’ Immunolog ia; EspañaFil: Matamoros, Nuria. Son Espases University Hospital. Servei d’ Immunolog ia; EspañaFil: 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 Unido