title: TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Martinez-Gallo
authors.forename: Lin
authors.initials: L
authors.lastname: Radigan
authors.forename: María Belén
authors.initials: MB
authors.lastname: Almejún
authors.forename: Natalia
authors.initials: N
authors.lastname: Martínez-Pomar
authors.forename: Núria
authors.initials: N
authors.lastname: Matamoros
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002648:Child; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006579:Heterozygote; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D055815:Young Adult; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000906:Antibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008024:Ligands; C495371:TLR9 protein, human; C108467:TNFRSF13B protein, human; C114631:TNFSF13 protein, human; D051217:Toll-Like Receptor 9; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase