title: The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency.
abstract: BACKGROUND
  TNFRSF13B, which encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), is mutated in 10% of patients with common variable immunodeficiency. One of the 2 most common TACI mutations in common variable immunodeficiency, C104R, abolishes ligand binding and is found predominantly in the heterozygous state. The murine TACI mutant C76R is the equivalent of the human TACI mutant C104R.
  
  
  OBJECTIVE
  We sought to define the consequence of the C76R mutation on TACI function in mice that express both wild-type TACI and the murine C76R mutant.
  
  
  METHODS
  Transgenic mice that express murine TACI C76R, the counterpart of human TACI C104R, on the TACI(+/-) B6/129 background (C76R/TACI(+/-) mice) were constructed. Serum immunoglobulins and antibody responses to the type II T-independent antigen trinitrophenylated (TNP)-Ficoll were determined by means of ELISA. B-cell proliferation in response to a proliferation-inducing ligand was determined based on tritiated thymidine incorporation into DNA. IgG1 secretion by B cells in response to a proliferation-inducing ligand plus IL-4 was determined by means of ELISA.
  
  
  RESULTS
  C76R/TACI(+/-) mice had significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll compared with TACI(+/+) B6/129 control animals, and their B cells were impaired in their capacity to proliferate and secrete IgG1 in response to TACI ligation. Unexpectedly, TACI(+/-) mice had similarly impaired B-cell function as C76R/TACI(+/-) littermates. Impaired TACI function caused by haploinsufficiency was confirmed in TACI(+/-) mice on the C57BL/6 background.
  
  
  CONCLUSIONS
  These results suggest that the human TACI mutant C104R might impair TACI function in heterozygotes through haploinsufficiency.
authors.affiliation: Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Haifa H
authors.initials: HH
authors.lastname: Jabara
authors.forename: Lilit
authors.initials: L
authors.lastname: Garibyan
authors.forename: Ingrid
authors.initials: I
authors.lastname: Rauter
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sannikova
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Dillon
authors.forename: Richard
authors.initials: R
authors.lastname: Bram
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology*; D005362:Ficoll / Q000031:analogs & derivatives / Q000276:immunology; D057895:Haploinsufficiency / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014301:Trinitrobenzenes / Q000276:immunology
chemical_list: D050505:Mutant Proteins; C020529:TNP-ficoll; C486361:Tnfrsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D014301:Trinitrobenzenes; D005362:Ficoll