title: TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development.
abstract: BACKGROUND
  Heterozygous C104R or A181E TNF receptor superfamily member 13b (TNFRSF13B) mutations impair removal of autoreactive B cells, weaken B-cell activation, and convey to patients with common variable immune deficiency (CVID) an increased risk for autoimmunity. How mutant transmembrane activator and CAML interactor (TACI) influences wild-type TACI function is unclear; different models suggest either a dominant negative effect or haploinsufficiency.
  
  
  OBJECTIVE
  We investigated potential TACI haploinsufficiency by analyzing patients with antibody-deficient Smith-Magenis syndrome (SMS) who possess only 1 TNFRSF13B allele and antibody-deficient patients carrying one c.204insA TNFRSF13B null mutation.
  
  
  METHODS
  We tested the reactivity of antibodies isolated from single B cells from patients with SMS and patients with a c.204insA TNFRSF13B mutation and compared them with counterparts from patients with CVID with heterozygous C104R or A181E TNFRSF13B missense mutations. We also assessed whether loss of a TNFRSF13B allele induced haploinsufficiency in naive and memory B cells and recapitulated abnormal immunologic features typical of patients with CVID with heterozygous TNFRSF13B missense mutations.
  
  
  RESULTS
  We found that loss of a TNFRSF13B allele does not affect TACI expression, activation responses, or establishment of central B-cell tolerance in naive B cells. Additionally, patients with SMS and those with a c.204insA TNFRSF13B mutation display normal regulatory T-cell function and peripheral B-cell tolerance. The lack of a TNFRSF13B allele did result in decreased TACI expression on memory B cells, resulting in impaired activation and antibody secretion.
  
  
  CONCLUSIONS
  TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181E TNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACI haploinsufficiency at later stages of B-cell development.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Conn. Electronic address: neil.romberg@yale.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Romberg
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Conn.
authors.forename: Manmeet
authors.initials: M
authors.lastname: Virdee
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chamberlain
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Tyler
authors.initials: T
authors.lastname: Oe
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Conn.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Perkins
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Tineke
authors.initials: T
authors.lastname: Cantaert
authors.affiliation: Division of Immunology, Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Rima
authors.initials: R
authors.lastname: Rachid
authors.affiliation: Department of Pediatrics, University of Connecticut School of Medicine, Hartford, Conn.
authors.forename: Sally
authors.initials: S
authors.lastname: Rosengren
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Conn.
authors.forename: Regina
authors.initials: R
authors.lastname: Palazzo
authors.affiliation: Division of Immunology, Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Raif
authors.initials: R
authors.lastname: Geha
authors.affiliation: Department of Medicine, Mount Sinai Medical Center, New York, NY.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn. Electronic address: eric.meffre@yale.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000917:Antibody Formation / Q000235:genetics; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D005260:Female; D057895:Haploinsufficiency; D057898:Hemizygote; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D058496:Smith-Magenis Syndrome / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein
keywords: B-cell tolerance; Smith-Magenis syndrome; TNFRSF13B; common variable immune deficiency; transmembrane activator and CAML interactor