TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development

Neil Romberg, Manmeet Virdee, Nicolas Chamberlain, Tyler Oe, Jean Nicolas Schickel, Tiffany Perkins, Tineke Cantaert, Rima Rachid, Sally Rosengren, Regina Palazzo, Raif Geha, Charlotte Cunningham-Rundles, Eric Meffre

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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. Conclusion 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.

Original languageEnglish
Pages (from-to)1315-1325
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Volume136
Issue number5
DOIs
StatePublished - Nov 2015

Keywords

  • B-cell tolerance
  • Smith-Magenis syndrome
  • TNFRSF13B
  • common variable immune deficiency
  • transmembrane activator and CAML interactor

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