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

J Allergy Clin Immunol. 2015 Nov;136(5):1315-25. doi: 10.1016/j.jaci.2015.05.012. Epub 2015 Jun 19.

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.

Keywords: B-cell tolerance; Smith-Magenis syndrome; TNFRSF13B; common variable immune deficiency; transmembrane activator and CAML interactor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibody Formation / genetics
  • Autoimmunity
  • B-Lymphocytes / immunology*
  • Child
  • Common Variable Immunodeficiency / immunology*
  • Female
  • Haploinsufficiency
  • Hemizygote
  • Humans
  • Immunologic Memory
  • Lymphocyte Activation / genetics
  • Male
  • Middle Aged
  • Mutation, Missense / genetics
  • Smith-Magenis Syndrome / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Transmembrane Activator and CAML Interactor Protein / genetics
  • Transmembrane Activator and CAML Interactor Protein / metabolism*
  • Young Adult

Substances

  • TNFRSF13B protein, human
  • Transmembrane Activator and CAML Interactor Protein