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

• Published in: Journal of allergy and clinical immunology 2015-11, Vol.136 (5), p.1315-1325
• Main Authors: Romberg, Neil, MD, Virdee, Manmeet, BS, Chamberlain, Nicolas, BS, Oe, Tyler, BA, Schickel, Jean-Nicolas, PhD, Perkins, Tiffany, MD, Cantaert, Tineke, PhD, Rachid, Rima, MD, Rosengren, Sally, MD, Palazzo, Regina, MD, Geha, Raif, MD, PhD, Cunningham-Rundles, Charlotte, MD, PhD, Meffre, Eric, PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Allergy and Immunology; Antibody Formation - genetics; Autoimmunity; B-cell tolerance; B-Lymphocytes - immunology; Cell growth; Child; common variable immune deficiency; Common Variable Immunodeficiency - immunology; Ear diseases; Female; Flow cytometry; Genes; Haploinsufficiency; Hemizygote; Humans; Immunologic Memory; Ligands; Lymphocyte Activation - genetics; Male; Medical research; Middle Aged; Mutation; Mutation, Missense - genetics; Smith-Magenis syndrome; Smith-Magenis Syndrome - immunology; Studies; T-Lymphocytes, Regulatory - immunology; TNFRSF13B; transmembrane activator and CAML interactor; Transmembrane Activator and CAML Interactor Protein - genetics; Transmembrane Activator and CAML Interactor Protein - metabolism; Young Adult
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.05.012

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.