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

Background Heterozygous C104R or A181E TNF receptor superfamily member 13b ( TNFRSF13B ) mutations impair removal of autoreactive B cells, weaken B-cellactivation, and convey to patients with common variable immune deficiency (CVID) an increased risk for autoimmunity. How mutant transmembrane activatorand 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 haploinsufficiencyby 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. MethodsWe tested the reactivity of antibodies isolated from single B cellsfrom 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 haploinsufficiencyin naive and memory B cellsand 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-celltolerance 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-celltolerance. 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 hemizygositydoes not recapitulate autoimmune features of CVID-associated C104R and A181E TNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACI haploinsufficiencyat later stages of B-celldevelopment.