Abstracts (complete list) - Wissenschaft Online

Ulrich Salzer, Chiara Bacchelli, Stephanie Jennings, Allesandro Plebani, Helen Chapel,
Hans D Ochs, Simon Urschel, Bernd H Belohradsky, H Bobby Gaspar, Bodo Grimbacher
Mutations in TACI/TNFRSF13b in patients with CVID – a
genetic, immunological and clinical study in a large patient
cohort
Background: TACI (TNFRSF13b) is an important regulator of B cell responses and
differentiation. We recently showed that TACI sequence variants are associated with
common variable immunodeficiency (CVID) and that some of these variants are present
in the general population at lower frequencies.
Results: We studied a cohort of 570 new CVID patients. 54 patients (9.5%) showed at
least one mutated TACI allele. 12 patients (22%) showed homozygous or compound
heterozygous (c.h.) mutations in TNFRSF13b, while most of the patients (n=42; 78%)
were heterozygous. 16 different mutations were identified, of which 13 have not been
described. TACI-C104R and A181E were the most frequent alleles (n=39; 72%), being
present also in about 2% of healthy controls, whereas their combined frequencies in
CVID were about 7%. Importantly, all of the variants seen in controls were
heterozygous and did not include frameshift or nonsense changes, which were exclusive
to the CVID population. Homozygous or c.h. mutated receptors did not bind the ligand
APRIL. Functional analysis of heterozygous TACI mutants implied that these may act
differently or are being compensated by the redundant system of BAFF/APRIL receptors.
Analysis of B cells in 31 TACI-deficient patients did not show a distinct B cell phenotype.
The patients presented with the full clinical spectrum of CVID. Autoimmunity was seen
in 11 of 39 patients (28%) and clinical signs of lymphoproliferation were present in 23
of 41 patients (56%).
Conclusions: TACI is a highly polymorphic gene, shows a complex pattern of sequence
variants and is mutated in 10% of CVID patients. While B cells with homozygous or c.h.
mutated TACI receptors showed specific functional defects, the role and significance of
heterozygous mutations is still unclear. In addition, the occurrence of heterozygous
TACI-C104R and A181E alleles in normal controls suggests that these variants act more
as disease modifiers rather than being disease causing in CVID. However, the
immunological and clinical phenotype of TACI-deficient patients was indistinguishable
from that of other CVID patients.
Supported by DFG SFB620/C2; NIH/NIAID: USIDnet grant # NO1-A1-30070 (B. G.),
the Primary Immunodeficiency Association and the Medical Research Council, UK (C.B.).