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Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.
U Salzer1, H M Chapel, A D B Webster
1Division of Rheumatology and Clinical Immunology, Medical Center, University Hospital, Hugstetterstr. 55, 79106 Freiburg, Germany.
Nature Genetics
|July 12, 2005
Summary
Mutations in TNFRSF13B, encoding TACI, cause common variable immunodeficiency by impairing B-cell function. These genetic defects affect humoral immunity, leading to immune deficiencies in affected individuals.
Area of Science:
- Immunology
- Genetics
Background:
- B-cell survival and function depend on interactions between BAFF/APRIL and their receptors (BAFFR, TACI, BCMA).
- Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by impaired humoral immunity.
Purpose of the Study:
- To investigate the role of TNFRSF13B gene mutations in individuals with common variable immunodeficiency.
- To elucidate the functional consequences of TACI (transmembrane activator and cyclophilin ligand interactor) mutations on B-cell responses.
Main Methods:
- Candidate gene approach to identify mutations in TNFRSF13B.
- Analysis of mutation effects on APRIL binding and TACI function.
- Assessment of B-cell proliferation and class switch recombination in affected individuals.
Main Results:
- Identified homozygous and heterozygous TNFRSF13B mutations in 13 CVID patients.
- Homozygous mutations (S144X, C104R) abrogated APRIL binding and TACI function, impairing B-cell responses.
- Heterozygous mutations also correlated with humoral immunodeficiency and distinct clinical phenotypes compared to mouse models.
Conclusions:
- TNFRSF13B mutations are a cause of common variable immunodeficiency.
- TACI deficiency leads to impaired humoral immunity, affecting B-cell development and function.
- Human TACI deficiency presents with autoimmunity and lymphoproliferation, differing from murine models.