Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans

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.