TACI (TNFRSF13B) – Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency, characterized by hypogammaglobulinemia and recurrent infections. TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI), a receptor critical for B-cell isotype switching and plasma cell differentiation. Variants in TNFRSF13B are detected in 10–15% of CVID cases, implicating TACI dysfunction in disease susceptibility.

Genetic studies across multiple cohorts have identified heterozygous and compound heterozygous TNFRSF13B mutations in over 200 unrelated CVID probands. The recurrent missense variant c.310T>C (p.Cys104Arg) is the most common, alongside other missense (e.g., p.Ile87Asn) and splice-site mutations, establishing a broad variant spectrum ([PMID:16007086]).

Family segregation analyses in four independent pedigrees demonstrate cosegregation of heterozygous TNFRSF13B mutations with CVID or selective IgA deficiency in 12 affected relatives, though with incomplete penetrance ([PMID:19210517]). Compound heterozygous alleles (e.g., p.Ile87Asn/p.Cys104Arg) underlie autosomal recessive presentations in rare families ([PMID:22627058]).

Functional assays reveal that TACI mutants exert dominant-negative or haploinsufficient effects on receptor assembly and signaling. The C104R mutant disrupts ligand-induced NF-κB activation via preassembled oligomer interference ([PMID:17492055]), while haploinsufficiency models recapitulate impaired APRIL-driven B-cell proliferation and antibody responses ([PMID:20889194]).

Mechanistically, TNFRSF13B mutations compromise APRIL/APRIL-mediated isotype switching and plasma cell differentiation, leading to reduced serum IgG and IgA levels, recurrent bacterial infections (HP:0002718), and decreased circulating antibody concentration (HP:0004313).

Despite the clear susceptibility conferred by TNFRSF13B variants, the incomplete penetrance and variable clinical expressivity mandate cautious interpretation in the diagnostic setting. Genetic testing for TACI mutations informs CVID workup but requires integration with immunophenotyping and family history.

Key Take-home: Heterozygous TNFRSF13B variants cause autosomal dominant susceptibility to CVID through dominant-negative and haploinsufficient mechanisms, supporting their use in genetic diagnosis when combined with clinical and immunologic evaluation.

References

• Nature Genetics • 2005 • TACI is mutant in common variable immunodeficiency and IgA deficiency. PMID:16007086
• Clinical and experimental immunology • 2009 • TACI mutations and disease susceptibility in patients with common variable immunodeficiency. PMID:19210517
• Human immunology • 2012 • A novel compound heterozygous TACI mutation in an autosomal recessive common variable immunodeficiency (CVID) family. PMID:22627058
• The Journal of Clinical Investigation • 2007 • Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID). PMID:17492055
• The Journal of Allergy and Clinical Immunology • 2010 • The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency. PMID:20889194

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