TACI deficiency — a complex system out of balance

TACI promotes T-cell independent antibody responses and plasma cell differentiation and counteracts BAFF driven B-cell activation. Mutations in TNFRSF13B (encoding TACI) are associated with common variable immunodeficiency (CVID) but are also found in 1-2% of the general population. Although not diseases causing, certain TNFRSF13B mutations predispose CVID patients to autoimmunity and lymphoproliferation. Recently, studies of TACI-deficient humans and murine models revealed novel aspects of TACI, especially its crosstalk with the TLR pathways, differential expression of TACI isoforms, and its role in the generation of autoreactive B-cells. Vice versa, these studies are instrumental for a better understanding of TACI deficiency in humans and suggest that gene dosage, mutation type, and additional clinical or laboratory abnormalities influence the relevance of TNFRSF13B variants in individual CVID patients. TACI is embedded in a complex and well-balanced system, which is vulnerable to genetic and possibly also environmental hits.