Common variable immunodeficiency: two mutations are better than one.

B cells from common variable immunodeficiency (CVID) patients who have one mutant copy of the gene encoding the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) often display dysfunctional antibody production. Interestingly, some individuals with mutations in both TACI alleles do not present with CVID, suggesting that TACI mutations influence CVID pathogenesis via dominant interference or haploinsufficiency. In this issue of the JCI, Romberg and colleagues report how TACI mutations impact B cell activation, removal of autoreactive B cells, and the development of autoimmune disease in CVID.