CVID-associated TACI mutations affect autoreactive B cell selection and activation

Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptorsuperfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cellactivation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7and TLR9and plays an important role during B cellactivation and the central removal of autoreactive B cellsin healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune toleranceand secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B celllymphoma 6–expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cellactivation with coincident impairment of central B celltolerance, whereas residual B cellresponsiveness in patients with one, but not two, TACI mutations enables autoimmune complications.