| Abstract: | Common variable immune deficiency (CVID) is an assorted group of primary diseasesthat clinically manifest with antibody deficiency, infection susceptibility, andautoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factorreceptor superfamily member TACI are associated with CVID and autoimmunemanifestations, whereas two mutated alleles prevent autoimmunity. To assess how thenumber of TACI mutations affects B cell activation andtolerance checkpoints, we analyzed healthy individuals and CVID patients carrying oneor two TACI mutations. We found that TACI interacts with thecleaved, mature forms of TLR7 and TLR9 and plays an important role during B cellactivation and the central removal of autoreactive B cells in healthy donors and CVIDpatients. However, only subjects with a single TACI mutationdisplayed a breached immune tolerance and secreted antinuclear antibodies (ANAs).These antibodies were associated with the presence of circulating B cell lymphoma6–expressing T follicular helper (Tfh) cells, likely stimulating autoreactiveB cells. Thus, TACI mutations may favor CVID by altering B cellactivation with coincident impairment of central B cell tolerance, whereas residual Bcell responsiveness in patients with one, but not two, TACImutations enables autoimmune complications. |
