Mutations in TNFRSF13B Encoding TACI Are Associated With Common Variable Immunodeficiency in Humans

Abstract

>Purpose of the Studies.To search for mutations of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor; also TNFRSF13B) in patients with common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IGAD).Study Populations.Salzer et al screened 162 unrelated individuals with CVID. Castigli et al studied 19 unrelated individuals with CVID and 16 with IGAD. Healthy individuals (100 and 50, respectively) served as controls.Methods.Genomic DNA from patients was subjected to reverse transcription and polymerase chain reaction sequencing analysis of the 5 exons of the gene encoding TACI. Binding of mutant TACI to ligands and stimulation of immunoglobulin production in vitro with TACI agonists in patients was also studied.Results.Salzer et al identified 13 individuals with CVID who had mutations in TACI. Castigli et al identified 4 individuals with CVID and 1 with IGAD and TACI mutations. None of the 150 controls studied had any of the identified TACI mutations. Interestingly, TACI mutations could cause disease in both the heterozygous and homozygous conditions. Patients’ cells had diminished binding to TACI ligands and showed diminished responses (immunoglobulin production) to TACI agonists in vitro. The clinical characteristics of the patients included hypogammaglobulinemia and impaired antibody responses, recurrent bacterial sinopulmonary infections, autoimmune disease (anemia, thyroiditis, positive antinuclear antibody), lymphoproliferative disease, and malignancy (B-cell lymphoma, gastric carcinoma).Conclusions.Approximately 8% to 20% of patients with severe combined immunodeficiency or IGAD may have heterozygous or homozygous mutation in TACI. This genetic alteration should be sought in patients with these disorders.Reviewer Comments.CVID and IGAD are among the most prevalent humoral immunodeficiencies at all ages. These studies represent important descriptions of defined mutations in patients with CVID and IGAD occurring in a significant fraction of these patients in 2 relatively genetically disparate populations. The ability to clearly define the underlying cause of disease in these patients will immediately lead to greater accuracy and confidence in diagnosis, earlier and more aggressive therapy, and, hopefully, improved outcomes.