title: Molecular basis of common variable immunodeficiency.
abstract: Common variable immunodeficiency (CVID) is the most prevalent human primary immunodeficiency requiring medical attention. Until recently, the only known genetic defect specific to CVID was the inducible costimulatory receptor (ICOS) deficiency, which accounts for less than 1% of the patients. Recently, mutations in the TNF receptor family member transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), which mediates isotype switching in B cells, were found to be present in 10% to 20% of patients with CVID. Mutations in TACI were also found in relatives of patients with CVID who had IgA deficiency (IgAD), as well as in a patient with isolated IgAD. In the majority of patients described to date, only one TACI allele is mutated, showing an autosomal dominant transmission of the disease. B cells from individuals with TACI mutations did not produce IgG and IgA in response to the TACI ligand a proliferation-inducing ligand (APRIL), probably reflecting impaired isotype switching. These results suggest that TACI mutations can lead to CVID and IgAD.
authors.affiliation: Division of Immunology, Children's Hospital, Boston, Massachusetts 02115, USA. emanuela.castigli@childrens.harvard.edu
authors.forename: Emanuela
authors.initials: E
authors.lastname: Castigli
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D017098:IgA Deficiency / Q000235:genetics; D017578:Immunoglobulin Class Switching; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha