Novel NF-kB mutations in common variable immunodeficiency (CVID)

Common variable immunedeficiency (CVID) is the most common symptomatic primary immunodeficiency. The cardinal manifestations are hypogammaglobulinaemia and recurrent infections. In fact, CVID is a heterogeneous cluster of disorders associated with not only infection but also autoimmune disease, sarcoidosis-like granulomatous inflammation, and neoplasia. In a minority of cases, CVID follows simple Mendelian inheritance, and in other cases, there is familial clustering, with CVID or autoimmunity, and in other cases, CVID is sporadic. The aim of this project was to investigate the genetic and cellular pathogenesis of cases of CVID. We established a large national cohort of patients with primary antibody deficiencies. First, we discovered a novel heterozygous mutation, S254R in TNFAIP3 (A20), from two patients with CVID and their family members. Biochemical analysis revealed that the S254R substitution in A20 impairs deubiquitination. Nevertheless, only one patient with the heterozygous (S254R) mutation in TNFAIP3 exhibited an activated NF-kB and apoptotic phenotype. This patient was also found to carry a mutation encoding an L307I substitution in TAX1BP1, an interacting partner of A20. We investigated this interaction and discovered biochemical evidence that TAX1BP1L307I enhances binding with A20S254R. Thus, the A20 phenotype is modified by a TAX1BP1 variant, consistent with non-allelic noncomplementation. Second, we describe three individuals with complete B cell deficiency within single kindred. We identified a novel heterozygous mutation in NFKB2 (encoding a D865G substitution) in each affected individual. Mutant p100 is poorly processed, after activation of the non-canonical NF-kB pathway with CD40L stimulation, both in vitro and in cells isolated from the proband. We discovered that the mutation inhibits p100 phosphorylation. Remarkably, unprocessable p100 exhibits IkB like activity, which serves to sequester p65 in the cytoplasm. In other words, the immune deficiency appears to arise from disruption of both canonical and non-canonical NF-kB pathways. In summary we have described two novel forms of CVID, one arising from an autosomal dominant mutation in NFKB2, and the other resulting from a low penetrance mutation in TNFAIP3, where the phenotype appears to depend on epistatic interaction with TAX1BP1