Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans

Abstract

The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b-/- mouse model.

An evolutionary approach to the medical implications of the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene

“…Coding variants 204insA, C104R, A181E and C193X have been previously observed in several case-control studies. [5][6][7] Among them, 204insA, A181E and C193X resulted private patient mutations, with A181E exclusive of cases with CVID and 204insA and C193X that are also found in cases with IgAD. On the contrary, substitution C104R was present both in Italians with CVID and IgAD and in healthy Italians.…”

“…4 After the initial claim of a strict association of TNFRSF13B mutations with both diseases, 5 the analysis of further control samples has shown the existence of some of these variants also in healthy individuals and, in familial cases, TNFRSF13B mutations do not always perfectly segregate with the pathological phenotype. 6 This has led to a reevaluation of the actual function of TNFRSF13B variants in IgAD and CVID onset, in which only the C104R and A181E mutations showed a clear correlation with the development of CVID. 7,8 However, even the A181E association was not statistically significant in all studies.…”

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

“…2,3 In about 90% of patients diagnosed with agammaglobulinemia and about 75% of cases with a Hyper-IgM syndrome, the underlying genetic defect has been identified. 2 Whereas mutations have been described in patients diagnosed with CVID, [4][5][6][7][8][9][10][11][12] in over 90% of these patients no associated genetic defect has been found. In fact, in most CVID patients a complex genetic trade rather than a single affected gene is likely to contribute to development of the disease.…”

Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease

“…We did not detect either mutation in 50 unrelated Lebanese controls. In addition, we did not detect any mutations in the coding regions of SP110 in 89 isolated cases of common variable immunodeficiency of European or Middle Eastern origin 4 .…”