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TACI is mutant in common variable immunodeficiency and IgA deficiency

Abstract

The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI). One of the four individuals with CVID had a single nucleotide insertion in the other TNFRSF13B allele. None of these mutations were present in 50 healthy subjects. TNFRSF13B mutations cosegregated with the phenotype of CVID or IgAD in family members of four index individuals that we studied. B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching. These results suggest that TACI mutations can result in CVID and IgAD.

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Figure 1: Schematic representation of the structure of TACI and its mutations in individuals with CVID and IgAD.
Figure 2: Analysis of TNFRSF13B mutations in family members of index individuals with CVID and IgAD.
Figure 3: FACS analysis of TACI expression on B cells from index individuals and controls.
Figure 4: TACI expression and BAFF binding by 293 cells transfected with TACI mutants.
Figure 5: IgG and IgA secretion in response to APRIL and BAFF by B cells from individuals with CVID and IgAD and with TACI mutations.

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Acknowledgements

We thank the affected individuals and their families for participation in the study and H. Jabara, J. Manis, H. Oettgen, N. Ramesh and L. Kunkel for discussions. This work was supported by grants from the US Public Health Service, the Jeffrey Modell Foundation, the New England Primary Immunodeficiency Network, the March of Dimes and the Wallace Fund.

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Correspondence to Raif S Geha.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Sequence analysis of the TACI gene in index CVID and IgAD patients. (PDF 1246 kb)

Supplementary Table 1

Percentage of circulating lymphocytes. (PDF 31 kb)

Supplementary Table 2

Primer used to amplify the 5 exons of TACI gene and TACI cDNA. (PDF 39 kb)

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Castigli, E., Wilson, S., Garibyan, L. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 37, 829–834 (2005). https://doi.org/10.1038/ng1601

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