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

Nature Genetics volume 37, pages 820–828 (2005)Cite this article

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.

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Figure 1: TACI mutations in CVID.
Figure 2: TACI deficiency impairs APRIL binding.
Figure 3: Proliferation and CSR in response to APRIL and BAFF.
Figure 4: B-cell subpopulations and Ig levels in TACI deficiency.
Figure 5: Tissue sections of a tonsil from an individual with TACI deficiency (a,c,e,g,i) compared with a normal control (b,d,f,h,j).

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Acknowledgements

We thank H. Eibel and K. Warnatz for advice; J. Deimel, R. Dräger, B. Ferry, M. Ibrahim, K. Ingold, J. Pfannstiel, A. Rump, A. Tardivel, M. Vogel, S. Workman and C. Woellner for assistance; A.-M. Eades-Perner, J. Puck and U. Walker for critically reading the manuscript; U. Hannelius and J. Kere for sharing their material and method for population-based screening; E. Walther for providing the tonsil specimens; and I. Vořechovský for providing the genotypes of CVID families. This research was supported by grants from the Deutsche Forschungsgemeinschaft, the Swedish research council and the European Union.

Author information

Authors and Affiliations

  1. Division of Rheumatology and Clinical Immunology, Medical Center, University Hospital, Hugstetterstr. 55, Freiburg, 79106, Germany

    U Salzer, M Schlesier, H H Peter & B Grimbacher

  2. Department of Immunology, Oxford Radcliffe Hospitals, Oxford, UK

    H M Chapel

  3. Department of Clinical Immunology, Royal Free Hospital, London, UK

    A D B Webster

  4. Division of Clinical Immunology, Karolinska Institute at Huddinge, Stockholm, Sweden

    Q Pan-Hammarström & L Hammarström

  5. Institute of Pathology, University of Freiburg, Germany

    A Schmitt-Graeff

  6. Medizinische Universitätsklinik I, Bonn, Germany

    J K Rockstroh

  7. Department of Biochemistry, University of Lausanne, Switzerland

    P Schneider

  8. Department of Health and Human Services, National Center for Biotechnology Information, National Institutes of Health, Bethesda, Maryland, USA

    A A Schäffer

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  1. U Salzer
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Correspondence to B Grimbacher.

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Supplementary information

Supplementary Fig. 1

Expression of TACI and BAFFR. (PDF 35 kb)

Supplementary Fig. 2

ELISA for detection of soluble TACI. (PDF 11 kb)

Supplementary Fig. 3

Proliferation of enriched B cells in response to anti-IgM, anti-IgM plus interleukin (IL)-2, snti-CD40, and anti-CD40 plus IL-4. (PDF 11 kb)

Supplementary Table 1

Clinical summary of patients with mutations in TNFRSF13B. (PDF 14 kb)

Supplementary Table 2

Primer sequences used in this study. (PDF 18 kb)

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Salzer, U., Chapel, H., Webster, A. et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37, 820–828 (2005). https://doi.org/10.1038/ng1600

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