Nature Genetics
37, 820 - 828 (2005)
Published online: 10 July 2005; | doi:10.1038/ng1600
Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humansU Salzer1, H M Chapel2, A D B Webster3, Q Pan-Hammarström4, A Schmitt-Graeff5, M Schlesier1, H H Peter1, J K Rockstroh6, P Schneider7, A A Schäffer8, L Hammarström4
& B Grimbacher11
Division of Rheumatology and Clinical Immunology, Medical Center, University Hospital, Hugstetterstr. 55, 79106 Freiburg, Germany. 2
Department of Immunology, Oxford Radcliffe Hospitals, Oxford, UK. 3
Department of Clinical Immunology, Royal Free Hospital, London, UK. 4
Division of Clinical Immunology, Karolinska Institute at Huddinge, Stockholm, Sweden. 5
Institute of Pathology, University of Freiburg, Germany. 6
Medizinische Universitätsklinik I, Bonn, Germany. 7
Department of Biochemistry, University of Lausanne, Switzerland. 8
National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Correspondence should be addressed to B Grimbacher grimbacher@medizin.ukl.uni-freiburg.de 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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