Abstract
Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. Mutations in the gene encoding TACI (TNFRSF13B) were previously found to be associated with CVID. Previous studies have identified a variety of sequence variants in TACI where A181E and C104R were the most common, with variable frequencies in different ethnic populations. So far, no mutations were identified in the recently reported “TACI highly conserved” (THC) cytoplasmic domain, important for the induction of class switch recombination. Our study evaluated immunological and clinical data on a cohort of 28 Argentinean pediatric CVID patients and allowed the identification of two novel mutations in TNFRSF13B, including one, S231R, affecting the highly conserved THC domain. In contrast, none of the patients presented with A181E and C104R mutations.
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References
Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.
Wang J, Cunningham-Rundles C. Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J Autoimmun. 2005;25:57–62.
Wehr C, Peter HH, Warnatz K. Response: improving classification in CVID. Blood. 2008;112:446–7.
Mellemkjaer L, Hammarstrom L, Andersen V, Yuen J, Heilmann C, Barington T, et al. Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study. Clin Exp Immunol. 2002;130:495–500.
Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86.
Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol. 2003;4:261–8.
Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005;37:829–34.
Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37:820–8.
van Zelm MC, Reisli I, van der Burg M, Castano D, van Noesel CJ, van Tol MJ, et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med. 2006;354:1901–12.
Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Bohm J, et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc Natl Acad Sci U S A. 2009;106:13945–50.
van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F, et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest. 2010;120:1265–74.
Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IAM, Dolman KM, et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Investig. 2010;120:214–22.
He B, Santamaria R, Xu W, Cols M, Chen K, Puga I, et al. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nat Immunol. 2010;11:836–45.
Pan-Hammarstrom Q, Salzer U, Du L, Bjorkander J, Cunningham-Rundles C, Nelson DL, et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007;39:429–30.
van de Ven AA, van Montfrans JM. Clinical complications in pediatric CVID are not restricted to patients with severely reduced class-switched memory B cells. Pediatr Allergy Immunol. 2010;22:347–8.
Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190–7.
Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111:77–85.
Mohammadi J, Liu C, Aghamohammadi A, Bergbreiter A, Du L, Lu J, et al. Novel mutations in TACI (TNFRSF13B) causing common variable immunodeficiency. J Clin Immunol. 2009;29:777–85.
Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 2002;30:3894–900.
Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116:7–15.
Castigli E, Wilson S, Garibyan L, Rachid R, Bonilla F, Schneider L, et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007;39:430–1.
Salzer U, Bacchelli C, Buckridge S, Pan-Hammarström Q, Jennings S, Lougaris V, et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood. 2009;113:1967–76.
Ng PC, Henikoff S. Accounting for human polymorphisms predicted to affect protein function. Genome Res. 2002;12:436–46.
Darce JR, Arendt BK, Wu X, Jelinek DF. Regulated expression of BAFF-binding receptors during human B cell differentiation. J Immunol. 2007;179:7276–86.
Hymowitz SG, Patel DR, Wallweber HJA, Runyon S, Yan M, Yin J, et al. Structures of APRIL–receptor complexes. J Biol Chem. 2005;280:7218–27.
Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science. 2000;288:2351–4.
Fried AJ, Rauter I, Dillon SR, Jabara HH, Geha RS. Functional analysis of transmembrane activator and calcium- modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. J Allergy Clin Immunol. 2011;128:226–8.
Magerus-Chatinet A, Neven B, Stolzenberg MC, Daussy C, Arkwright PD, Lanzarotti N, et al. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation. J Clin Investig. 2011;121:106–12.
Acknowledgments
The study was supported by Agencia Nacional de Promoción Científica y Tecnológica (PICT2004 No. 21235). We wish to thank Verónica Goris for the assistance in the bioinformatics analysis of amino acid substitutions.
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The authors have no financial conflict of interest.
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Almejún, M.B., Sajaroff, E., Galicchio, M. et al. Immunological Characteristics and Two Novel Mutations in TACI in a Cohort of 28 Pediatric Patients with Common Variable Immunodeficiency. J Clin Immunol 32, 89–97 (2012). https://doi.org/10.1007/s10875-011-9613-8
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DOI: https://doi.org/10.1007/s10875-011-9613-8