BLyS, a TNF family member, is crucial for B cell proliferation and differentiation by acting through its three receptors, TACI, BCMA and BAFF-R. The knock out model for BLyS is characterized by an immunological phenotype reminiscent of the human phenotype of common variable immunodeficiency (CVID). CVID is characterized by a defective B cell compartment, evidencing the putative importance of BLyS in its pathogenesis. On the contrary, the transgenic model for BLys is characterized by autoimmune manifestations, underlying its role in B cell regulation. In fact, mutations in TACI, one of the three BLyS receptors, are associated with CVID. Based on these facts, we hypothesized that BLyS could be a candidate gene for CVID. We screened 78 patients with CVID using DHPLC and direct sequencing: No disease causing mutations were identified. A novel heterozygous single nucleotide polymorphism (SNP) was found in exon 1 of one individual, however this SNP (G189A) does not lead to an amino acid substitution.
This is a preview of subscription content, log in via an institution to check access.
REFERENCES
Spickett GP: Current perspectives on common variable immunodeficiency (CVID). Clin Exp Allergy 31(4):536–542, 2001 Review
Cunningham-Rundles C, Bodian C: Common variable immunodeficiency: Clinical and immunological features of 248 patients. Clin Immunol 92(1):34–48, 1999
Goldacker S, Warnatz K: Tackling the heterogeneity of CVID. Curr Opin Allergy Clin Immunol 5(6):504–509, 2005 Review
Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck G, Eibel H, Schlesier M, Peter HH: Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: A new approach to classify a heterogeneous disease. Blood 99(5):1544–1551, 2002
Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, Eibel H, Fischer B, Schäffer A, Mages HW, Kroczek RA, Peter HH: Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4:261–268, 2003
Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Peter MHH, Rockstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B: Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37:820–828, 2005
Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, Geha RS: TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 37:829–834, 2005
Shu HB, Hu WH, Johnson H: TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol 65(5):680–683, 1999
Mukhopadhyay A, Ni J, Zhai Y, Yu GL, Aggarwal BB: Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-kappaB, and c-Jun NH2-terminal kinase. J Biol Chem 274(23):15978–15981, 1999
Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J: BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189(11):1747–1756, 1999
Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM: BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285(5425):260–263, 1999
Tribouley C, Wallroth M, Chan V, Paliard X, Fang E, Lamson G, Pot D, Escobedo J, Williams LT: Characterization of a new member of the TNF family expressed on antigen presenting cells. Biol Chem 380(12):1443–1447, 1999
Gross JA, Dillon SR, Mudri S, Johnston J, Littau A, Roque R, Rixon M, Schou O, Foley KP, Haugen H, McMillens S, Waggie K, Schrechhise RV, Shoemaker K, Vu T, Moore M, Grossman A, Clegg CH: TACI-Ig neutralized molecules critical for B cell development and autoimmune disease. Impaired B cell maturation in mice lacking BLyS. Immunity 15:289–302, 2001
Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles D, Frew E, Scott ML: An essential role for BAFF in the normal development of B cells trough a BCMA-independent pathway. Science 293:2111–2114, 2001
Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL: Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 190(11):1697–1710, 1999
Stewart DM, McAvory MJ, Hilbert DM, Nelson DL: B lymphocytes from individuals with common variable immunodeficiency respond to B lymphocyte stimulator (BLyS protein) in vitro. Clin Immunol 109(2):137–143, 2003
Kawasaki A, Tsuchiya N, Fukazawa T, Hashimoto H, Tokunaga K: analysis on the association of human BLyS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis. Genes Immun 3(7):424–429, 2002
AKNOWLEDGMENTS
We would like to thank the referring physicians for their collaboration, Mrs. Jessica Pfannstiel and Mrs. Giovanna Falsetti for excellent technical assistance. This work was partly supported by the Center for Primary Immunodeficiencies “Mario Di Martino” and Camillo Golgi Foundation, Brescia. B.G. and U.S. were supported by grants of the Deutsche Forschungsgemeinschaft (DFG) GR1617/3 and SFB620/C2, and a USIDnet grant NO1-A1-30070. Both groups were supported by EU Contract No. SP23-CT-2005-006411, EURO-POLICY-PID.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Losi, C.G., Salzer, U., Gatta, R. et al. Mutational Analysis of Human BLyS in Patients with Common Variable Immunodeficiency. J Clin Immunol 26, 396–399 (2006). https://doi.org/10.1007/s10875-006-9026-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-006-9026-2