Abstract
B lymphocyte subpopulations, previously defined classification schemes (Freiburg, Paris, EuroClass), TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF13 (APRIL) gene mutations, CTLA-4 and ICOS gene polymorphisms were analyzed in 25 common variable immunodeficiency (CVID) patients and 25 healthy controls. Patients were also divided into two subgroups due to some disease severity criteria. SG (severe disease group) (n:11) included patients who have splenomegaly and/or granulomatous diseases and/or bronchiectasis and/or lower baseline IgG values (<270 mg/dl). MG (moderate disease group) (n:14) patients diagnosed as having ESID/PAGID criteria but does not fulfill SG inclusion criteria. The onset of infectious symptoms and age at diagnosis were 50.0 ± 45.7 and 78.5 ± 54.5 months, respectively. Parental consanguinity rate was 54.5% in SG and 7.1% in MG. Switched-memory B cells (CD19 + 27 + IgD-IgM-) showed significant decrease in CVID patients and these cells were also significantly lower in SG compared to MG. CVID patients had significantly higher percentages of CD19 + κ + B cells and CD19 + λ + B cells than healthy controls. Freiburg classification: 87,5% of patients (n:21) were in group I and 12.5% were in Group II. Eighteen (75%) CVID patients with a low percentage of CD21low B cells were in Group Ib while three patients classified as Group Ia. The significantly lower levels of IgG and IgA in Group Ia is a novel finding. The percentages of patients for Paris Classification groups MB0, MB1, MB2 were 88%, 4% and 8%, respectively. There was a significant increase of splenomegaly, lymphadenopathy and autoimmune cytopenia in Group MB0. EuroClass: 45.8% of patients were smB+ and 54.2% were smB-. Splenomegaly and lymphadenopathy were significantly higher in smB- group. TACI: One patient carried heterozygous C104R mutation which was known as disease causing. APRIL: G67R and N96S SNPs were detected in most of the patients and healthy controls. BAFF-R: P21R/H159Y compound heterozygous mutation (n:1) and P21R heterozygous mutations (n:3) were detected. +49 A > G changes in exon 1 of CTLA-4 gene: GG and AG genotypes increase the risk of CVID development 1.32 and 2.18 fold, respectively. 1564 T > C polymorphisms on 3′UTR region in exon 2 of ICOS gene was not found to be significantly different in CVID patients. CVID classifications were not helpful in determining the genetic etiology of CVID.
Similar content being viewed by others
References
Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. BJH Review. 2009;145:709–27.
Park MA, Li JT, Hugan JB, Muddox DE, Abraham RS. Common varible immunodeficiency: a new look at an old disease. Lancet. 2008;372:489–502.
Notarangelo LD. Primary Immunodeficiencies. J Allergy Clin Immunol. 2010;125:182–94.
Pan-Hammarström Q, Hammarström L. Antibody deficiency diseases. Eur J Immunol. 2008;38:327–33.
Salzer U, Grimbacher B. Common variable immunodeficiency: the power of co-stimulation. Semin Immunol. 2006;18:337–46.
Vorechovsky I, Cullen M, Carrington M, Hammarström L, Webster AD. Fine mapping of IgAD1 in IgA deficiency and common variable immunodeficiency; identification and characterization of haplotypes shared by affected members of 101 multipl-case families. J Immunol. 2000;164:4408–16.
Roifman CM, Rao CP, Lederman HM, Lavi S, Quinn P, Gelfand EW. Increased susceptibility to mycoplasma infection in patients with hypogammaglobulinemia. Am J Med. 1986;80:590–4.
Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.
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.
Brandt D, Gershwin ME. Common variable immunodeficiency and autoimmunity. Autoimmun Rev. 2006;5:465–70.
Gathmann B, Binder N, Ehl S, Kindle G, The ESID. registry working party. The European internet-based patient and research database for primary immunodeficiencies: update 2011. Clin Exp Immunol. 2012;167:479–91.
Cunningham-Rundles C. Common variable immunodeficiency. Curr Allergy Asthma Rep. 2001;1:421–29.
Conley M, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiency). Clin Immunol. 1999;93:190–7.
Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck G, et al. 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. 2002;99:1544–51.
Moratto D, Gulino AV, Fontana S, Mori L, Pirovano S, Soresina A, et al. Combined decrease of defined B and T cell subsets in a group of common variable immunodeficiency patients. Clin Immunol. 2006;121:203–14.
Morimoto Y, Routes JM. Granulomatous disease in common variable immunodeficiency. Curr Allergy Asthma Rep. 2005;8:370–5.
Mouillot G, Carmagnat M, Gerard L, Garnier JL, Fieschi C, Vince N, et al. B cell and T cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. J Clin Immunol. 2010;30:746–55.
Kopecky O, Lukesova S. Genetic defects in common variable immunodeficiency. Int J Immunogenet. 2007;34:225–9.
Grimbacher B, Hutloff A, Schleiser M, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol. 2003;4:261–8.
van Zelm MC, Reisli I, van der Burg M, et al. An antibody deficiency syndrome due to mutations in the CD19 gene. N Eng J Med. 2006;354:1901–12.
Rivoisy C, Gerard L, Boutboul D, Malphettes M, Fieschi C, Durieu I, et al. Parental consanguinity is associated with a severe phenotype in common variable immunodeficiency. J Clin Immunol. 2012;32:98–105.
Kuijpers TW, Bende RJ. Baars Pa, et al. CD20 deficiency in humans results in impaired T-cell independent antibody responses. J Clin Invest. 2010;120:214–22.
Van Zelm MC, Smet J, Adams B, et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest. 2010;120:1265–74.
Sanchez-Ramon S, Radigan L, Yu JE, Bard S, Cunningham-Rundles C. Memory B cells in common variable immunodeficiency: Clinical associations and sex differences. Clin Immunol. 2008;128:314–21.
Aksu G, Genel F, Koturoglu G, Kurugol Z, Kutukculer N. Serum immunoglobulin (IgG, IgM, IgA) and IgG subclass concentrations in healthy children: a study using nephelometric technique. Turk J Pediatr. 2006;48:19–24.
Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-van der Cruyssen F, Mouthon L, Chevret S, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol. 2003;23:385–400.
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.
Ikinciogullari A, Kendirli T, Dogu F, Egin Y, Reisli İ, Cin S, Babacan E. Peripheral blood lymphocyte subsets in healthy Turkish children. Turk J Pediatr. 2004;46:125–30.
Spickett GP. Current perspectives on common variable immunodeficiency. Clin Exp Allergy. 2001;31:536–42.
Rezaei N, Aghamohammadi A, Moin A, et al. Frequency and clinical manifestations of patients with primary immunodeficiency disorders in Iran: Update from Iranian Primary Immunodeficiency registry. J Clin Immunol. 2006;26:519–32.
Edeer Karaca N, Gulez N, Aksu G, Kutukculer N. Common variable immunodeficiency: familial inheritance and autoimmune manifestations in two siblings. Turk J Pediatr. 2010;52:89–93.
The French National registry of primary immunodeficiency diseases. Clin Immunol 2010; 135; 264–72.
Azarsiz E, Eder Karaca N, Gülez N, Aksu G, Kutukculer N. Consanguinity rate and delay in diagnosis in Turkish patients with combined immunodeficiency. J Clin Immunol. 2011;31:106–11.
Llobet MP, Soler-Palacin P, Detkova D, Hernandez M, Caragil I, Espanol T. Common variable immunodeficiency: 20-yr experience at a single center. Pediatr Allergy Immunol. 2009;20:113–8.
Sala Cunill A, Soler-Palacin P, Martin de Vicente C, Labrador Horrillo M, Luengo Sanchez O, Figueras Nadal C. Common variablee immunodeficiency. Prognostic factors for lung damage. Med Clin (Barc). 2010;134:64–7.
Brandt D, Gershwin ME. Common variable immune deficiency and autoimmunity. Autoimmun Rev. 2006;5:465–70.
Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, Plebani A. J Immunol. 2012;188:497–503.
Alachkar H, Tauben Heim N, Haeney MR, Durandy A, Arkwright PD. Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency. Clin Immunol. 2006;120:310–8.
Al Kindi M, Mundy J, Sullivan T, Smith W, Kette F, Smith A, Heddle R, Hissaria P. Utility of peripheral blood B cell subsets analysis in common variable immunodeficiency. Clin Exp Immunol. 2012;167:275–81.
Schatorje EJH, Gemen EFA, Driessen GJA, Leuvenink J, van Hout RWNM, van der Burg M, de Vries E. Age-matched reference values for B lymphocyte subpopulations and CVID classifications in children. Scand J Immunol. 2011;74:502–10.
Zhang M, Srivastava G, Lu L. The pre-B cell receptor ana its function during B cell development. Cell Mol Immunol. 2004;2:89–94.
Wang YH, Stephan RP, Scheffold A, et al. Differential surrogate light chains expressions governs B cell differentiation. Blood. 2002;99:2459–67.
Salzer U, Chapel HM, Webster AD, Pan-hammarström Q, Schmitt-Graeff A, Schleiser M, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37:820–8.
Castigli E, Wison 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.
Mohammadi J, Liu C, Aghamohammadi A, Bergbreiter A, Du L, Lu J, et al. Novel mutations in TACI (TNFRSF13B) causing common variable immunodeficency. J Clin Immunol. 2009;29:777–85.
Zhang L, Radigan L, Salzer U, Behrens TW, Grimbacher B, Diaz DG, et al. Transmembran activator ana calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes in heterozygotes. J Allergy Clin Immunol. 2007;120:1178–85.
Salzer U, Bacchelli C, Buckridge S, Pan-Hammarström Q, Jennings S, Lougaris V, et al. Relevance of biallelic versus monoallelic mutations in distinguishing disease causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood. 2009;113:1967–76.
Speletas M, Mamara A, Papadopoulou-Alataki E, Lordanakis G, Liadaki K, Bardaka F, Kanariou M, Germenis AE. TNFRSF13B/TACI alterations in Greek patients with antibody deficiencies. J Clin Immunol. 2011;31:550–9.
Salzer U, Grimbacher B. TACItly changing tunes: farewell to a yin ana yang of BAFF receptor ana TACI in humoral immunity? New genetic defects in common variable immunodeficiency. Curr Opinion in Allergy Clin Immunology. 2005;5:496–503.
van de Ven AAJM, van de Corput L, van Tilburg CM, Tesselaar K, van Gent R, Sanders EAM, Boes M, Bloem AC, van Montfrans JM. Lymphocyte characteristics in children with common variable immunodeficiency. Clin Immunol. 2010;135:63–71.
Salzer U, Neumann C, Thiel J, Woelner C, Pan-Hammarström Q, Lougaris V, Hagena T, Jung J, Birmelin J, et al. Screening of functional and positional candidate genes in families with common variable immunodeficiency. BMC Immunol. 2008;9:1–9.
Barroeta A, Cancrini C, Finocchi A, Conti F, La Rocca MA, Graziani S, Di Cesare S, et al. Molecular characterization of TNFRSF13B gene in pediatric patients with hypogammaglobulinemia. XIVth Meeting of the European Society for Immunodeficiencies (ESID) Abstract book, Istanbul, 2010, pp.84, poster 128.
Mouillot G, Debre P, Oksenhendler E. Screening of the TNFRSF13C and ICOS genes in the DEFI study of adult patients with hypogammaglobulinemia. XIVth Meeting of the European Society for Immunodeficiencies (ESID) Abstract book, Istanbul, 2010, pp.87, poster 136.
Speletas M, Mamara A, Bardaka F, Liadaki K, Argentou N, Tsitsami E, et al. BAFF-R deficiency due to TNFRSF13C-P21R homozygosity resulting in mild immunodeficiency syndrome. XIVth Meeting of the European Society for Immunodeficiencies (ESID) Abstract book, Istanbul, 2010, pp.86, poster 133.
Yong PF, Salzer U, Grimbacher B. The role of co-stimulation in antibody deficiencies. ICOS and common variable immunodeficiency. Immunol Rev. 2009;229:101–13.
Salzer U, Maul-Pavicic A, Cunningham-Rundles C, Urschel S, Belohradsky BH, Litzman J, et al. ICOS deficiency in patients with common variable immunodeficiency. Clin Immunol. 2004;113:234–40.
Acknowledgements
1)This research was partly funded by Dubai-Harvard Foundation Medical Research (DHFMR). We thank Dr. Raif Geha and Dr.Luigi D. Notarangelo for their excellent support.
2) Some of the medical records of our common variable immunodeficiency patients included in this study were obtained from ESID (European Society for Immunodeficiencies) Registry Database.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kutukculer, N., Gulez, N., Karaca, N.E. et al. Three Different Classifications, B Lymphocyte Subpopulations, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF13 (APRIL) Gene Mutations, CTLA-4 and ICOS Gene Polymorphisms in Turkish Patients with Common Variable Immunodeficiency. J Clin Immunol 32, 1165–1179 (2012). https://doi.org/10.1007/s10875-012-9717-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-012-9717-9