Predominantly Antibody Deficiencies

Document Type : Review


1 Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran

2 Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children Medical Center, Tehran University of Medical Sciences, Tehran, Iran


Primary antibody deficiencies (PADs) are frequent primary immunodeficiencies in humans, characterized by hypogammaglobulinemia, defects in production of specific antibodies, and recurrent infections. Information about PADs is quickly developing, leading to improved diagnoses and efficient disease management. This study is a review of the pathogenesis, diagnosis, clinical manifestations, and management of PAD disorders such as agammaglobulinemia, common variable immunodeficiency, monogenic defects associated with hypogammaglobulinemia, class switch recombination deficiencies, selective IgA deficiency, subclass immunoglobulin isotypes deficiencies, specific antibody deficiency, and transient hypogammaglobulinemia. 


1. Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol. 2018;38(1):129-43. 2. Abolhassani H, Kiaee F, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, et al. Fourth Update on the Iranian National Registry of Primary Immunodeficiencies: Integration of Molecular Diagnosis. J Clin Immunol. 2018;38(7):816-32. 3. Yazdani R, Abolhassani H, Kiaee F, Habibi S, Azizi G, Tavakol M, et al. Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort. J Clin Immunol Pract. 2019;7(3):864-878 4. Aghamohammadi A, Farhoudi A, Moin M, Rezaei N, Kouhi A, Pourpak Z, et al. Clinical and immunological features of 65 Iranian patients with common variable immunodeficiency. Clin Diagn Lab Immunol. 2005;12(7):825-32. 5. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92(1):34-48. 6. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Medicine. 1985;64(3):145-56. 7. McKinney RE, Jr., Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients Rev Infect Dis. 1987;9(2):334-56. 8. Rudge P, Webster AD, Revesz T, Warner T, Espanol T, Cunningham-Rundles C, et al. Encephalomyelitis in primary hypogammaglobulinaemia. Brain. 1996;119 (1):1- 15. 9. Bjorkander J, Bake B, Hanson LA. Primary hypogammaglobulinaemia: impaired lung function and body growth with delayed diagnosis and inadequate treatment. Eur J Respir Dis. 1984;65(7):529-36. 10. Seymour B, Miles J, Haeney M. Primary antibody deficiency and diagnostic delay. J Clin Pathol. 2005;58(5):546-7. 11. Aghamohammadi A, Moin M, Farhoudi A, Rezaei N, Pourpak Z, Movahedi M, et al. Efficacy of intravenous immunoglobulin on the prevention of pneumonia in patients with agammaglobulinemia. FEMS Immunol Med Microbiol. 2004;40(2):113-8. 12. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2002;109(6):1001-4. 13. Isgro A, Marziali M, Mezzaroma I, Luzi G, Mazzone AM, Guazzi V, et al. Bone marrow clonogenic capability, cytokine production, and thymic output in patients with common variable immunodeficiency. J Immunol. 2005;174(8):5074- 81. 14. Pan-Hammarstrom Q, Hammarstrom L. Antibody deficiency diseases. Eur J Immunol. 2008;38(2):327-33. 15. Immunological development and antibody deficiency diseases. Br Med J. 1967;1(5536):320-1. 16. Conley ME, Broides A, Hernandez-Trujillo V, Howard V, Kanegane H, Miyawaki T, et al. Genetic analysis of patients with defects in early Bcell development. Immunol Rev. 2005;203:216-34. 17. Minegishi Y, Rohrer J, Conley ME. Recent progress in the diagnosis and treatment of patients with defects in early B-cell development. Curr Opin Pediatr. 1999;11(6):528-32. 18. Abolhassani H, Parvaneh N, Rezaei N, Hammarstrom L, Aghamohammadi A. Genetic defects in B-cell development and their clinical consequences. J Investig Allergol Clin Immunol. 2014;24(1):6-22. 19. Barr TA, Gray M, Gray D. B cells: programmers of CD4 T cell responses. J Investig Allergol Clin Immunol. 2012;12(3):222-31. 20. Hardy RR. B-cell commitment: deciding on the players. Curr Opin Immunol. 2003;15(2):158- 65. 21. Liadaki K, Sun J, Hammarstrom L, PanHammarstrom Q. New facets of antibody deficiencies. Curr Opin Immunol. 2013;25(5):629- 38. 22. Tsukada S, Rawlings DJ, Witte ON. Role of Bruton's tyrosine kinase in immunodeficiency. Curr Opin Immunol. 1994;6(4):623-30. 23. Conley ME. Early defects in B cell development. urr Opin Allergy Clin Immunol. 2002;2(6):517-22. 24. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr. 2002;141(4):566- 71. 25. Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002;104(3):221-30. 26. Norouzi S, Aghamohammadi A, Mamishi S, Rosenzweig SD, Rezaei N. Bacillus CalmetteGuerin (BCG) complications associated with primary immunodeficiency diseases. J Infect. 2012;64(6):543-54. 27. Mamishi S, Eghbali AN, Rezaei N, Abolhassani H, Parvaneh N, Aghamohammadi A. A single center 14 years study of infectious complications leading to hospitalization of patients with primary antibody deficiencies. Braz J Infect Dis. 2010;14(4):351-5. 28. Moin M, Aghamohammadi A, Farhoudi A, Pourpak Z, Rezaei N, Movahedi M, et al. X-linked agammaglobulinemia: a survey of 33 Iranian patients. Immunol Invest. 2004;33(1):81-93. 29. Stewart DM, Lian L, Nelson DL. The clinical spectrum of Bruton's agammaglobulinemia. Curr Allergy Asthma Rep. 2001;1(6):558-65. 30. Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014;5:162. 31. 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(3):190-7. 32. Abolhassani H, Vitali M, Lougaris V, Giliani S, Parvaneh N, Parvaneh L, et al. Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects. Expert Rev Clin Immunol. 2016;12(4):479-86. 33. Azizi G, Abolhassani H, Asgardoon MH, Rahnavard J, Dizaji MZ, Yazdani R, et al. The use of Immunoglobulin Therapy in Primary Immunodeficiency Diseases. ndocr Metab Immune Disord Drug Targets. 2016;16(2):80-8. 34. Yel L, Minegishi Y, Coustan-Smith E, Buckley RH, Trubel H, Pachman LM, et al. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N Engl J Med. 1996;335(20):1486-93. 35. Cunningham-Rundles C, Siegal FP, Cunningham-Rundles S, Lieberman P. Incidence of cancer in 98 patients with common varied immunodeficiency. J Clin Immunol. 1987;7(4):294- 9. 36. Knight AK, Cunningham-Rundles C. Inflammatory and autoimmune complications of common variable immune deficiency. Autoimmun Rev. 2006;5(2):156-9. 37. Luzi G, Businco L, Aiuti F. Primary immunodeficiency syndromes in Italy: a report of the national register in children and adults. J Clin Immunol. 1983;3(4):316-20. 38. Notarangelo L, Casanova JL, Fischer A, Puck J, Rosen F, Seger R, et al. Primary immunodeficiency diseases: an update. J Allergy Clin Immunol. 2004;114(3):677-87. 39. Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116(1):7-15.40. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency - an update. Arthritis Res Ther. 2012;14(5):223. 41. Geha RS, Notarangelo LD, Casanova JL, Chapel H, Conley ME, Fischer A, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification CommitteeJ Allergy Clin Immunol. 2007;120(4):776-94. 42. Holm AM, Aukrust P, Damas JK, Muller F, Halvorsen B, Froland SS. Abnormal interleukin-7 function in common variable immunodeficiency. Blood. 2005;105(7):2887-90. 43. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med. 1993;86(1):31-42. 44. Aghamohammadi A, Moazzami K, Rezaei N, Karimi A, Movahedi M, Gharagozlou M, et al. ENT manifestations in Iranian patients with primary antibody deficiencies. J Laryngol Otol. 2008;122(4):409-13. 45. Martinez Garcia MA, de Rojas MD, Nauffal Manzur MD, Munoz Pamplona MP, Compte Torrero L, Macian V, et al. Respiratory disorders in common variable immunodeficiency. Respir Med. 2001;95(3):191-5. 46. Pourpak Z, Aghamohammadi A, Sedighipour L, Farhoudi A, Movahedi M, Gharagozlou M, et al. Effect of regular intravenous immunoglobulin therapy on prevention of pneumonia in patients with common variable immunodeficiency. J Microbiol Immunol Infect. 2006;39(2):114-20. 47. Sweinberg SK, Wodell RA, Grodofsky MP, Greene JM, Conley ME. Retrospective analysis of the incidence of pulmonary disease in hypogammaglobulinemia. J Allergy Clin Immunol. 1991;88(1):96-104. 48. Kainulainen L, Varpula M, Liippo K, Svedstrom E, Nikoskelainen J, Ruuskanen O. Pulmonary abnormalities in patients with primary hypogammaglobulinemia. . J Allergy Clin Immunol. 1999;104(5):1031-6. 49. Park JE, Beal I, Dilworth JP, Tormey V, Haddock J. The HRCT appearances of granulomatous pulmonary disease in common variable immune deficiency. Eur J Radiol. 2005;54(3):359-64. 50. Thickett KM, Kumararatne DS, Banerjee AK, Dudley R, Stableforth DE. Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings. QJM. 2002;95(10):655-62. 51. Carsetti R, Rosado MM, Donnanno S, Guazzi V, Soresina A, Meini A, et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol. 2005;115(2):412-7. 52. Vodjgani M, Aghamohammadi A, Samadi M, Moin M, Hadjati J, Mirahmadian M, et al. Analysis of class-switched memory B cells in patients with common variable immunodeficiency and its clinical implications. J Investig Allergol Clin Immunol. 2007;17(5):321-8.53. Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol. 1997;159(12):6236-41. 54. Buckley RH. Pulmonary complications of primary immunodeficiencies. Paediatr Respir Rev. 2004;5:225-33. 55. Davies CW, Juniper MC, Gray W, Gleeson FV, Chapel HM, Davies RJ. Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A. Thorax. 2000;55(1):88-90. 56. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114(2):415-21. 57. Koss MN, Hochholzer L, Langloss JM, Wehunt WD, Lazarus AA. Lymphoid interstitial pneumonia: clinicopathological and immunopathological findings in 18 cases. Pathology. 1987;19(2):178-85. 58. Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and Xlinked agammaglobulinemia. Am J Surg Pathol. 1996;20(10):1240-52. 59. Teahon K, Webster AD, Price AB, Weston J, Bjarnason I. Studies on the enteropathy associated with primary hypogammaglobulinaemia. Gut. 1994;35(9):1244-9. 60. Zullo A, Romiti A, Rinaldi V, Vecchione A, Tomao S, Aiuti F, et al. Gastric pathology in patients with common variable immunodeficiency. Gut. 1999;45(1):77-81. 61. Aukrust P, Lien E, Kristoffersen AK, Muller F, Haug CJ, Espevik T, et al. Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency-- possible immunologic and clinical consequences. Blood. 1996;87(2):674-81. 62. Cunningham-Rundles C, Lieberman P, Hellman G, Chaganti RS. Non-Hodgkin lymphoma in common variable immunodeficiency. Am J Hematol. 1991;37(2):69-74. 63. Boileau J, Mouillot G, Gerard L, Carmagnat M, Rabian C, Oksenhendler E, et al. Autoimmunity in common variable immunodeficiency: correlation with lymphocyte phenotype in the French DEFI study. J Autoimmun. 2011;36(1):25-32. 64. Filipovich AH, Mathur A, Kamat D, Kersey JH, Shapiro RS. Lymphoproliferative disorders and other tumors complicating immunodeficiencies. Immunodeficiency. 1994;5(2):91-112. 65. Kinlen LJ, Webster AD, Bird AG, Haile R, Peto J, Soothill JF, et al. Prospective study of cancer in patients with hypogammaglobulinaemia. Lancet. 1985;1(8423):263-6. 66. Kokron CM, Errante PR, Barros MT, Baracho GV, Camargo MM, Kalil J, et al. Clinical and laboratory aspects of common variable immunodeficiency. An Acad Bras Cienc. 2004;76(4):707-26. 67. 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(3):495-500. 68. Sander CA, Medeiros LJ, Weiss LM, Yano T, Sneller MC, Jaffe ES. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Am J Surg Pathol. 1992;16(12):1170-82. 69. Abolhassani H, Aghamohammadi A, Imanzadeh A, Mohammadinejad P, Sadeghi B, Rezaei N. Malignancy phenotype in common variable immunodeficiency. J Invest Allergol Clin Immunol. 2012;22(2):133-4. 70. Seppanen M, Aghamohammadi A, Rezaei N. Is there a need to redefine the diagnostic criteria for common variable immunodeficiency? Expert Rev Clin Immunol. 2014;10(1):1-5. 71. Aghamohammadi A, Kanegane H, Moein M, Farhoudi A, Pourpak Z, Movahedi M, et al. Identification of an SH2D1A mutation in a hypogammaglobulinemic male patient with a diagnosis of common variable immunodeficiency. Int J Hematol. 2003;78(1):45-7. 72. Kanegane H, Tsukada S, Iwata T, Futatani T, Nomura K, Yamamoto J, et al. Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry. Clin Exp Immunol. 2000;120(3):512-7. 73. Pasquier B, Yin L, Fondaneche MC, Relouzat F, Bloch-Queyrat C, Lambert N, et al. Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product J Exp Med. 2005;201(5):695-701. 74. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. Allergy Clin Immunol. 2006;117(4 Suppl):S525-53. 75. Fasth A, Nystrom J. Safety and efficacy of subcutaneous human immunoglobulin in children with primary immunodeficiency. Acta Paediatr. 2007;96(10):1474-8. 76. Roifman CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet. 1987;1(8541):1075-7. 77. Quartier P, Debre M, De Blic J, de Sauverzac R, Sayegh N, Jabado N, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. 1999;134(5):589-96. 78. Daly KA, Giebink GS, Lindgren B, Margolis RH, Westover D, Hunter LL, et al. Randomized trial of the efficacy of trimethoprim-sulfamethoxazole and prednisone in preventing post-tympanostomy tube morbidity. Pediatr Infect Dis J. 1995;14(12):1068-74. 79. De Diego JI, Prim MP, Alfonso C, Sastre N, Rabanal I, Gavilan J. Comparison of amoxicillin and azithromycin in the prevention of recurrent acute otitis media. Int J Pediatr Otorhinolaryngol. 2001;58(1):47-51. 80. Teele DW, Klein JO, Word BM, Rosner BA, Starobin S, Earle R, Jr., et al. Antimicrobial prophylaxis for infants at risk for recurrent acute otitis media. Vaccine. 2000;19 Suppl 1:140-3. 81. Reiser M, Li K, Lockey RF, Wang JW. Lipopolysaccharide responsive beige-like anchor subcellular localization involving in vesicle trafficking responsive to lipopolysaccharide. Austin J Clin Immunol Immunopathol. 2014;1:1-8. 82. Azizi G, Abolhassani H, Mahdaviani SA, Chavoshzadeh Z, Eshghi P, Yazdani R, et al. Clinical, immunologic, molecular analyses and outcomes of iranian patients with LRBA deficiency: A longitudinal study. Pediatr Allergy Immunol. 2017;28(5):478-84. 83. Azizi G, Abolhassani H, Zaki-Dizaji M, Habibi S, Mohammadi H, Shaghaghi M, et al. Polyautoimmunity in Patients with LPS-Responsive Beige-Like Anchor (LRBA) Deficiency. Immunol Invest. 2018;47(5):457-67. 84. Carter RH, Fearon DT. Pillars Article: CD19: Lowering the threshold for antigen receptor stimulation of B lymphocytes. Science, 1992. 256: 105-107. J Immunol. 2010;184(5):2233-5. 85. Matsumoto AK, Martin DR, Carter RH, Klickstein LB, Ahearn JM, Fearon DT. Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J Exp Med. 1993;178(4):1407-17. 86. van Zelm MC, Bartol SJ, Driessen GJ, Mascart F, Reisli I, Franco JL, et al. Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. The J Allergy Clin Immunol. 2014. 87. van Zelm MC, Smet J, van der Burg M, Ferster A, Le PQ, Schandene L, et al. Antibody deficiency due to a missense mutation in CD19 demonstrates the importance of the conserved tryptophan 41 in immunoglobulin superfamily domain formation. Hum Mol Genet. 2011;20(9):1854-63. 88. Artac H, Reisli I, Kara R, Pico-Knijnenburg I, Adin-Cinar S, Pekcan S, et al. B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele. Genes Immun. 2010;11(7):523-30. 89. 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(4):1265-74. 90. Kanegane H, Agematsu K, Futatani T, Sira MM, Suga K, Sekiguchi T, et al. Novel mutations in a Japanese patient with CD19 deficiency. Genes Immun. 2007;8(8):663-70. 91. 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(18):1901- 12. 92. Thiel J, Kimmig L, Salzer U, Grudzien M, Lebrecht D, Hagena T, et al. Genetic CD21 deficiency is associated with hypogammaglobulinemia. J Allergy Clin Immunol . 2012;129(3):801-10.93. Vince N, Boutboul D, Mouillot G, Just N, Peralta M, Casanova JL, et al. Defects in the CD19 complex predispose to glomerulonephritis, as well as IgG1 subclass deficiency. J Allergy Clin Immunol. 2011;127(2):538-4. 94. Yong PF, Thaventhiran JE, Grimbacher B. "A rose is a rose is a rose," but CVID is Not CVID common variable immune deficiency (CVID), what do we know in 2011? Adv Immunol. 2011;111:47- 107. 95. Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, et al. CD20 deficiency in humans results in impaired T cellindependent antibody responses. J Clinical Invest. 2010;120(1):214-22. 96. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J Immunol. 1980;125(4):1678-85. 97. Tedder TF, Forsgren A, Boyd AW, Nadler LM, Schlossman SF. Antibodies reactive with the B1 molecule inhibit cell cycle progression but not activation of human B lymphocytes. Eur J Immunol. 1986;16(8):881-7. 98. Tedder TF, Boyd AW, Freedman AS, Nadler LM, Schlossman SF. The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol. 1985;135(2):973-9. 99. Kanzaki M, Lindorfer MA, Garrison JC, Kojima I. Activation of the calcium-permeable cation channel CD20 by alpha subunits of the Gi protein. J Biol Chem. 1997;272(23):14733-9. 100. Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF. Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J Cell Biol. 1993;121(5):1121-32. 101. Clark EA, Lane PJ. Regulation of human Bcell activation and adhesion Annu Rev Immunol. 1991;9:97-127. 102. Richter G, Burdach S. ICOS: a new costimulatory ligand/receptor pair and its role in Tcell activion. Onkologie. 2004;27(1):91-5. 103. Coyle AJ, Gutierrez-Ramos JC. The role of ICOS and other costimulatory molecules in allergy and asthma. Springer Semin Immunopathol. 2004;25(3-4):349-59. 104. Yong PF, Tarzi M, Chua I, Grimbacher B, Chee R. Common variable immunodeficiency: an update on etiology and management. Immunol Allergy Clin North Am. 2008;28(2):367-86, ix-x. 105. Durandy A, Cantaert T, Kracker S, Meffre E. Potential roles of activation-induced cytidine deaminase in promotion or prevention of autoimmunity in humans. Autoimmunity. 2013;46(2):148-56. 106. de la Torre I, Moura RA, Leandro MJ, Edwards J, Cambridge G. B-cell-activating factor receptor expression on naive and memory B cells: relationship with relapse in patients with rheumatoid arthritis following B-cell depletion therapy. Ann Rheum Dis. 2010;69(12):2181-8. 107. Wang HY, Ma CA, Zhao Y, Fan X, Zhou Q, Edmonds P, et al. Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc Natl Acad Sci U S A. 2013;110(13):5127-32.108. Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. 2000;102(5):565-75. 109. Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, Catalan N, et al. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol. 2003;4(10):1023-8. 110. Peron S, Metin A, Gardes P, Alyanakian MA, Sheridan E, Kratz CP, et al. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med. 2008;205(11):2465-72. 111. Micol R, Kayal S, Mahlaoui N, Beaute J, Brosselin P, Dudoit Y, et al. Protective effect of IgM against colonization of the respiratory tract by nontypeable Haemophilus influenzae in patients with hypogammaglobulinemia. J Allergy Clin Immunol. 2012;129(3):770-7. 112. Quartier P, Bustamante J, Sanal O, Plebani A, Debre M, Deville A, et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to ActivationInduced Cytidine Deaminase deficiency. Clin Immunol. 2004;110(1):22-9. 113. Durandy A, Hivroz C, Mazerolles F, Schiff C, Bernard F, Jouanguy E, et al. Abnormal CD40- mediated activation pathway in B lymphocytes from patients with hyper-IgM syndrome and normal CD40 ligand expression. J Immunol. 1997;158(6):2576-84. 114. Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol. 1999;118 Suppl 1:1-28. 115. Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol. 2000;120(2):225-31. 116. Ammann AJ, Hong R. Selective IgA deficiency: presentation of 30 cases and a review of the literature. Medicine. 1971;50(3):223-36. 117. Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94(5):1-63. 118. Buckley RH, Dees SC. Correlation of milk precipitins with IgA deficiency. N Engl J Med. 1969;281(9):465-9. 119. Burrows PD, Cooper MD. IgA deficiency. Adv Immunol. 1997;65:245-76. 120. Hanson LA, Bjorkander J, Carlsson B, Roberton D, Soderstrom T. The heterogeneity of IgA deficiency. J Clin Immunol. 1988;8(3):159-62. 121. Carvalho Neves Forte W, Ferreira De Carvalho Junior F, Damaceno N, Vidal Perez F, Gonzales Lopes C, Mastroti RA. Evolution of IgA deficiency to IgG subclass deficiency and common variable immunodeficiency. Allergol Immunopathol. 2000;28(1):18-20. 122. Espanol T, Catala M, Hernandez M, Caragol I, Bertran JM. Development of a common variable immunodeficiency in IgA-deficient patients. Clin Imunology Immunopathol. 1996;80(3 Pt 1):333-5. 123. Gutierrez MG, Kirkpatrick CH. Progressive immunodeficiency in a patient with IgA deficiency. Ann Allergy Asthma Immunol. 1997;79(4):297- 301. 124. Ishizaka A, Nakanishi M, Yamada S, Sakiyama Y, Matsumoto S. Development of hypogammaglobulinaemia in a patient with common variable immunodeficiency. Eur J Pediatr. 1989;149(3):175-6. 125. Johnson ML, Keeton LG, Zhu ZB, Volanakis JE, Cooper MD, Schroeder HW, Jr. Agerelated changes in serum immunoglobulins in patients with familial IgA deficiency and common variable immunodeficiency (CVID). Clin Exp Immunol. 1997;108(3):477-83. 126. Litzman J, Burianova M, Thon V, Lokaj J. Progression of selective IgA deficiency to common variable immunodeficiency in a 16 year old boy. Allergologia et immunopathologia. 1996;24(4):174- 6. 127. Slyper AH, Pietryga D. Conversion of selective IgA deficiency to common variable immunodeficiency in an adolescent female with 18q deletion syndrome. Eur J Pediatr. 1997;156(2):155- 6. 128. Smith CI, Hammarstrom L, Lindahl M, Lockner D. Kinetics of the spontaneously occurring common variable hypogammaglobulinemia: an analysis of two individuals with previously normal immunoglobulin levels. Clin Immunol Immunopathol. 1985;37(1):22-9. 129. Smith CI, Hammarstrom L, Palmblad J. Development of a serologically complete IgA deficiency in a patient with common variable hypogammaglobulinemia. Clin Lab Immunol. 1985;17(4):191-5. 130. Schroeder HW, Jr. Genetics of IgA deficiency and common variable immunodeficiency. Clin Rev Allergy Immunol. 2000;19(2):127-40. 131. Schroeder HW, Jr., Schroeder HW, 3rd, Sheikh SM. The complex genetics of common variable immunodeficiency. J Investig Med. 2004;52(2):90-103. 132. Schroeder HW, Jr., Zhu ZB, March RE, Campbell RD, Berney SM, Nedospasov SA, et al. Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, - A1 haplotypes. Mol Med. 1998;4(2):72-86. 133. Stavnezer J. Immunology. A touch of antibody class. Science. 2000;288(5468):984-5. 134. Borte S, Pan-Hammarstrom Q, Liu C, Sack U, Borte M, Wagner U, et al. Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency. Blood. 2009;114(19):4089-98. 135. 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(8):829-34. 136. Islam KB, Baskin B, Nilsson L, Hammarstrom L, Sideras P, Smith CI. Molecular analysis of IgA deficiency. Evidence for impaired switching to IgA. J Immunol. 1994;152(3):1442-52. 137. Wang Z, Yunis D, Irigoyen M, Kitchens B, Bottaro A, Alt FW, et al. Discordance between IgA switching at the DNA level and IgA expression at the mRNA level in IgA-deficient patients. Clin Immunol. 1999;91(3):263-70. 138. Kalfa VC, Roberts RL, Stiehm ER. The syndrome of chronic mucocutaneous candidiasis with selective antibody deficiency. Ann Allergy Asthma Immunol. 2003;90(2):259-64. 139. Thieffry S, Arthuis M, Aicardi J, Lyon G. [Ataxiatelangiectasis. (7 personal cases)]. Rev Neurol. 1961;105:390-405. 140. Pan-Hammarstrom Q, Dai S, Zhao Y, van Dijk-Hard IF, Gatti RA, Borresen-Dale AL, et al. ATM is not required in somatic hypermutation of VH, but is involved in the introduction of mutations in the switch mu region. J Immunol. 2003;170(7):3707-16. 141. Oxelius VA, Laurell AB, Lindquist B, Golebiowska H, Axelsson U, Bjorkander J, et al. IgG subclasses in selective IgA deficiency: importance of IgG2-IgA deficiency. N Engl J Med. 1981;304(24):1476-7. 142. Vorechovsky I, Blennow E, Nordenskjold M, Webster AD, Hammarstrom L. A putative susceptibility locus on chromosome 18 is not a major contributor to human selective IgA deficiency: evidence from meiotic mapping of 83 multiple-case families. J Immunol. 1999;163(4):2236-42. 143. Cunningham-Rundles C. Selective IgA deficiency. In: Stiehm ER, Ochs HD, Winkelstein JA, editors. Immunologic Disorders in Infants and Children. Philadelphia: Elsevier Saunders; 2004. p. 427-46. 144. Aghamohammadi A, Cheraghi T, Gharagozlou M, Movahedi M, Rezaei N, Yeganeh M, et al. IgA deficiency: correlation between clinical and immunological phenotypes. J Clin Immunol. 2009;29(1):130-6. 145. Litzman J, Vlkova M, Pikulova Z, Stikarovska D, Lokaj J. T and B lymphocyte subpopulations and activation/differentiation markers in patients with selective IgA deficiency. Clin Exp Immunol. 2007;147(2):249-54. 146. Aghamohammadi A, Abolhassani H, Biglari M, Abolmaali S, Moazzami K, Tabatabaeiyan M, et al. Analysis of switched memory B cells in patients with IgA deficiency. Int Arch Allergy Immunol. 2011;156(4):462-8. 147. Aghamohammadi A, Mohammadi J, Parvaneh N, Rezaei N, Moin M, Espanol T, et al. Progression of selective IgA deficiency to common variable immunodeficiency. Int Arch Allergy Immunol. 2008;147(2):87-92. 148. Ozkan H, Atlihan F, Genel F, Targan S, Gunvar T. IgA and/or IgG subclass deficiency in children with recurrent respiratory infections and its relationship with chronic pulmonary damage. J Investig Allergol Clin Immunol. 2005;15(1):69-74. 149. Cunningham-Rundles C. Physiology of IgA and IgA deficiency. J Clin Immunol. 2001;21(5):303-9. 150. Aittoniemi J, Koskinen S, Laippala P, Laine S, Miettinen A. The significance of IgG subclasses and mannan-binding lectin (MBL) for susceptibility to infection in apparently healthy adults with IgA deficiency. Clin Exp Immunol. 1999;116(3):505-8. 151. Bossuyt X, Moens L, Van Hoeyveld E, Jeurissen A, Bogaert G, Sauer K, et al. Coexistence of (partial) immune defects and risk of recurrent respiratory infections. Clin Chem. 2007;53(1):124- 30. 152. Edwards E, Razvi S, Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine. Clin Immunol. 2004;111(1):93-7. 153. French MA, Denis KA, Dawkins R, Peter JB. Severity of infections in IgA deficiency: correlation with decreased serum antibodies to pneumococcal polysaccharides and decreased serum IgG2 and/or IgG4. Clin Expe Immunol. 1995;100(1):47-53. 154. Wang N, Shen N, Vyse TJ, Anand V, Gunnarson I, Sturfelt G, et al. Selective IgA deficiency in autoimmune diseases. Mol Med. 2011;17(11-12):1383-96. 155. Lilic D, Sewell WA. IgA deficiency: what we should-or should not-be doing. J Clin Pathol. 2001;54(5):337-8. 156. Gustafson R, Gardulf A, Granert C, Hansen S, Hammarstrom L. Prophylactic therapy for selective IgA deficiency. Lancet. 1997;350(9081):865. 157. Sundin U, Nava S, Hammarstrom L. Induction of unresponsiveness against IgA in IgAdeficient patients on subcutaneous immunoglobulin infusion therapy. Clin Exp Immunol. 1998;112(2):341-6. 158. Maguire GA, Kumararatne DS, Joyce HJ. Are there any clinical indications for measuring IgG subclasses? Ann Clin Biochem. 2002;39(Pt 4):374- 7. 159. Buckley RH. Immunoglobulin G subclass deficiency: fact or fancy? Curr Allergy Asthma Rep. 2002;2(5):356-60. 160. Wasserman RL, Sorensen RU. Evaluating children with respiratory tract infections: the role of immunization with bacterial polysaccharide vaccine. Pediatr Infect Dis J. 1999;18(2):157-63. 161. Sorensen RU, Moore C. Immunology in the pediatrician's office. Pediatr Clin North Am. 1994;41(4):691-714. 162. Sorensen RU, Moore C. Antibody deficiency syndromes. Pediatr Clin North Am. 2000;47(6):1225-52. 163. Epstein MM, Gruskay F. Selective deficiency in pneumococcal antibody response in children with recurrent infections. Ann Allergy Asthma Immunol. 1995;75(2):125-31. 164. Hidalgo H, Moore C, Leiva LE, Sorensen RU. Preimmunization and postimmunization pneumococcal antibody titers in children with recurrent infections. Ann Allergy Asthma Immunol. 1996;76(4):341-6. 165. Javier FC, 3rd, Moore CM, Sorensen RU. Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital. Ann Allergy Asthma Immunol. 2000;84(1):25-30. 166. De Donato S, Granoff D, Minutello M, Lecchi G, Faccini M, Agnello M, et al. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine. 1999;17(23- 24):3094-101. 167. Ambrosino DM, Siber GR, Chilmonczyk BA, Jernberg JB, Finberg RW. An immunodeficiency characterized by impaired antibody responses to polysaccharides. N Engl J Med. 1987;316(13):790-3. 168. Timens W, S P. Impaired immune response to polysaccharides. N Engl J Med. 1987;317(13):837-9. 169. Boyle RJ, Le C, Balloch A, Tang ML. The clinical syndrome of specific antibody deficiency in children. Clin Exp Immunol. 2006;146(3):486-92. 170. Sorensen RU, Leiva LE, Javier FC, 3rd, Sacerdote DM, Bradford N, Butler B, et al. Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations. J Allergy Clin Immunol. 1998;102(2):215-21. 171. Ambrosino DM, Umetsu DT, Siber GR, Howie G, Goularte TA, Michaels R, et al. Selective defect in the antibody response to Haemophilus influenzae type b in children with recurrent infections and normal serum IgG subclass levels. J Allergy Clin Immunol. 1988;81(6):1175-9. 172. Sorensen RU, Leiva LE, Giangrosso PA, Butler B, Javier FC, 3rd, Sacerdote DM, et al. Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children with recurrent infections who are unresponsive to the polysaccharide vaccine. Pediatr Infect Dis J. 1998;17(8):685-91. 173. McGeady SJ. Transient hypogammaglobulinemia of infancy: need to reconsider name and definition. J Pediatr. 1987;110(1):47-50. 174. Dogu F, Ikinciogullari A, Babacan E. Transient hypogammaglobulinemia of infancy and early childhood: outcome of 30 cases. Turk J Pediatr. 2004;46(2):120-4. 175. Buckley RH. Humoral immunodeficiency. Clinical immunology and immunopathology. 1986;40(1):13-24. 176. Kilic SS, Tezcan I, Sanal O, Metin A, Ersoy F. Transient hypogammaglobulinemia of infancy: clinical and immunologic features of 40 new cases. Pediatr Int. 2000;42(6):647-50. 177. Yates AB, Shaw SG, Moffitt JE. Spontaneous resolution of profound hypogammaglobulinemia. South Med J. 2001;94(12):1215-6. 178. Tiller TL, Jr., Buckley RH. Transient hypogammaglobulinemia of infancy: review of the literature, clinical and immunologic features of 11 new cases, and long-term follow-up. J Pediatr. 1978;92(3):347-53.