Advanced Biomedical Research

Genetic defects and the role of helper T-cells in the pathogenesis of common variable immunodeficiency

Authors

1 Department of Immunology, Faculty of Medicine, Isfahan, Iran

2 Department of Immunology, Faculty of Medicine; Cellular and Molecular Immunology Research Center, Isfahan, Iran

3 Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Common variable immunodeficfiiency (CVID) is a primary immunodeficiency syndrome representing a heterogeneous set of disorders resulting mostly in antibody deficiency and recurrent infections. However, inflammatory and autoimmune disorders and some kinds of malignancies are frequently reported as a part of the syndrome. Although it is one of the most widespread primary immunodeficiency, only recently some genetic defects in CVID have been identified. Mutations have been detected in inducible T-cell costimulator (ICOS), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell activating factor-receptor (BAFF-R), B-cell receptor complex (CD19, CD21 and CD81) and CD20. On the other hand, recent studies have shown a decrease in T-helper-17 cells frequency and their characteristic cytokines in CVID patients and this emphasis on the vital role of the T-cells in immunopathogenesis of the CVID. Furthermore, in the context of autoimmune diseases accompanying CVID, interleukin 9 has recently attracted a plenty of considerations. However, the list of defects is expanding as exact immunologic pathways and genetic disorders in CVID are not yet defined. In this review, we have a special focus on the immunopathogenesis of CVID, recent advances in understanding the underlying etiology and genetics for patients.

Keywords

 
1. Hammarström L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 2000;120:225-31.  Back to cited text no. 1
    
2. Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol 2009;145:709-27.  Back to cited text no. 2
    
3. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Primary immunodeficiency diseases. Clin Exp Immunol 1999;118 Suppl 1:1-28.  Back to cited text no. 3
    
4. 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.  Back to cited text no. 4
    
5. McCabe RP. Gastrointestinal manifestations of non-aids immunodeficiency. Curr Treat Options Gastroenterol 2002;5:17-25.  Back to cited text no. 5
    
6. Kalha I, Sellin JH. Common variable immunodeficiency and the gastrointestinal tract. Curr Gastroenterol Rep 2004;6:377-83.  Back to cited text no. 6
    
7. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency - An update. Arthritis Res Ther 2012;14:223.  Back to cited text no. 7
    
8. Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program 2012;2012:301-5.  Back to cited text no. 8
    
9. Ahn S, Cunningham-Rundles C. Role of B cells in common variable immune deficiency. Expert Rev Clin Immunol 2009;5:557-64.  Back to cited text no. 9
    
10. Pradhan V, Gorakshakar A. Are mannose-binding lectin gene 2 (MBL2) polymorphisms and MBL deficiency associated with infections? Indian J Hum Genet 2011;17:45-7.  Back to cited text no. 10
[PUBMED]  Medknow Journal  
11. Holm AM, Aukrust P, Damås JK, Müller F, Halvorsen B, Frøland SS. Abnormal interleukin-7 function in common variable immunodeficiency. Blood 2005;105:2887-90.  Back to cited text no. 11
    
12. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: Clinical and immunological features of 248 patients. Clin Immunol 1999;92:34-48.  Back to cited text no. 12
    
13. Barbosa RR, Silva SP, Silva SL, Melo AC, Pedro E, Barbosa MP, et al. Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T-cell homeostasis and B-cell differentiation. PLoS One 2011;6:e22848.  Back to cited text no. 13
    
14. Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest 2010;120:214-22.  Back to cited text no. 14
    
15. Offer SM, Pan-Hammarström Q, Hammarström L, Harris RS. Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One 2010;5:e12260.  Back to cited text no. 15
    
16. Salzer U, Chapel HM, Webster AD, Pan-Hammarström 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.  Back to cited text no. 16
    
17. Sekine H, Ferreira RC, Pan-Hammarström Q, Graham RR, Ziemba B, de Vries SS, et al. Role for Msh5 in the regulation of Ig class switch recombination. Proc Natl Acad Sci U S A 2007;104:7193-8.  Back to cited text no. 17
    
18. van Zelm MC, Reisli I, van der Burg M, Castaño 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.  Back to cited text no. 18
    
19. van Zelm MC, Smet J, Adams B, Mascart F, Schandené 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.  Back to cited text no. 19
    
20. Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Böhm 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.  Back to cited text no. 20
    
21. Bacchelli C, Buckridge S, Thrasher AJ, Gaspar HB. Translational mini-review series on immunodeficiency: Molecular defects in common variable immunodeficiency. Clin Exp Immunol 2007;149:401-9.  Back to cited text no. 21
    
22. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1999;397:263-6.  Back to cited text no. 22
    
23. Abbas AK, Litchman AH, Pillai SH. B cell activation and antibody production. In: Abbas AK, editor. Cellular and Molecular Immunology, 1 st ed. Philadelphia: Elsevier-Saunders; 2012. p. 243-67.  Back to cited text no. 23
    
24. Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, Plebani A, et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J Immunol 2006;177:4927-32.  Back to cited text no. 24
    
25. Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, van der Burg M, et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 2006;107:3045-52.  Back to cited text no. 25
    
26. Vieira PL, Wassink L, Smith LM, Nam S, Kingsbury GA, Gutierrez-Ramos JC, et al. ICOS-mediated signaling regulates cytokine production by human T cells and provides a unique signal to selectively control the clonal expansion of Th2 helper cells. Eur J Immunol 2004;34:1282-90.  Back to cited text no. 26
    
27. Nurieva RI, Duong J, Kishikawa H, Dianzani U, Rojo JM, Ho Ic, et al. Transcriptional regulation of th2 differentiation by inducible costimulator. Immunity 2003;18:801-11.  Back to cited text no. 27
    
28. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 2003;4:261-8.  Back to cited text no. 28
    
29. 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.  Back to cited text no. 29
    
30. Takahashi N, Matsumoto K, Saito H, Nanki T, Miyasaka N, Kobata T, et al. Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients. J Immunol 2009;182:5515-27.  Back to cited text no. 30
    
31. Schneider P. The role of APRIL and BAFF in lymphocyte activation. Curr Opin Immunol 2005;17:282-9.  Back to cited text no. 31
    
32. Kopecky´ O, Lukesová S. Genetic defects in common variable immunodeficiency. Int J Immunogenet 2007;34:225-9.  Back to cited text no. 32
    
33. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 1999;189:1747-56.  Back to cited text no. 33
    
34. Castigli E, Scott S, Dedeoglu F, Bryce P, Jabara H, Bhan AK, et al. Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acad Sci U S A 2004;101:3903-8.  Back to cited text no. 34
    
35. Castigli E, Wilson SA, Scott S, Dedeoglu F, Xu S, Lam KP, et al. TACI and BAFF-R mediate isotype switching in B cells. J Exp Med 2005;201:35-9.  Back to cited text no. 35
    
36. He B, Xu W, Santini PA, Polydorides AD, Chiu A, Estrella J, et al. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 2007;26:812-26.  Back to cited text no. 36
    
37. Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 2002;3:822-9.  Back to cited text no. 37
    
38. 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.  Back to cited text no. 38
    
39. Pan-Hammarström Q, Salzer U, Du L, Björkander 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.  Back to cited text no. 39
    
40. 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.  Back to cited text no. 40
    
41. Lougaris V, Gallizzi R, Vitali M, Baronio M, Salpietro A, Bergbreiter A, et al. A novel compound heterozygous TACI mutation in an autosomal recessive common variable immunodeficiency (CVID) family. Hum Immunol 2012;73:836-9.  Back to cited text no. 41
    
42. Salzer U, Grimbacher B. Monogenetic defects in common variable immunodeficiency: What can we learn about terminal B cell differentiation? Curr Opin Rheumatol 2006;18:377-82.  Back to cited text no. 42
    
43. Aghamohammadi A, Lougaris V, Plebani A, Miyawaki T, Durandy A, Hammarström L. Predominantly antibody deficiencies. In: Rezaei N, Aghamohammadi A, Notarangelo LD, editors. Primary Immunodeficiency Diseases: Definition, Diagnosis and Management. Berlin Heidelberg: Springer-Verlag; 2008. p. 97-130.  Back to cited text no. 43
    
44. Carter RH, Fearon DT. CD19: Lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 1992;256:105-7.  Back to cited text no. 44
    
45. Fearon DT, Carroll MC. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu Rev Immunol 2000;18:393-422.  Back to cited text no. 45
    
46. Levy S, Todd SC, Maecker HT. CD81 (TAPA-1): A molecule involved in signal transduction and cell adhesion in the immune system. Annu Rev Immunol 1998;16:89-109.  Back to cited text no. 46
    
47. 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;8:663-70.  Back to cited text no. 47
    
48. Mackay F, Schneider P, Rennert P, Browning J. BAFF AND APRIL: A tutorial on B cell survival. Annu Rev Immunol 2003;21:231-64.  Back to cited text no. 48
    
49. Ng LG, Sutherland AP, Newton R, Qian F, Cachero TG, Scott ML, et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol 2004;173:807-17.  Back to cited text no. 49
    
50. Thompson JS, Bixler SA, Qian F, Vora K, Scott ML, Cachero TG, et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 2001;293:2108-11.  Back to cited text no. 50
    
51. Rodig SJ, Shahsafaei A, Li B, Mackay CR, Dorfman DM. BAFF-R, the major B cell-activating factor receptor, is expressed on most mature B cells and B-cell lymphoproliferative disorders. Hum Pathol 2005;36:1113-9.  Back to cited text no. 51
    
52. Schweighoffer E, Vanes L, Nys J, Cantrell D, McCleary S, Smithers N, et al. The BAFF receptor transduces survival signals by co-opting the B cell receptor signaling pathway. Immunity 2013;38:475-88.  Back to cited text no. 52
    
53. Losi CG, Silini A, Fiorini C, Soresina A, Meini A, Ferrari S, et al. Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeficiency. J Clin Immunol 2005;25:496-502.  Back to cited text no. 53
    
54. Liang Y, Buckley TR, Tu L, Langdon SD, Tedder TF. Structural organization of the human MS4A gene cluster on Chromosome 11q12. Immunogenetics 2001;53:357-68.  Back to cited text no. 54
    
55. Tedder TF, Engel P. CD20: A regulator of cell-cycle progression of B lymphocytes. Immunol Today 1994;15:450-4.  Back to cited text no. 55
    
56. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J Immunol 1980;125:1678-85.  Back to cited text no. 56
    
57. Liang Y, Tedder TF. Identification of a CD20-, FcepsilonRIbeta-, and HTm4-related gene family: Sixteen new MS4A family members expressed in human and mouse. Genomics 2001;72:119-27.  Back to cited text no. 57
    
58. Park JH, Resnick ES, Cunningham-Rundles C. Perspectives on common variable immune deficiency. Ann N Y Acad Sci 2011;1246:41-9.  Back to cited text no. 58
    
59. Quast T, Eppler F, Semmling V, Schild C, Homsi Y, Levy S, et al. CD81 is essential for the formation of membrane protrusions and regulates Rac1-activation in adhesion-dependent immune cell migration. Blood 2011;118:1818-27.  Back to cited text no. 59
    
60. Andria ML, Hsieh CL, Oren R, Francke U, Levy S. Genomic organization and chromosomal localization of the TAPA-1 gene. J Immunol 1991;147:1030-6.  Back to cited text no. 60
    
61. Ulgiati D, Pham C, Holers VM. Functional analysis of the human complement receptor 2 (CR2/CD21) promoter: Characterization of basal transcriptional mechanisms. J Immunol 2002;168:6279-85.  Back to cited text no. 61
    
62. 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;129:801-8106.  Back to cited text no. 62
    
63. Tampella G, Baronio M, Vitali M, Soresina A, Badolato R, Giliani S, et al. Evaluation of CARMA1/CARD11 and Bob1 as candidate genes in common variable immunodeficiency. J Investig Allergol Clin Immunol 2011;21:348-53.  Back to cited text no. 63
    
64. Ganjalikhani Hakemi M, Ghaedi K, Andalib A, Homayouni V, Hosseini M, Rezaei A. RORC2 gene silencing in human Th17 cells by siRNA: Design and evaluation of highly efficient siRNA. Avicenna J Med Biotechnol 2013;5:10-9.  Back to cited text no. 64
    
65. Adibrad M, Deyhimi P, Ganjalikhani Hakemi M, Behfarnia P, Shahabuei M, Rafiee L. Signs of the presence of Th17 cells in chronic periodontal disease. J Periodontal Res 2012;47:525-31.  Back to cited text no. 65
    
66. Ganjalikhani Hakemi M, Ghaedi K, Andalib A, Hosseini M, Rezaei A. Optimization of human Th17 cell differentiation in vitro: Evaluating different polarizing factors. in vitro Cell Dev Biol Anim 2011;47:581-92.  Back to cited text no. 66
    
67. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011;34:108-21.  Back to cited text no. 67
    
68. 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.  Back to cited text no. 68
    
69. Lopes-da-Silva S, Rizzo LV. Autoimmunity in common variable immunodeficiency. J Clin Immunol 2008;28 Suppl 1:S46-55.  Back to cited text no. 69
    
70. 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.  Back to cited text no. 70
    
71. Boileau J, Mouillot G, Gérard 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;36:25-32.  Back to cited text no. 71
    
72. Brandtzaeg P. Mucosal immunity: Induction, dissemination, and effector functions. Scand J Immunol 2009;70:505-15.  Back to cited text no. 72
    
73. Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008;9:641-9.  Back to cited text no. 73
    
74. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 2008;454:350-2.  Back to cited text no. 74
    
75. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol 2009;27:485-517.  Back to cited text no. 75
    
76. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol 2005;175:7867-79.  Back to cited text no. 76
    
77. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science 2002;298:1630-4.  Back to cited text no. 77
    
78. Hilbert DM, Cancro MP, Scherle PA, Nordan RP, Van Snick J, Gerhard W, et al. T cell derived IL-6 is differentially required for antigen-specific antibody secretion by primary and secondary B cells. J Immunol 1989;143:4019-24.  Back to cited text no. 78
    
79. Sanos SL, Diefenbach A. Innate lymphoid cells: From border protection to the initiation of inflammatory diseases. Immunol Cell Biol 2013;91:215-24.  Back to cited text no. 79
    
80. Pearson C, Uhlig HH, Powrie F. Lymphoid microenvironments and innate lymphoid cells in the gut. Trends Immunol 2012;33:289-96.  Back to cited text no. 80
    
81. Nowak EC, Noelle RJ. Interleukin-9 as a T helper type 17 cytokine. Immunology 2010;131:169-73.  Back to cited text no. 81
    
82. Leng RX, Pan HF, Ye DQ, Xu Y. Potential roles of IL-9 in the pathogenesis of systemic lupus erythematosus. Am J Clin Exp Immunol 2012;1:28-32.  Back to cited text no. 82
    
83. Ouyang H, Shi Y, Liu Z, Feng S, Li L, Su N, et al. Increased interleukin-9 and CD4+IL-9+ T cells in patients with systemic lupus erythematosus. Mol Med Rep 2013;7:1031-7.  Back to cited text no. 83
    
84. Nowak EC, Weaver CT, Turner H, Begum-Haque S, Becher B, Schreiner B, et al. IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med 2009;206:1653-60.  Back to cited text no. 84
    
85. Cunningham-Rundles C. Common variable immunodeficiency. Curr Allergy Asthma Rep 2001;1:421-9.  Back to cited text no. 85
    
86. Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep 2009;9:347-52.  Back to cited text no. 86
    
Advanced Biomedical Research
Volume 2014, January
January 2014
Pages 1-7