The Genetic Heterogeneity of Common VariableImmunodeficiency (CVID)
Abstract
CVID represents the most frequent symptomatic primary humoral immunodeficiency. Clinical presentation includes hypogammaglobulinemia, recurrent infections, autoimmune phaenomena and increased lymphoma and cancer risk. While the first cases were reported in the early 50’s, the first genetic cause of CVID was described after 5 decades. After the first description, and also thanks to the advances in the field of biomedical research, several additional genetic causes of CVID have been described. The current genetic landscape of CVID includes numerous genetic alterations that may cause or contribute to the development of CVID, underscoring the complexity and heterogeneity of this disorder.
1. Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program. 2012;2012:301-5.
2. Bruton OC, Apt L, Gitlin D, Janeway CA. Absence of serum gamma globulins. AMA Am J Dis Child. 1952;84(5):632-6.
3. 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. Nature Immunology. 2003;4(3):261-8.
4. 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(8):3045-52.
5. 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.
6. 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(8):820-8.
7. Yan M, Wang H, Chan B, Roose-Girma M, Erickson S, Baker T, et al. Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol. 2001;2(7):638-43.
8. 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(4):429-30.
9. 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(4):430-1.
10. 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(8):836-9.
11. Salzer U, Bacchelli C, Buckridge S, Pan-Hammarstrom 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(9):1967-76.
12. 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. Journal of Clinical Immunology. 2005;25(5):496-502.
13. Pieper K, Rizzi M, Speletas M, Smulski CR,Sic H, Kraus H, et al. A common single nucleotide polymorphism impairs B-cell activating factor receptor’s multimerization, contributing to common variable immunodeficiency. J Allergy Clin Immunol. 2014;133(4):1222-5.
14. 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(33):13945-50.
15. Losi CG, Salzer U, Gatta R, Lougaris V, Cattaneo G, Meini A, et al. Mutational analysis of human BLyS in patients with common variable immunodeficiency. J Clin Immunol. 2006;26(4):396-9.
16. Salzer U, Neumann C, Thiel J, Woellner C, Pan-Hammarstrom Q, Lougaris V, et al. Screening of functional and positional candidate genes in families with common variable immunodeficiency. BMC Immunol. 2008;9:3.
17. Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJM, van Tol MJD, et al. An Antibody-Deficiency Syndrome Due to Mutations in the CD19 Gene. 2006;354(18):1901-12.
18. 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.
19. 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(1):214-22.
20. 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.
21. 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.e6.
22. Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK, et al. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. Blood. 2013;121(16):3112-6.
23. Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL, et al. Lossof-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117-25.
24. Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, et al. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013;65(8):2161-71.
25. Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866-71.
26. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88-97.
27. Kracker S, Curtis J, Ibrahim MAA, Sediva A, Salisbury J, Campr V, et al. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome. The Journal of allergy and clinical immunology. 2014;134(1):233-6.
28. Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9):3923-8.
29. Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211(13):2537-47.30. Lougaris V, Faletra F, Lanzi G, Vozzi D, Marcuzzi A, Valencic E, et al. Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. Clin Immunol. 2015;159(1):33-6.
31. Lougaris V, Patrizi O, Baronio M, Tabellini G, Tampella G, Lanzi G, et al. p85α is an intrinsic regulator of human natural killer cell effector functions. 2016;138(2):605-8. e3.
32. Ruiz-García R, Vargas-Hernández A, Chinn IK, Angelo LS, Cao TN, Coban-Akdemir Z, et al. Mutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment. J Allergy Clin Immunol. 2018;142(2):605-17.e7.
33. 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.
34. Lopez-Herrera G, Tampella G, Pan-Hammarstrom Q, Herholz P, Trujillo-Vargas CM, Phadwal K, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986-1001.
35. Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. 2012;130(6):1428-32.
36. Gamez-Diaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, et al. The extended phenotype of LPS-responsive beigelike anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223-30.
37. Bakhtiar S, Gamez-Diaz L, Jarisch A, Soerensen J, Grimbacher B, Belohradsky B, et al. Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency. Front Immunol. 2017;8:52.
38. Alroqi FJ, Charbonnier LM, Baris S, Kiykim A, Chou J, Platt CD, et al. Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018;141(3):1050-9 e10.
39. Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436-40.
40. Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, et al. Abatacept as a LongTerm Targeted Therapy for LRBA Deficiency. J Allergy Clin Immunol Pract. 2019;7(8):2790- 800.e15.
41. Lindsley AW, Qian Y, Valencia CA, Shah K, Zhang K, Assa’ad A. Combined immune deficiency in a patient with a novel NFKB2 mutation. J Clin Immunol. 2014;34(8):910-5.
42. Lee CE, Fulcher DA, Whittle B, Chand R, Fewings N, Field M, et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood. 2014;124(19):2964-72.
43. Lougaris V, Tabellini G, Vitali M, Baronio M, Patrizi O, Tampella G, et al. Defective natural killer-cell cytotoxic activity in NFKB2-mutated CVID-like disease. J Allergy Clin Immunol. 2015;135(6):1641-3.
44. Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, et al. Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. Am J Hum Genet. 2015;97(3):389-403.
45. Lougaris V, Moratto D, Baronio M, Tampella G, van der Meer JWM, Badolato R, et al. Early and late B-cell developmental impairment in nuclear factor kappa B, subunit 1-mutated common variable immunodeficiency disease. J Allergy Clin Immunol. 2017;139(1):349-52.e1.
46. Schipp C, Nabhani S, Bienemann K, Si-manovsky N, Kfir-Erenfeld S, Assayag-Asherie N, et al. Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans. Haematologica. 2016;101(10):e392-e6.
47. Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D, et al. NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation. J Clin Immunol. 2016;36(6):533-40.
48. Lougaris V, Patrizi O, Baronio M, Tabellini G, Tampella G, Damiati E, et al. NFKB1 regulates human NK cell maturation and effector functions. Clin Immunol. 2017;175:99-108.
49. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410-6.
50. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623-7.
51. Miska J, Lui JB, Toomer KH, Devarajan P, Cai X, Houghton J, et al. Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines. J Exp Med. 2018;215(3):841-58.
52. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370(10):911-20.
53. Schepp J, Proietti M, Frede N, Buchta M, Hubscher K, Rojas Restrepo J, et al. Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood. Arthritis Rheumatol. 2017;69(8):1689-700.
54. Schepp J, Bulashevska A, Mannhardt-Laakmann W, Cao H, Yang F, Seidl M, et al. Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency. J Clin Immunol. 2016;36(3):179-86.
55. Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, Jones A, et al. Treatment Strategies for Deficiency of Adenosine Deaminase 2. N Engl J Med. 2019;380(16):1582-4.
56. Sekine H, Ferreira RC, Pan-Hammarstrom 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(17):7193-8.
57. Sobacchi C, Marrella V, Rucci F, Vezzoni P, Villa A. RAG-dependent primary immunodeficiencies. Human mutation. 2006;27(12):1174-84.
58. Abolhassani H, Wang N, Aghamohammadi A, Rezaei N, Lee YN, Frugoni F, et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(6):1375-80.
59. Buchbinder D, Baker R, Lee YN, Ravell J, Zhang Y, McElwee J, et al. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J Clin Immunol. 2015;35(2):119-24.
60. Schröder C, Baerlecken NT, Pannicke U, Dörk T, Witte T, Jacobs R, et al. Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy. Clin Immunol. 2017;179:1-7.
2. Bruton OC, Apt L, Gitlin D, Janeway CA. Absence of serum gamma globulins. AMA Am J Dis Child. 1952;84(5):632-6.
3. 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. Nature Immunology. 2003;4(3):261-8.
4. 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(8):3045-52.
5. 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.
6. 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(8):820-8.
7. Yan M, Wang H, Chan B, Roose-Girma M, Erickson S, Baker T, et al. Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol. 2001;2(7):638-43.
8. 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(4):429-30.
9. 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(4):430-1.
10. 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(8):836-9.
11. Salzer U, Bacchelli C, Buckridge S, Pan-Hammarstrom 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(9):1967-76.
12. 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. Journal of Clinical Immunology. 2005;25(5):496-502.
13. Pieper K, Rizzi M, Speletas M, Smulski CR,Sic H, Kraus H, et al. A common single nucleotide polymorphism impairs B-cell activating factor receptor’s multimerization, contributing to common variable immunodeficiency. J Allergy Clin Immunol. 2014;133(4):1222-5.
14. 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(33):13945-50.
15. Losi CG, Salzer U, Gatta R, Lougaris V, Cattaneo G, Meini A, et al. Mutational analysis of human BLyS in patients with common variable immunodeficiency. J Clin Immunol. 2006;26(4):396-9.
16. Salzer U, Neumann C, Thiel J, Woellner C, Pan-Hammarstrom Q, Lougaris V, et al. Screening of functional and positional candidate genes in families with common variable immunodeficiency. BMC Immunol. 2008;9:3.
17. Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJM, van Tol MJD, et al. An Antibody-Deficiency Syndrome Due to Mutations in the CD19 Gene. 2006;354(18):1901-12.
18. 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.
19. 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(1):214-22.
20. 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.
21. 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.e6.
22. Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK, et al. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. Blood. 2013;121(16):3112-6.
23. Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL, et al. Lossof-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117-25.
24. Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, et al. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013;65(8):2161-71.
25. Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866-71.
26. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88-97.
27. Kracker S, Curtis J, Ibrahim MAA, Sediva A, Salisbury J, Campr V, et al. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome. The Journal of allergy and clinical immunology. 2014;134(1):233-6.
28. Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9):3923-8.
29. Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211(13):2537-47.30. Lougaris V, Faletra F, Lanzi G, Vozzi D, Marcuzzi A, Valencic E, et al. Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. Clin Immunol. 2015;159(1):33-6.
31. Lougaris V, Patrizi O, Baronio M, Tabellini G, Tampella G, Lanzi G, et al. p85α is an intrinsic regulator of human natural killer cell effector functions. 2016;138(2):605-8. e3.
32. Ruiz-García R, Vargas-Hernández A, Chinn IK, Angelo LS, Cao TN, Coban-Akdemir Z, et al. Mutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment. J Allergy Clin Immunol. 2018;142(2):605-17.e7.
33. 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.
34. Lopez-Herrera G, Tampella G, Pan-Hammarstrom Q, Herholz P, Trujillo-Vargas CM, Phadwal K, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986-1001.
35. Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. 2012;130(6):1428-32.
36. Gamez-Diaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, et al. The extended phenotype of LPS-responsive beigelike anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223-30.
37. Bakhtiar S, Gamez-Diaz L, Jarisch A, Soerensen J, Grimbacher B, Belohradsky B, et al. Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency. Front Immunol. 2017;8:52.
38. Alroqi FJ, Charbonnier LM, Baris S, Kiykim A, Chou J, Platt CD, et al. Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018;141(3):1050-9 e10.
39. Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436-40.
40. Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, et al. Abatacept as a LongTerm Targeted Therapy for LRBA Deficiency. J Allergy Clin Immunol Pract. 2019;7(8):2790- 800.e15.
41. Lindsley AW, Qian Y, Valencia CA, Shah K, Zhang K, Assa’ad A. Combined immune deficiency in a patient with a novel NFKB2 mutation. J Clin Immunol. 2014;34(8):910-5.
42. Lee CE, Fulcher DA, Whittle B, Chand R, Fewings N, Field M, et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood. 2014;124(19):2964-72.
43. Lougaris V, Tabellini G, Vitali M, Baronio M, Patrizi O, Tampella G, et al. Defective natural killer-cell cytotoxic activity in NFKB2-mutated CVID-like disease. J Allergy Clin Immunol. 2015;135(6):1641-3.
44. Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, et al. Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. Am J Hum Genet. 2015;97(3):389-403.
45. Lougaris V, Moratto D, Baronio M, Tampella G, van der Meer JWM, Badolato R, et al. Early and late B-cell developmental impairment in nuclear factor kappa B, subunit 1-mutated common variable immunodeficiency disease. J Allergy Clin Immunol. 2017;139(1):349-52.e1.
46. Schipp C, Nabhani S, Bienemann K, Si-manovsky N, Kfir-Erenfeld S, Assayag-Asherie N, et al. Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans. Haematologica. 2016;101(10):e392-e6.
47. Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D, et al. NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation. J Clin Immunol. 2016;36(6):533-40.
48. Lougaris V, Patrizi O, Baronio M, Tabellini G, Tampella G, Damiati E, et al. NFKB1 regulates human NK cell maturation and effector functions. Clin Immunol. 2017;175:99-108.
49. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410-6.
50. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623-7.
51. Miska J, Lui JB, Toomer KH, Devarajan P, Cai X, Houghton J, et al. Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines. J Exp Med. 2018;215(3):841-58.
52. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370(10):911-20.
53. Schepp J, Proietti M, Frede N, Buchta M, Hubscher K, Rojas Restrepo J, et al. Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood. Arthritis Rheumatol. 2017;69(8):1689-700.
54. Schepp J, Bulashevska A, Mannhardt-Laakmann W, Cao H, Yang F, Seidl M, et al. Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency. J Clin Immunol. 2016;36(3):179-86.
55. Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, Jones A, et al. Treatment Strategies for Deficiency of Adenosine Deaminase 2. N Engl J Med. 2019;380(16):1582-4.
56. Sekine H, Ferreira RC, Pan-Hammarstrom 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(17):7193-8.
57. Sobacchi C, Marrella V, Rucci F, Vezzoni P, Villa A. RAG-dependent primary immunodeficiencies. Human mutation. 2006;27(12):1174-84.
58. Abolhassani H, Wang N, Aghamohammadi A, Rezaei N, Lee YN, Frugoni F, et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(6):1375-80.
59. Buchbinder D, Baker R, Lee YN, Ravell J, Zhang Y, McElwee J, et al. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J Clin Immunol. 2015;35(2):119-24.
60. Schröder C, Baerlecken NT, Pannicke U, Dörk T, Witte T, Jacobs R, et al. Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy. Clin Immunol. 2017;179:1-7.
| Files | ||
| Issue | Vol 3, No 1 (2020) | |
| Section | Review Article | |
| DOI | https://doi.org/10.22034/igj.2020.224622.1036 | |
| Keywords | ||
| Common Variable Immunodeficiency (CVID) hypogammaglobulinemia autoimmunity | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Lougaris V, Plebani A. The Genetic Heterogeneity of Common VariableImmunodeficiency (CVID). Immunol Genet J. 2020;3(1):1-14.
