Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

CD19 Deficiency Due to Genetic Defects in the CD19 and CD81 Genes

  • Menno C. van ZelmEmail author
  • Ismail Reisli
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_24-1

Definition

An immunodeficiency defined by deleterious mutations and/or deletions in CD19 or CD81 encoding CD19 and CD81 B cell surface proteins.

Prevalence

To date, 10 patients have been identified with CD19 deficiency due to mutations in CD19 and 1 patient due to a deleterious mutation in CD81.

Physiology of CD19 and the Complex Members CD21, CD81, and CD225

B-cell lineage commitment from hematopoietic stem cells is a stepwise process and critically depends on several transcription factors, including E2A, EBF, and Pax5 (Lin and Grosschedl 1995; Urbanek et al. 1994; Zhuang et al. 1994). In addition to functioning as B-cell commitment factor, Pax5 directly regulates CD19 gene expression (Kozmik et al. 1992). As a result, CD19 membrane expression – first described in 1983 (Nadler et al. 1983) – is a direct marker of committed B cells and is reflective of the expression of Pax5 (Fig. 1). CD19 is expressed prior to surface immunoglobulin (Ig) and two previously characterized markers that...
This is a preview of subscription content, log in to check access.

References

  1. Artac H, Reisli I, Kara R, Pico-Knijnenburg I, Adin-Cinar S, Pekcan S, Jol-van der Zijde CM, van Tol MJ, Bakker-Jonges LE, van Dongen JJ, et al. B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele. Genes Immun. 2010;11:523–30.CrossRefGoogle Scholar
  2. Bousfiha A, Jeddane L, Al-Herz W, Ailal F, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, et al. The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol. 2015;35:727–38.CrossRefGoogle Scholar
  3. Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF. The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J Immunol. 1992;149:2841–50.PubMedGoogle Scholar
  4. Chen YX, Welte K, Gebhard DH, Evans RL. Induction of T cell aggregation by antibody to a 16kd human leukocyte surface antigen. J Immunol. 1984;133:2496–501.PubMedGoogle Scholar
  5. 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;93:190–7.CrossRefGoogle Scholar
  6. Conley ME, Dobbs AK, Farmer DM, Kilic S, Paris K, Grigoriadou S, Coustan-Smith E, Howard V, Campana D. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol. 2009;27:199–227.CrossRefGoogle Scholar
  7. Diamant E, Keren Z, Melamed D. CD19 regulates positive selection and maturation in B lymphopoiesis: lack of CD19 imposes developmental arrest of immature B cells and consequential stimulation of receptor editing. Blood. 2005;105:3247–54.CrossRefGoogle Scholar
  8. Freeman SA, Jaumouille V, Choi K, Hsu BE, Wong HS, Abraham L, Graves ML, Coombs D, Roskelley CD, Das R, et al. Toll-like receptor ligands sensitize B-cell receptor signalling by reducing actin-dependent spatial confinement of the receptor. Nat Commun. 2015;6:6168.CrossRefGoogle Scholar
  9. Kanegane H, Agematsu K, Futatani T, Sira MM, Suga K, Sekiguchi T, van Zelm MC, Miyawaki T. Novel mutations in a Japanese patient with CD19 deficiency. Genes Immun. 2007;8:663–70.CrossRefGoogle Scholar
  10. Keppler SJ, Gasparrini F, Burbage M, Aggarwal S, Frederico B, Geha RS, Way M, Bruckbauer A, Batista FD. Wiskott-Aldrich syndrome interacting protein deficiency uncovers the role of the co-receptor CD19 as a generic hub for PI3 kinase signaling in B cells. Immunity. 2015;43:660–73.CrossRefGoogle Scholar
  11. Kozmik Z, Wang S, Dorfler P, Adams B, Busslinger M. The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP. Mol Cell Biol. 1992;12:2662–72.CrossRefGoogle Scholar
  12. Lin H, Grosschedl R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature. 1995;376:263–7.CrossRefGoogle Scholar
  13. Maecker HT, Levy S. Normal lymphocyte development but delayed humoral immune response in CD81-null mice. J Exp Med. 1997;185:1505–10.CrossRefGoogle Scholar
  14. Matsumoto AK, Kopicky-Burd J, Carter RH, Tuveson DA, Tedder TF, Fearon DT. Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19. J Exp Med. 1991;173:55–64.CrossRefGoogle Scholar
  15. 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;178:1407–17.CrossRefGoogle Scholar
  16. Mattila PK, Feest C, Depoil D, Treanor B, Montaner B, Otipoby KL, Carter R, Justement LB, Bruckbauer A, Batista FD. The actin and tetraspanin networks organize receptor nanoclusters to regulate B cell receptor-mediated signaling. Immunity. 2013;38:461–74.CrossRefGoogle Scholar
  17. Miyazaki T, Muller U, Campbell KS. Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81. EMBO J. 1997;16:4217–25.CrossRefGoogle Scholar
  18. Moore MD, Cooper NR, Tack BF, Nemerow GR. Molecular cloning of the cDNA encoding the Epstein-Barr virus/C3d receptor (complement receptor type 2) of human B lymphocytes. Proc Natl Acad Sci U S A. 1987;84:9194–8.CrossRefGoogle Scholar
  19. Morbach H, Schickel JN, Cunningham-Rundles C, Conley ME, Reisli I, Franco JL, Meffre E. CD19 controls Toll-like receptor 9 responses in human B cells. J Allergy Clin Immunol. 2016;137:889–98.e6.CrossRefGoogle Scholar
  20. Mouillot G, Carmagnat M, Gerard L, Garnier JL, Fieschi C, Vince N, Karlin L, Viallard JF, Jaussaud R, Boileau J, 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.CrossRefGoogle Scholar
  21. Nadler LM, Stashenko P, Hardy R, van Agthoven A, Terhorst C, Schlossman SF. Characterization of a human B cell-specific antigen (B2) distinct from B1. J Immunol. 1981;126:1941–7.PubMedGoogle Scholar
  22. Nadler LM, Anderson KC, Marti G, Bates M, Park E, Daley JF, Schlossman SF. B4, a human B lymphocyte-associated antigen expressed on normal, mitogen-activated, and malignant B lymphocytes. J Immunol. 1983;131:244–50.PubMedGoogle Scholar
  23. Oren R, Takahashi S, Doss C, Levy R, Levy S. TAPA-1, the target of an antiproliferative antibody, defines a new family of transmembrane proteins. Mol Cell Biol. 1990;10:4007–15.CrossRefGoogle Scholar
  24. Otero DC, Rickert RC. CD19 function in early and late B cell development. II. CD19 facilitates the pro-B/pre-B transition. J Immunol. 2003;171:5921–30.CrossRefGoogle Scholar
  25. Reisli I, Artac H, Pekcan S, Kara R, Yumiu K, Karagol C, Cimen O, Sen M, Artac M. CD19 deficiency: a village screening study. Turk Arch Ped. 2009;44:127–30.Google Scholar
  26. Sato S, Miller AS, Howard MC, Tedder TF. Regulation of B lymphocyte development and activation by the CD19/CD21/CD81/Leu 13 complex requires the cytoplasmic domain of CD19. J Immunol. 1997;159:3278–87.PubMedGoogle Scholar
  27. Skendros P, Rondeau S, Chateil JF, Bui S, Bocly V, Moreau JF, Theodorou I, Aladjidi N. Misdiagnosed CD19 deficiency leads to severe lung disease. Pediatr Allergy Immunol. 2014;25:603–6.PubMedGoogle Scholar
  28. Stamenkovic I, Seed B. CD19, the earliest differentiation antigen of the B cell lineage, bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related cytoplasmic tail. J Exp Med. 1988;168:1205–10.CrossRefGoogle Scholar
  29. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J Immunol. 1980;125:1678–85.PubMedGoogle Scholar
  30. Takahashi S, Doss C, Levy S, Levy R. TAPA-1, the target of an antiproliferative antibody, is associated on the cell surface with the Leu-13 antigen. J Immunol. 1990;145:2207–13.PubMedGoogle Scholar
  31. Tedder TF, Isaacs CM. Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol. 1989;143:712–7.PubMedGoogle Scholar
  32. Tedder TF, Clement LT, Cooper MD. Expression of C3d receptors during human B cell differentiation: immunofluorescence analysis with the HB-5 monoclonal antibody. J Immunol. 1984;133:678–83.PubMedGoogle Scholar
  33. Thiel J, Kimmig L, Salzer U, Grudzien M, Lebrecht D, Hagena T, Draeger R, Voelxen N, Bergbreiter A, Jennings S, et al. Genetic CD21 deficiency is associated with hypogammaglobulinemia. J Allergy Clin Immunol. 2012;129:801–810.e6.CrossRefGoogle Scholar
  34. Treanor B, Depoil D, Gonzalez-Granja A, Barral P, Weber M, Dushek O, Bruckbauer A, Batista FD. The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Immunity. 2010;32:187–99.CrossRefGoogle Scholar
  35. Tsitsikov EN, Gutierrez-Ramos JC, Geha RS. Impaired CD19 expression and signaling, enhanced antibody response to type II T independent antigen and reduction of B-1 cells in CD81-deficient mice. Proc Natl Acad Sci U S A. 1997;94:10844–9.CrossRefGoogle Scholar
  36. Urbanek P, Wang ZQ, Fetka I, Wagner EF, Busslinger M. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell. 1994;79:901–12.CrossRefGoogle Scholar
  37. van Zelm MC, van der Burg M, de Ridder D, Barendregt BH, de Haas EF, Reinders MJ, Lankester AC, Revesz T, Staal FJ, van Dongen JJ. Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression. J Immunol. 2005;175:5912–22.CrossRefGoogle Scholar
  38. van Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJM, van Tol MJD, Woellner C, Grimbacher B, Patiño PJ, van Dongen JJM, Franco JL. An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med. 2006;354:1901–12.CrossRefGoogle Scholar
  39. van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F, Ferster A, Kuo CC, Levy S, van Dongen JJ, van der Burg M. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest. 2010;120:1265–74.CrossRefGoogle Scholar
  40. van Zelm MC, Smet J, van der Burg M, Ferster A, Le PQ, Schandene L, van Dongen JJ, Mascart F. 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;20:1854–63.CrossRefGoogle Scholar
  41. van Zelm MC, Bartol SJ, Driessen GJ, Mascart F, Reisli I, Franco JL, Wolska-Kusnierz B, Kanegane H, Boon L, van Dongen JJ, van der Burg M. Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. J Allergy Clin Immunol. 2014;134:135–44.CrossRefGoogle Scholar
  42. Vince N, Boutboul D, Mouillot G, Just N, Peralta M, Casanova JL, Conley ME, Bories JC, Oksenhendler E, Malphettes M, et al. Defects in the CD19 complex predispose to glomerulonephritis, as well as IgG1 subclass deficiency. J Allergy Clin Immunol. 2011;127:538–541e1–5.CrossRefGoogle Scholar
  43. Wang Y, Brooks SR, Li X, Anzelon AN, Rickert RC, Carter RH. The physiologic role of CD19 cytoplasmic tyrosines. Immunity. 2002;17:501–14.CrossRefGoogle Scholar
  44. Warnatz K, Wehr C, Drager R, Schmidt S, Eibel H, Schlesier M, Peter HH. Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology. 2002;206:502–13.CrossRefGoogle Scholar
  45. Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, Vlkova M, Hernandez M, Detkova D, Bos PR, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111:77–85.CrossRefGoogle Scholar
  46. Weis JH, Morton CC, Bruns GA, Weis JJ, Klickstein LB, Wong WW, Fearon DT. A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32. J Immunol. 1987;138:312–5.PubMedGoogle Scholar
  47. Wentink MW, Lambeck AJ, van Zelm MC, Simons E, van Dongen JJ, IJspeert H, Scholvinck EH, van der Burg M. CD21 and CD19 deficiency: Two defects in the same complex leading to different disease modalities. Clin Immunol. 2015;161:120–7.CrossRefGoogle Scholar
  48. Zhuang Y, Soriano P, Weintraub H. The helix-loop-helix gene E2A is required for B cell formation. Cell. 1994;79:875–84.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Immunology and PathologyCentral Clinical School, Monash UniversityMelbourneAustralia
  2. 2.Department of Respiratory MedicineThe Alfred HospitalMelbourneAustralia
  3. 3.The Jeffrey Modell Diagnostic and Research Centre for Primary ImmunodeficienciesMelbourneAustralia
  4. 4.Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Department of PediatricsNecmettin Erbakan UniversityKonyaTurkey

Section editors and affiliations

  • Klaus Warnatz
    • 1
  • Joris M. van Montfrans
    • 2
  1. 1.Center for Chronic ImmunodeficiencyUniversity Medical Center and University of FreiburgFreiburgGermany
  2. 2.UMC UtrechtUtrechtNetherlands