Encyclopedia of Medical Immunology

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

CD20 Deficiency, Lessons Related to Therapeutic Biologicals and Primary Immunodeficiency

  • Taco W. KuijpersEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_26-1


CD20 was one of the first B-cell-specific differentiation antigens identified (Stashenko et al. 1980). Nowadays, anti-CD20 immunotherapy using chimeric monoclonal antibodies (MoAbs) is used for the treatment of B-cell neoplasia, EBV-associated immunopathology, and a growing list of diseases with presumed autoimmune origin (Franks et al. 2016; Miano 2016; Claes et al. 2015; Froissart et al. 2015).

CD20, encoded by membrane-spanning 4 domains, subfamily a, member 1 (MS4A1; OMIM*112210), belongs to the MS4A family of molecules with multiple membrane-spanning domains (Liang et al. 2001; Liang and Tedder 2001) and is expressed on pre-B and mature B cells but is downregulated upon differentiation into plasma cells (Tedder and Engel 1994). CD20 is unlikely to have a natural ligand, but in vitro studies with CD20, MoAbs have demonstrated its involvement in the regulation of B-cell activation and proliferation (Tedder et al. 1985, 1986).

The CD20gene structure and expression...

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  1. 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.CrossRefGoogle Scholar
  2. Cancro MP. Signalling crosstalk in B cells: managing worth and need. Nat Rev Immunol. 2009;9:657–61.CrossRefGoogle Scholar
  3. Claes N, Fraussen J, Stinissen P, Hupperts R, Somers V. B cells are multifunctional players in multiple sclerosis pathogenesis: insights from therapeutic interventions. Front Immunol. 2015;6:642.CrossRefGoogle Scholar
  4. Claudio E, Brown K, Park S, Wang H, Siebenlist U. BAFF-induced NEMO-independent processing of NF-kB2 in maturing B cells. Nat Immunol. 2002;3:958–65.CrossRefGoogle Scholar
  5. Eggleton P, Bremer E, Tarr JM, de Bruyn M, Helfrich W, Kendall A, Haigh RC, Viner NJ, Winyard PG. Frequency of Th17 CD20+ cells in the peripheral blood of rheumatoid arthritis patients is higher compared to healthy subjects. Arthritis Res Ther. 2011;13:R208.CrossRefGoogle Scholar
  6. Franks SE, Getahun A, Hogarth PM, Cambier JC. Targeting B cells in treatment of autoimmunity. Curr Opin Immunol. 2016;43:39–45.CrossRefGoogle Scholar
  7. Froissart A, Veyradier A, Hié M, Benhamou Y, Coppo P, French Reference Center for Thrombotic Microangiopathies. Rituximab in autoimmune thrombotic thrombocytopenic purpura: a success story. Eur J Intern Med. 2015;26(9):659–65.CrossRefGoogle Scholar
  8. Golay JT, Clark EA, Beverley PC. The CD20 (Bp35) antigen is involved in activation of B cells from the G0 to the G1 phase of the cell cycle. J Immunol. 1985;135:3795–801.PubMedGoogle Scholar
  9. Grumont RJ, Rourke IJ, O’Reilly LA, Strasser A, Miyake K, Sha W, Gerondakis S. B lymphocytes differentially use the Rel and nuclear factor kB1 (NF-kB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med. 1998;187:663–74.CrossRefGoogle Scholar
  10. Grumont RJ, Rourke IJ, Gerondakis S. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev. 1999;13:400–11.CrossRefGoogle Scholar
  11. Henry C, Ramadan A, Montcuquet N, Pallandre JR, Mercier-Letondal P, Deschamps M, Tiberghien P, Ferrand C, Robinet E. CD3+CD20+ cells may be an artifact of flow cytometry: comment on the article by Wilk et al. Arthritis Rheum. 2010;62:2561–3. (author reply 2563–2565)CrossRefGoogle Scholar
  12. Hultin LE, Hausner MA, Hultin PM, Giorgi JV. CD20 (pan-B cell) antigen is expressed at a low level on a subpopulation of human T lymphocytes. Cytometry. 1993;14:196–204.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, Beaumont T, Tedder TF, van Noesel CJ, Eldering E, van Lier RA. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest. 2010;120:214–22.CrossRefGoogle Scholar
  15. 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(2):119–27.CrossRefGoogle Scholar
  16. Liang Y, Buckley TR, Tu L, Langdon SD, Tedder TF. Structural organization of the human MS4A gene cluster on Chromosome 11q12. Immunogenetics. 2001;53(5):357–68.CrossRefGoogle Scholar
  17. Mackay F, Figgett WA, Saulep D, Lepage M, Hibbs ML. B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor. Immunol Rev. 2010;237:205–25.CrossRefGoogle Scholar
  18. Miano M. How I manage Evans syndrome and AIHA cases in children. Br J Haematol. 2016;172(4):524–34.CrossRefGoogle Scholar
  19. O’Keefe TL, Williams GT, Davies SL, Neuberger MS. Mice carrying a CD20 gene disruption. Immunogenetics. 1998;48(2):125–32.CrossRefGoogle Scholar
  20. Okroj M, Osterborg A, Blom AM. Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies. Cancer Treat Rev. 2013;39:632–6.CrossRefGoogle Scholar
  21. Saijo K, Mecklenbrauker I, Santana A, Leitger M, Schmedt C, Tarakhovsky A. Protein kinase C beta controls nuclear factor kB activation in B cells through selective regulation of the IkB kinase alpha. J Exp Med. 2002;195:1647–52.CrossRefGoogle Scholar
  22. Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E, Scott ML. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science. 2001;293:2111–4.CrossRefGoogle Scholar
  23. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J Immunol. 1980;125(4):1678–85.PubMedGoogle Scholar
  24. Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today. 1994;15(9):450–4.CrossRefGoogle Scholar
  25. Tedder TF, et al. The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol. 1985;135(2):973–9.PubMedGoogle Scholar
  26. Tedder TF, et al. 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.CrossRefGoogle Scholar
  27. Tedder TF, et al. Cloning of a complementary DNA encoding a new mouse B lymphocyte differentiation antigen, homologous to the human B1 (CD20) antigen, and localization of the gene to chromosome 19. J Immunol. 1988;141(12):4388–94.PubMedGoogle Scholar
  28. Tedder TF, Klejman G, Schlossman SF, Saito H. Structure of the gene encoding the human B lymphocyte differentiation antigen CD20 (B1). J Immunol. 1989;142(7):2560–8.PubMedGoogle Scholar
  29. Thompson JS, Bixler SA, Qian F, Vora K, Scott ML, Cachero TG, Hession C, Schneider P, Sizing ID, Mullen C, et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science. 2001;293:2108–11.CrossRefGoogle Scholar
  30. Townsend MJ, Monroe JG, Chan AC. B-cell targeted therapies in human autoimmune diseases: an updated perspective. Immunol Rev. 2010;237:264–83.CrossRefGoogle Scholar
  31. Tsuiji M, et al. A checkpoint for autoreactivity in human IgM+ memory B cell development. J Exp Med. 2006;203(2):393–400.CrossRefGoogle Scholar
  32. Uchida J, Lee Y, Hasegawa M, Liang Y, Bradney A, Oliver JA, Bowen K, Steeber DA, Haas KM, Poe JC, Tedder TF. Mouse CD20 expression and function. Int Immunol. 2004a;16:119–29.CrossRefGoogle Scholar
  33. Uchida J, et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004b;199(12):1659–69.CrossRefGoogle Scholar
  34. van der Kolk LE, et al. CD20-induced B cell death can bypass mitochondria and caspase activation. Leukemia. 2002;16(9):1735–44.CrossRefGoogle Scholar
  35. Weller S, et al. Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood. 2004;104(12):3647–54.CrossRefGoogle Scholar
  36. Wilk E, Witte T, Marquardt N, Horvath T, Kalippke K, Scholz K, Wilke N, Schmidt RE, Jacobs R. Depletion of functionally active CD20+ T cells by rituximab treatment. Arthritis Rheum. 2009;60:3563–71.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Pediatric Hematology, Immunology and Infectious DiseasesAcademic Medical Center (AMC), Emma Children’s HospitalAmsterdamThe Netherlands

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