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Gene Review

CR2  -  complement component (3d/Epstein Barr...

Homo sapiens

Synonyms: C3DR, CD21, CR, CVID7, Complement C3d receptor, ...
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Disease relevance of CR2


High impact information on CR2

  • Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex [5].
  • This complex reduces the threshold for B cell activation via the B cell receptor by bridging Ag specific recognition and CD21-mediated complement recognition [6].
  • CR2 also can be ligated by CD23, a lectin-like membrane protein that resides on cells that may present antigen to B cells [7].
  • CR2 binds fragments of C3 that are covalently attached to glycoconjugates [7].
  • Immunostaining for the EBV receptor was strongly positive in six of the seven leiomyomas and leiomyosarcomas from the patients with AIDS [8].

Chemical compound and disease context of CR2

  • Activation of Epstein-Barr virus/C3d receptor (gp140, CR2, CD21) on human B lymphoma cell surface triggers Cbl tyrosine phosphorylation, its association with p85 subunit, Crk-L and Syk and its dissociation with Vav [9].
  • We have quantitatively assessed binding by the two isotypic forms of CR2 for two of its ligands, the polymerized iC3b (p(iC3b)) fragment of C3, and gp350/220, the EBV membrane protein [10].
  • Furthermore, RTA-induced expression of CD21 glycoprotein, which is an EBV receptor, efficiently facilitated EBV infection [11].
  • We show that 293 cells express a relatively low level of CD21, that binding of fluorescein-labeled EBV to 293 cells can be detected, and that both the binding of virus to cells and infection can be blocked with antibodies specific for CD21 [12].
  • One, who had developed grade III steroid-responsive GVHD, died in CR2 from opportunistic infections [13].

Biological context of CR2

  • Amino acid sequence analysis of tryptic peptides of CR2 revealed a strong degree of homology with the human C3b/C4b receptor, CR1 [2].
  • Nucleotide sequence analysis of the CR2 cDNA confirmed that the site of oligonucleotide hybridization was identical to that predicted from the peptide sequence, including flanking sequences not included within the oligonucleotide probes [2].
  • Triggering of CR2 with mAb OKB7 that recognizes an epitope associated with the ligand binding site of the receptor induced an increase in intracellular free calcium concentration in HPB-ALL cells [14].
  • CR2 activation did not trigger tyrosine phosphorylation of PI 3-kinase p85 subunit, but induced direct interaction of tyrosine phosphorylated p95 with the Src homology 2 domain of p85 subunit, as shown using glutathione-S-transferase fusion proteins [15].
  • Murine CR2 contained 16 potential N-linked glycosylation sites of which 6 were conserved, 4 altered, and 6 lost during human evolution [16].

Anatomical context of CR2

  • In the final stage of surface marker-defined maturation, CR2 was lost from high density polymorphonuclear neutrophils and CR1 was maximally expressed [17].
  • We have investigated the expression, molecular association, ligand binding properties, and ability to transduce intracellular signals of CR1 and CR2 C3 receptors on cells of the human HPB-ALL T cell line [14].
  • Astrocyte CR2 cDNA presented 100% homology with the lymphocyte CR2 cDNA between the position 181 bp to 600 bp and position 1017 bp to 1347 bp [18].
  • Astrocyte CR2 was functional, in that it specifically bound C3d and the EBV surface protein gp340, and the binding was blocked specifically with polyclonal anti-CR2 [18].
  • The expression of CR2 extends to both CD1+ and CD1- cells in the thymus [19].

Associations of CR2 with chemical compounds

  • CD21 shedding is induced by stimulation with PMA plus Ca(2+) ionophore, or by stimulation of the BCR with anti-IgM+anti-CD40 [20].
  • The effect of NAC was shown to be irrelevant to the transcriptional levels of CD21 mRNA and the intracellular glutathione levels [21].
  • Other thiol-antioxidants, such as 2-mercaptoethanol, pyrrolidine dithiocarbamate, and glutathione, showed similar effect to NAC on CD21 expression [21].
  • This interaction is specific as evidenced by inhibition with nonconjugated virus, anti-CR2 antibodies, aggregated C3, and an antibody to the gp350 viral glycoprotein that the virus uses to bind to CR2 [22].
  • The complex, which was immunoprecipitated also with anti-CD19, could be dissociated by Nonidet P-40, accounting for its absence in previous studies of CR2 [23].

Physical interactions of CR2

  • The CD21/CD19/TAPA-1 complex brings together independently functioning subunits to enable the B cell to respond to low concentrations of antigen [24].
  • Antibodies against a peptide with the CR2 binding sequence on C3d react with a peptide carrying the IFN alpha CR2 binding motif (residues 92-99) and with recombinant IFN alpha [1].
  • CD19 and CD21 mAb each specifically coprecipitated proteins of the same size as those precipitated by TAPA-1 and Leu-13 mAb from B cell lines and cDNA-transfected K562 cell lines [25].
  • C3i displayed dual uptake kinetics to B lymphocytes, comprising of rapid binding to CR1 and slower binding to CR2 [26].
  • Thus, CR2 bound to p53 and p68 through two distinct binding sites localized on the N-terminal and on the central part of its carboxy-terminal domain, characterized by the amino acid sequences of KHRERNYYTD and KEAFHLEARE, respectively [27].

Regulatory relationships of CR2

  • Our observations have significance for the biology of normal human T cells because the majority of peripheral blood T cells that express CR1 also expressed CR2 and because a change in (Ca2+)i was induced by mAb OKB7 in purified normal T cells [14].
  • GGT is expressed on several B and T cell lines independently of CD21 expression [28].
  • These properties of nucleolin were identical with those of the p95 previously described and induced by CR2 activation [29].
  • Capping of the EBV receptor induced co-capping of the C3 receptor and vice versa [30].
  • Soluble CD21 binds complement fragments and activates monocytes through binding to membrane CD23 [31].

Other interactions of CR2

  • In situ hybridization studies suggest the expression of CR1 and CR2 mRNA in human epidermis [32].
  • Monoclonal anti-CR2 antibody HB5, but not OKB-7, blocks IFN alpha binding to Raji cells [1].
  • Alterations in B cell development are most likely due to engagement of pre-B cell receptor-mediated or other regulatory pathways by hCR2 in a CD19- and possibly C3 ligand-dependent manner [33].
  • Lower levels of adhesion were also observed after engagement of CD21, CD22, and CD23 [34].
  • Together, these data suggest that TAPA-1 and Leu-13 are broadly expressed members of a signal transduction complex in which lineage-specific proteins, such as CD19 and CD21, provide cell-specific functions [25].

Analytical, diagnostic and therapeutic context of CR2

  • Ligation of the functional domain of complement receptor type 2 (CR2, CD21) is relevant for complex formation in T cell lines [35].
  • Immunoprecipitation studies with B cell lines solubilized by digitonin have shown CD19 to be part of a multimolecular complex that includes CD21 (CR2) and other unidentified proteins [25].
  • Expression of CR2 by astrocytes was confirmed at mRNA level by reverse-transcriptase PCR, using different combinations of seven specific CR2 oligonucleotides, and by partial sequencing of the astrocyte CR2 cDNA [18].
  • The mean percentage of CD20+ cells co-expressing CR2 was 71% (s.d., +/- 15%) in the HIV-seropositive patients and 94% (s.d., +/- 4%) in the control group [4].
  • Medium-resolution solution structures for CR2 SCR 1-2, C3d, and their complex were determined by X-ray scattering and analytical ultracentrifugation [36].


  1. Epstein Barr virus/complement C3d receptor is an interferon alpha receptor. Delcayre, A.X., Salas, F., Mathur, S., Kovats, K., Lotz, M., Lernhardt, W. EMBO J. (1991) [Pubmed]
  2. Identification of a partial cDNA clone for the C3d/Epstein-Barr virus receptor of human B lymphocytes: homology with the receptor for fragments C3b and C4b of the third and fourth components of complement. Weis, J.J., Fearon, D.T., Klickstein, L.B., Wong, W.W., Richards, S.A., de Bruyn Kops, A., Smith, J.A., Weis, J.H. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  3. Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines. Cole, J.L., Housley, G.A., Dykman, T.R., MacDermott, R.P., Atkinson, J.P. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  4. In vivo decrease in the expression of complement receptor 2 on B-cells in HIV infection. Scott, M.E., Landay, A.L., Lint, T.F., Spear, G.T. AIDS (1993) [Pubmed]
  5. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Fearon, D.T., Carroll, M.C. Annu. Rev. Immunol. (2000) [Pubmed]
  6. CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system. Levy, S., Todd, S.C., Maecker, H.T. Annu. Rev. Immunol. (1998) [Pubmed]
  7. The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Fearon, D.T., Carter, R.H. Annu. Rev. Immunol. (1995) [Pubmed]
  8. Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. McClain, K.L., Leach, C.T., Jenson, H.B., Joshi, V.V., Pollock, B.H., Parmley, R.T., DiCarlo, F.J., Chadwick, E.G., Murphy, S.B. N. Engl. J. Med. (1995) [Pubmed]
  9. Activation of Epstein-Barr virus/C3d receptor (gp140, CR2, CD21) on human B lymphoma cell surface triggers Cbl tyrosine phosphorylation, its association with p85 subunit, Crk-L and Syk and its dissociation with Vav. Lottin-Divoux, S., Jean, D., Le Romancer, M., Frade, R. Cell. Signal. (2006) [Pubmed]
  10. Interaction of iC3b with recombinant isotypic and chimeric forms of CR2. Kalli, K.R., Ahearn, J.M., Fearon, D.T. J. Immunol. (1991) [Pubmed]
  11. Activation of CD21 and CD23 gene expression by Kaposi's sarcoma-associated herpesvirus RTA. Chang, H., Gwack, Y., Kingston, D., Souvlis, J., Liang, X., Means, R.E., Cesarman, E., Hutt-Fletcher, L., Jung, J.U. J. Virol. (2005) [Pubmed]
  12. CD21-Dependent infection of an epithelial cell line, 293, by Epstein-Barr virus. Fingeroth, J.D., Diamond, M.E., Sage, D.R., Hayman, J., Yates, J.L. J. Virol. (1999) [Pubmed]
  13. Bone marrow transplantation depleted of T cells followed by repletion with incremental doses of donor lymphocytes for relapsing patients with chronic myeloid leukemia: a therapeutic strategy. Novitzky, N., Rubinstein, R., Hallett, J.M., du Toit, C.E., Thomas, V.L. Transplantation (2000) [Pubmed]
  14. Expression, molecular association, and functions of C3 complement receptors CR1 (CD35) and CR2 (CD21) on the human T cell line HPB-ALL. Delibrias, C.C., Fischer, E., Bismuth, G., Kazatchkine, M.D. J. Immunol. (1992) [Pubmed]
  15. Signaling through the EBV/C3d receptor (CR2, CD21) in human B lymphocytes: activation of phosphatidylinositol 3-kinase via a CD19-independent pathway. Bouillie, S., Barel, M., Frade, R. J. Immunol. (1999) [Pubmed]
  16. Comparative structure and evolution of murine CR2. The homolog of the human C3d/EBV receptor (CD21). Fingeroth, J.D. J. Immunol. (1990) [Pubmed]
  17. The sequential appearance of Ia-like antigens and two different complement receptors during the maturation of human neutrophils. Ross, G.D., Jarowski, C.I., Rabellino, E.M., Winchester, R.J. J. Exp. Med. (1978) [Pubmed]
  18. Identification and characterization of complement C3 receptors on human astrocytes. Gasque, P., Chan, P., Mauger, C., Schouft, M.T., Singhrao, S., Dierich, M.P., Morgan, B.P., Fontaine, M. J. Immunol. (1996) [Pubmed]
  19. CR1(CD35) and CR2(CD21) complement C3 receptors are expressed on normal human thymocytes and mediate infection of thymocytes with opsonized human immunodeficiency virus. Delibrias, C.C., Mouhoub, A., Fischer, E., Kazatchkine, M.D. Eur. J. Immunol. (1994) [Pubmed]
  20. B cell activation leads to shedding of complement receptor type II (CR2/CD21). Masilamani, M., Kassahn, D., Mikkat, S., Glocker, M.O., Illges, H. Eur. J. Immunol. (2003) [Pubmed]
  21. Redox control of EBV infection: prevention by thiol-dependent modulation of functional CD21/EBV receptor expression. Nishinaka, Y., Nakamura, H., Okada, N., Okada, H., Yodoi, J. Antioxid. Redox Signal. (2001) [Pubmed]
  22. Infection of human thymocytes by Epstein-Barr virus. Watry, D., Hedrick, J.A., Siervo, S., Rhodes, G., Lamberti, J.J., Lambris, J.D., Tsoukas, C.D. J. Exp. Med. (1991) [Pubmed]
  23. Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19. Matsumoto, A.K., Kopicky-Burd, J., Carter, R.H., Tuveson, D.A., Tedder, T.F., Fearon, D.T. J. Exp. Med. (1991) [Pubmed]
  24. Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. Matsumoto, A.K., Martin, D.R., Carter, R.H., Klickstein, L.B., Ahearn, J.M., Fearon, D.T. J. Exp. Med. (1993) [Pubmed]
  25. The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. Bradbury, L.E., Kansas, G.S., Levy, S., Evans, R.L., Tedder, T.F. J. Immunol. (1992) [Pubmed]
  26. Complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) cooperate in the binding of hydrolyzed complement factor 3 (C3i) to human B lymphocytes. Leslie, R.G., Prodinger, W.M., Nielsen, C.H. Eur. J. Immunol. (2003) [Pubmed]
  27. Binding sites of the Epstein-Barr virus and C3d receptor (CR2, CD21) for its three intracellular ligands, the p53 anti-oncoprotein, the p68 calcium binding protein and the nuclear p120 ribonucleoprotein. Barel, M., Balbo, M., Gauffre, A., Frade, R. Mol. Immunol. (1995) [Pubmed]
  28. Gamma-glutamyl transpeptidase, an ecto-enzyme regulator of intracellular redox potential, is a component of TM4 signal transduction complexes. Nichols, T.C., Guthridge, J.M., Karp, D.R., Molina, H., Fletcher, D.R., Holers, V.M. Eur. J. Immunol. (1998) [Pubmed]
  29. Activation of the EBV/C3d receptor (CR2, CD21) on human B lymphocyte surface triggers tyrosine phosphorylation of the 95-kDa nucleolin and its interaction with phosphatidylinositol 3 kinase. Barel, M., Le Romancer, M., Frade, R. J. Immunol. (2001) [Pubmed]
  30. Surface markers on human B and T-lymphocytes. IX. Two-color immunofluorescence studies on the association between ebv receptors and complement receptors on the surface of lymphoid cell lines. Yefenof, E., Klein, G., Jondal, M., Oldstone, M.B. Int. J. Cancer (1976) [Pubmed]
  31. Decreased levels of serum soluble complement receptor-II (CR2/CD21) in patients with rheumatoid arthritis. Masilamani, M., von Kempis, J., Illges, H. Rheumatology (Oxford, England) (2004) [Pubmed]
  32. Expression and localization of proteins of the complement system in human skin. Dovezenski, N., Billetta, R., Gigli, I. J. Clin. Invest. (1992) [Pubmed]
  33. Expression of human complement receptor type 2 (CD21) in mice during early B cell development results in a reduction in mature B cells and hypogammaglobulinemia. Marchbank, K.J., Kulik, L., Gipson, M.G., Morgan, B.P., Holers, V.M. J. Immunol. (2002) [Pubmed]
  34. Transmembrane signals generated through MHC class II, CD19, CD20, CD39, and CD40 antigens induce LFA-1-dependent and independent adhesion in human B cells through a tyrosine kinase-dependent pathway. Kansas, G.S., Tedder, T.F. J. Immunol. (1991) [Pubmed]
  35. Ligation of the functional domain of complement receptor type 2 (CR2, CD21) is relevant for complex formation in T cell lines. Prodinger, W.M., Larcher, C., Schwendinger, M., Dierich, M.P. J. Immunol. (1996) [Pubmed]
  36. Solution structure of the complex between CR2 SCR 1-2 and C3d of human complement: an X-ray scattering and sedimentation modelling study. Gilbert, H.E., Eaton, J.T., Hannan, J.P., Holers, V.M., Perkins, S.J. J. Mol. Biol. (2005) [Pubmed]
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