Role of the CD19 and CD21/35 Receptor Complex in Innate Immunity, Host Defense and Autoimmunity

  • Karen M. Haas
  • Thomas F. Tedder
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 560)


Humoral immune responses to foreign and self-antigens must be tightly regulated to facilitate protective immunity to pathogens while avoiding autoimmune responses. The outcome of these responses is determined in part by signals generated through the B lymphocyte antigen receptor (BCR). These signals are further supplemented and fine- tuned by other cell-surface molecules that modify and provide a context for BCR signal transduction. Such molecules, or “response regulators”, influence these events by positively or negatively biasing the context of BCR signaling, thus establishing appropriate signaling thresholds. Response regulators amplify or dampen BCR signaling by regulating the activity of intracellular kinases, phosphatases, and other effector proteins. Included among the list of BCR signal transduction response regulators is CD19, which integrates multiple intracellular signaling pathways. On the B cell surface, CD19 interacts directly with CD21 (complement receptor 2, CR2), a receptor for the C3d complement cleavage product that forms covalent bonds with foreign Ags or immune complexes to effectively link innate and acquired immunity. This review summarizes recent findings that have clarified how the CD19/CD21 receptor complex functions to regulate B cell responses in host defense and autoimmunity.


Marginal Zone Complement Receptor Follicular Dendritic Cell Complement Receptor Type CD19 Expression Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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8. References

  1. 1.
    T. F. Tedder, Response-regulators of B lymphocyte signaling thresholds provide a context for antigen receptor signal transduction. Semin. Immunol. 10, 259–265 (1998).PubMedCrossRefGoogle Scholar
  2. 2.
    S. Sato, D. A. Steeber, P. J. Jansen and T. F. Tedder, CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19. J. Immunol. 158, 4662–4669 (1997).PubMedGoogle Scholar
  3. 3.
    S. Sato, N. Ono, D. A. Steeber, D. S. Pisetsky and T. F. Tedder, CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J. Immunol. 157, 4371–4378 (1996).PubMedGoogle Scholar
  4. 4.
    T. F. Tedder and C. M. Isaacs, Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes: A new member of the immunoglobulin superfamily. J. Immunol. 143, 712–717 (1989).PubMedGoogle Scholar
  5. 5.
    L.-J. Zhou, D. C. Ord, A. L. Hughes and T. F. Tedder, Structure and domain organization of the CD19 antigen of human, mouse and guinea pig B lymphocytes. Conservation of the extensive cytoplasmic domain. J. Immunol. 147, 1424–1432 (1991).PubMedGoogle Scholar
  6. 6.
    I. Krop, A. L. Shaffer, D. T. Fearon and M. S. Schlissel, The signaling activity of murine CD19 is regulated during B cell development. J. Immunol. 157, 48–56 (1996).PubMedGoogle Scholar
  7. 7.
    A. W. Boyd, K. C. Anderson, A. S. Freedman, D. C. Fisher, B. Slaughenhoupt, S. F. Schlossman and L. M. Nadler, Studies of in vitro activation and differentiation of human B lymphocytes. I. Phenotypic and functional characterization of the B cell population responding to anti-Ig antibody. J. Immunol. 134, 1516–1523 (1985).PubMedGoogle Scholar
  8. 8.
    L. E. Bradbury, G. S. Kansas, S. Levy, R. L. Evans and T. F. Tedder, The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J. Immunol. 149, 2841–2850 (1992).PubMedGoogle Scholar
  9. 9.
    S. Levy, S. C. Todd and H. T. Maecker, CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system Annu. Rev. Immunol 16, 89–110 (1998).PubMedCrossRefGoogle Scholar
  10. 10.
    H. T. Maecker and S. Levy Normal lymphocyte development but delayed humoral immune response in CD81-null mice. J. Exp. Med. 185, 1505–1510 (1997).PubMedCrossRefGoogle Scholar
  11. 11.
    T. Miyazaki, U. Muller and K. S. Campbell, Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81. EMBO J. 16, 4217–4225 (1997).PubMedCrossRefGoogle Scholar
  12. 12.
    E. N. Tsitsikov, J.-C. Gutierrez-Ramos and R. S. Geha, 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. USA 94, 10844–10849 (1997).PubMedCrossRefGoogle Scholar
  13. 13.
    T. Shoham, R. Rajapaksa, C. Boucheix, E. Rubinstein, J. C. Poe, T. F. Tedder and S. Levy, The tetraspanin CD81 regulates the expression of CD19 during B cell development in a postendoplasmic reticulum compartment. J. Immunol. 171, 4062–4072 (2003).PubMedGoogle Scholar
  14. 14.
    G. A. Deblandre, O. P. Marinx, S. S. Evans, S. Majjaj, O. Leo, D. Caput, G. A. Huez and M. G. Wathelet, Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth. J. Biol. Chem. 270, 23860–23866 (1995).PubMedCrossRefGoogle Scholar
  15. 15.
    L. E. Bradbury, V. S. Goldmacher and T. F. Tedder, The CD19 signal transduction complex of B lymphocytes: deletion of the CD19 cytoplasmic domain alters signal transduction but not complex formation with TAPA-1 and Leu-13. J. Immunol. 151, 2915–2927 (1993).PubMedGoogle Scholar
  16. 16.
    A. K. Matsumoto, D. R. Martin, R. H. Carter, L. B. Klickstein, J. M. Aheam and D. T. Fearon, Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J. Exp. Med. 178, 1407–1417 (1993).PubMedCrossRefGoogle Scholar
  17. 17.
    C. J. van Noesel, A. C. Lankester, G. M. van Schijndel and R. A. van Lier, The CR2/CD19 complex on human B cells contains the src-family kinase Lyn. Int. Immunol., 5, 699–705 (1993).PubMedCrossRefGoogle Scholar
  18. 18.
    F._M. Uckun, A. L. Bukhardt, L. Jarvis, X. Jun, B. Stealey, I. Dibirdik, D. E. Myers, L. Tuel-Ahlgren and J. B. Bolen, Signal transduction through the CD19 receptor during discrete developmental stages of human B-cell ontogeny. J. Biol. Chem. 268, 21172–21184 (1993).PubMedGoogle Scholar
  19. 19.
    N._J. Chalupny, S. B. Kanner, G. L. Schieven, S. Wee, L. K. Gilliland, A. Aruffo and J. A. Ledbetter, Tyrosine phosphorylation of CD19 in pre-B and mature B cells. EMBO J. 12, 2691–2696 (1993).PubMedGoogle Scholar
  20. 20.
    M. Fujimoto, J. C. Poe, P. J. Jansen, S. Sato and T. F. Tedder CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein tyrosine kinase activation. J. Immunol. 162, 7088–7094 (1999).PubMedGoogle Scholar
  21. 21.
    M. Fujimoto, Y. Fujimoto, J. C. Poe, P. J. Jansen, C. A. Lowell, A. L. DeFranco and T. F. Tedder, CD19 regulates Src-family protein tyrosine kinase activation in B lymphocytes through processive amplification. Immunity 13, 47–57 (2000).PubMedCrossRefGoogle Scholar
  22. 22.
    M. Hasegawa, M. Fujimoto, J. C. Poe, D. A. Steeber, C. A. Lowell and T. F. Tedder, A CD19-dependent signaling pathway regulates autoimmunity in Lyn-deficient mice. J. Immunol. 167, 2469–2478 (2001).PubMedGoogle Scholar
  23. 23.
    M. Fujimoto, J. C. Poe, M. Inaoki and T. F. Tedder, CD19 regulates B lymphocyte responses to transmembrane signals. Semin. Immunol. 10, 267–277 (1998).PubMedCrossRefGoogle Scholar
  24. 24.
    P. A. Zipfel, M. Grove, K. Blackburn, M. Fujimoto, T. F. Tedder and A. M. Pendergast, The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19. J. Immunol. 165, 6872–6879 (2000).PubMedGoogle Scholar
  25. 25.
    A. Cherukuri, P. C. Cheng, H. W. Sohn and S. K. Pierce, The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts. Immunity 14, 169–179 (2001).PubMedCrossRefGoogle Scholar
  26. 26.
    M. Fujimoto, A. P. Bradney, J. C. Poe, D. A. Steeber and T. F. Tedder, Modulation of B lymphocyte antigen receptor signal transduction by a CD19/CD22 regulatory loop. Immunity 11, 191–200 (1999).PubMedCrossRefGoogle Scholar
  27. 27.
    S. Sato, P. J. Jansen and T. F. Tedder, CD19 and CD22 reciprocally regulate Vav tyrosine phosphorylation during B lymphocyte signaling. Proc. Natl. Acad. Sci., USA 94, 13158–13162 (1997).PubMedCrossRefGoogle Scholar
  28. 28.
    W. K. Weng, L. Jarvis and T. W. LeBien, Signaling through CD19 activates vav/mitogen-activated protein kinase pathway and induces formation of a Cd19/vav/phosphatidylinositol 3-kinase complex in human B cell precursors. J. Biol. Chem. 269, 32514–32521 (1994).PubMedGoogle Scholar
  29. 29.
    D. A. Tuveson, R. H. Carter, S. P. Soltoff and D. T. Fearon, CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase. Science 260, 986–989 (1993).PubMedCrossRefGoogle Scholar
  30. 30.
    A. M. Buhl, C. M. Pleiman, R. C. Rickert and J. C., Qualitative regulation of B cell antigen receptor signaling by CD19: Selective requirement for P13-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization. J. Exp. Med. 186, 1897–1910 (1997).PubMedCrossRefGoogle Scholar
  31. 31.
    G. M. Doody, D. D. Balladeau, E. Clayton, A. Hutchings, R. Berland, S. McAdam, P. J. Leibson and M. Turner, Vav-2 controls NFAT-dependent transcription in B-but not T-lymphocytes. EMBO J. 19, 6173–6184 (2000).PubMedCrossRefGoogle Scholar
  32. 32.
    S. R. Brooks, X. Li, E. J. Volanakis and R. H. Carter, Systematic analysis of the role of CD19 cytoplasmic tyrosines in enhancement of activation in Dandi human B cells: clustering of phospholipase C and Vav and of Grb2 and Sos with different CD19 tyrosines. J. Immunol. 164, 3123–3131 (2000).PubMedGoogle Scholar
  33. 33.
    J. C. Poe, M. Fujimoto, P. J. Jansen, A. S. Miller and T. F. Tedder, CD22 forms a quatemary complex with SHIP, Grb2 and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux. J. Biol. Chem. 275, 17420–17427 (2000).PubMedCrossRefGoogle Scholar
  34. 34.
    R. H. Carter and D. T. Fearon, CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256, 105–107 (1992).PubMedCrossRefGoogle Scholar
  35. 35.
    P. W. Dempsey, M. E. D. Allison, S. Akkaraju, C. C. Goodnow and D. T. Fearon, C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271, 348–350 (1996).PubMedCrossRefGoogle Scholar
  36. 36.
    R. M. Tooze, G. M. Doody and D. T. Fearon, Counterregulation by the coreceptors CD19 and CD22 of MAP kinase activation by membrane immunoglobulin. Immunity 7, 59–67 (1997).PubMedCrossRefGoogle Scholar
  37. 37.
    T. F. Tedder, M. Inaoki and S. Sato, The CD19/21 complex regulates signal transduction thresholds goveming humoral immunity and autoimmunity. Immunity 6, 107–118 (1997).PubMedCrossRefGoogle Scholar
  38. 38.
    P. Engel, L.-J. Zhou, D. C. Ord, S. Sato, B. Koller and T. F. Tedder, Abnormal B lymphocyte development, activation and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3, 39–50 (1995).PubMedCrossRefGoogle Scholar
  39. 39.
    L.-J. Zhou, H. M. Smith, T. J. Waldschmidt, R. Schwarting, J. Daley and T. F. Tedder, Tissue-specific expression of the human CD19 gene in transgenic mice inhibits antigen-independent B lymphocyte development. Mol. Cell. Biol. 14, 3884–3894 (1994).PubMedGoogle Scholar
  40. 40.
    R. C. Rickert, K. Rajewsky and J. Roes, Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 376, 352–355 (1995).PubMedCrossRefGoogle Scholar
  41. 41.
    S. Sato, D. A. Steeber and T. F. Tedder, The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation. Proc. Natl. Acad. Sci. USA 92, 11558–11562 (1995).PubMedCrossRefGoogle Scholar
  42. 42.
    S. Sato, A. S. Miller, M. C. Howard and T. F. Tedder, Regulation of B lymphocyte development and activation by the CD19/CD21/CD81/Leu 13 complex requires the cytoplasmic domain of CD19. J. Immunol. 159, 3278–3287 (1997).PubMedGoogle Scholar
  43. 43.
    A. Pezzutto, B. Dorken, P. S. Rabinovitch, J. A. Ledbetter, G. Moldenhauer and E. A. Clark, CD19 monoclonal antibody HD37 inhibits anti-immunoglobulin-induced B cell activation and proliferation. J. Immunol. 138, 2793–2799 (1987).PubMedGoogle Scholar
  44. 44.
    T. B. Barrett, G. L. Shu, K. E. Draves, A. Pezzutto and E. A. Clark, Signaling through CD19, Fc receptors or transforming growth factor-β: each inhibits the activation of resting human B cells differently. Eur. J. Immunol. 20, 1053–1059 (1990).PubMedCrossRefGoogle Scholar
  45. 45.
    R. E. Callard, K. P. Rigley, S. H. Smith, S. Thurstan and J. G. Shields, CD19 regulation of human B cell responses, B cell proliferation and antibody secretion are inhibited or enhanced by ligation of the CD19 surface glycoprotein depending on the stimulating signal used. J. Immunol. 148, 2983–2987 (1992).PubMedGoogle Scholar
  46. 46.
    D. T. Fearon and R. H. Carter, The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Annu. Rev. Immunol. 13, 127–149 (1995).PubMedCrossRefGoogle Scholar
  47. 47.
    C. J. M. van Noesel, A. C. Lankester and R. A. W. van Lier, Dual antigen recognition by B cells. Immunol. Today 14, 8–11 (1993).PubMedCrossRefGoogle Scholar
  48. 48.
    J. M. Ahearn, M. B. Fischer, D. Croix, S. Goerg, M. Ma, J. Xia, X. Zhou, R. G. Howard, T. L. Rothstein and M. C. Carroll, Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. Immunity 4, 251–262 (1996).PubMedCrossRefGoogle Scholar
  49. 49.
    H. Molina, V. M. Holers, B. Li, Y.-F. Fang, S. Mariathasan, J. Goellner, J. Strauss-Schoenberger, R. W. Karr and D. D. Chaplin, Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc. Natl. Acad. Sci. USA 93, 3357–3361 (1996).PubMedCrossRefGoogle Scholar
  50. 50.
    M. Hasegawa, M. Fujimoto, J. C. Poe, D. A. Steeber and T. F. Tedder, CD19 can regulate B lymphocyte signal transduction independent of complement activation. J. Immunol. 167, 3190–3200 (2001).PubMedGoogle Scholar
  51. 51.
    T. F. Tedder, L. T. Clement and M. D. Cooper Discontinuous expression of a membrane antigen (HB-7) during B lymphocyte differentiation. Tissue Antigens 24, 140–149 (1984).PubMedCrossRefGoogle Scholar
  52. 52.
    K. Takahashi, Y. Kozono, T. J. Waldschmidt, D. Berthiaume, R. J. Quigg, A. Baron and V. M. Holers, Mouse complement receptors type 1 (CR1; Cd35) and type (CR2; CD21). Expression on normal B cell subpopulations and decreased levels during the development of autoimmunity in MRL/lpr mice. J. Immunol. 159, 1557–1569 (1997).PubMedGoogle Scholar
  53. 53.
    H. Molina, T. Kinoshita, K. Inoue, J.-C. Carel and V. M. Holers, A molecular and immunochemical characterization of mouse CR2. Evidence for a single gene model of mouse complement receptors 1 and 2. J. Immunol. 145, 2974–2983 (1990).PubMedGoogle Scholar
  54. 54.
    M. D. Moore, N. R. Cooper, B. F. Tack and G. R. Nemerow, Molecular cloning of the cDNA encoding the Epstein-Barr virus/C3d receptor (complement receptor type 2) of human B lymphocytes. Proc. Natl. Acad. Sci. USA. 84, 9194–9198. (1987).PubMedCrossRefGoogle Scholar
  55. 55.
    J. J. Weis, D. T. Fearon, L. B. Klickstein, W. W. Wong, S. A. Richards, A. d. Kops, J. A. Smith and J. H. Weis, 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. Proc. Natl. Acad. Sci. USA 83, 5639–5643. (1986).PubMedCrossRefGoogle Scholar
  56. 56.
    J. C. Carel, B. L. Myones, B. Frazier and V. M. Holers, Structural requirements for C3d,g/Epstein-Barr virus receptor (CR2/CD21) ligand binding, internalization and viral infection. J. Biol. Chem. 265, 12293–12297 (1990).PubMedGoogle Scholar
  57. 57.
    D. T. Fearon and M. C. Carroll, Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu. Rev. Immunol. 18, 393–422 (2000).PubMedCrossRefGoogle Scholar
  58. 58.
    J. M. Ahcarn and D. T. Fearon, Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21). Adv. Immunol. 46, 183–219 (1989).Google Scholar
  59. 59.
    K. M. Haas, M. Hasegawa, D. A. Steeber, J. C. Poe, M. D. Zabel, C. B. Bock, D. R. Karp, D. E. Briles, J. H. Weis and T. F. Tedder, Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses. Immunity 17, 713–723 (2002).PubMedCrossRefGoogle Scholar
  60. 60.
    Z. Chen, S. B. Koralov, M. Gendelman, M. C. Carroll and G. Kelsoe, Humoral immune responses in Cr2-/- Mice: Enhanced affinity maturation but impaired antibody persistence. J. Immunol. 164, 4522–4532 (2000).PubMedGoogle Scholar
  61. 61.
    X. Wu, N. Jiang, Y. Fang, C. Xu, D. Mao, J. Singh, Y. Fu and H. Molina, Impaired affinity maturation in Cr2-/- mice is rescued by adjuvants without improvement in germinal center development. J. Immunol. 165, 3119–3127 (2000).PubMedGoogle Scholar
  62. 62.
    A. W. Griffioen, G. T. Rijkers, P. Janssens-Korpela and B. J. Zegers, Pneumococcal polysaccharides complexed with C3d bind to human B lymphocytes via complement receptor type 2. Infect. Immun. 59, 1839–1845. (1991).PubMedGoogle Scholar
  63. 63.
    T. Manser, K. M. Tumas-Brundage, L. P. Casson, A. M. Giusti, S. Hande, E. Notidis and K. A. Vora, The roles of antibody variable region hypermutation and selection in the development of the memory B-cell compartment. Immunol. Rev. 162, 183–196 (1998).PubMedCrossRefGoogle Scholar
  64. 64.
    J. Pryjma, J. H. Humphrey and G. G. Klaus, C3 activation and T-independent B cell stimulation. Nature 252, 505–506. (1974).PubMedCrossRefGoogle Scholar
  65. 65.
    O. G. Pozdnyakova, H.K. Guttormsen, F. N. Lalani, M. C. Carroll and D. L. Kasper, Impaired antibody response to group B streptococcal type III capsular polysaccharide in C3-and complement receptor 2-deficient mice. J Immunol. 170, 84–90. (2003).PubMedGoogle Scholar
  66. 66.
    M. J. Peset Llopis, G. Harms, M. J. Hardonk and W. Timens, Human immune response to pneumococcal polysaccharides: complement-mediated localization preferentially on CD21-positive splenic marginal zone B cells and follicular dendritic cells. J. Allergy Clin. Immunol. 97, 1015–1024 (1996).PubMedCrossRefGoogle Scholar
  67. 67.
    R. Guinamard, M. Okigaki, J. Schlessinger and J. V. Ravetch, Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral responses. Nature Immunol. 1, 31–36 (2000).CrossRefGoogle Scholar
  68. 68.
    S. E. Henson, D. Smith, S. A. Boackle, V. M. Holers and D. R. Karp, Generation of recombinant human C3dg tetramers for the analysis of CD21 binding and function. J. Immunol. Methods 258, 97–109. (2001).PubMedCrossRefGoogle Scholar
  69. 69.
    W. Timens, A. Boes, T. Rozeboom-Uiterwijk and S. Poppema, Immaturity of the human splenic marginal zone in infancy. Possible contribution to the deficient infant immune response. J. Immunol. 143, 3200–3206. (1989).PubMedGoogle Scholar
  70. 70.
    A. Cariappa, M. Tang, C. Parng, E. Nebelitskiy, M. Carroll, K. Georgopoulos and S. Pillai, The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 14, 603–615. (2001).PubMedCrossRefGoogle Scholar
  71. 71.
    J. E. Figueroa and P. Densen, Infectious diseases associated with complement deficiencies. Clin. Microbiol. Rev. 4, 359–395. (1991).PubMedGoogle Scholar
  72. 72.
    L. A. Burman, R. Norrby and B. Trollfors, Invasive pneumococcal infections: incidence, predisposing factors, and prognosis. Rev. Infect. Dis. 7, 133–142. (1985).PubMedGoogle Scholar
  73. 73.
    I. D. Riley and R. M. Douglas, An epidemiologic approach to pneumococcal disease. Rev. Infect. Dis. 3, 233–245. (1981).PubMedGoogle Scholar
  74. 74.
    M. Botto and M. J. Walport, Hereditary deficiency of C3 in animals and humans. Int. Rev. Immunol. 10, 37–50 (1993).PubMedGoogle Scholar
  75. 75.
    J. A. Winkelstein, The role of complement in the host’s defense against Streptococcus pneumoniae. Rev. Infect. Dis. 3, 289–298. (1981).PubMedGoogle Scholar
  76. 76.
    E. J. Brown, S. W. Hosea, C. H. Hammer, C. G. Burch and M. M. Frank, A quantitative analysis of the interactions of antipneumococcal antibody and complement in experimental pneumococcal bacteremia. J. Clin. Invest. 69, 85–98. (1982).PubMedGoogle Scholar
  77. 77.
    G. J. Noet, S. L. Katz and P. J. Edelson, The role of C3 in mediating binding and ingestion of group B streptococcus serotype III by murine macrophages. Pediatr. Res. 30, 118–123. (1991).Google Scholar
  78. 78.
    M. S. Borzy, A. Gewurz, L. Wolff, D. Houghton and E. Lovrien, Inherited C3 deficiency with recurrent infections and glomerulonephritis. Am. J. Dis. Child. 142, 79–83. (1988).PubMedGoogle Scholar
  79. 79.
    E. J. Brown, S. W. Hosea and M. M. Frank, The role of complement in the localization of pneumococci in the splanchnic reticuloendothelial system during experimental bacteremia. J. Immunol. 126, 2230–2235. (1981).PubMedGoogle Scholar
  80. 80.
    A. Circolo, G. Garnier, W. Fukuda, X. Wang, T. Hidvegi, A. J. Szalai, D. E. Briles, J. E. Volanakis, R. A. Wetsel and H. R. Colten, Genetic disruption of the murine complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA. Immunopharmacology 42, 135–149. (1999).PubMedCrossRefGoogle Scholar
  81. 81.
    Y. Fang, C. Xu, Y.-X. Fu, V. M. Holers and H. Molina, Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. J. Immunol. 160, 5273–5279 (1998).PubMedGoogle Scholar
  82. 82.
    J. Arvieux, H. Yssel and M. G. Colomb, Antigen-bound C3b and C4b enhance antigen-presenting cell function in activation of human T-cell clones. Immunology 65, 229–235. (1988).PubMedGoogle Scholar
  83. 83.
    S. A. Boackle, V. M. Holers and D. R. Karp CD21 augments antigen presentation in immune individuals. Eur. J. Immunol. 27, 122–129 (1997).PubMedCrossRefGoogle Scholar
  84. 84.
    S. A. Boackle, M. A. Morris, V. M. Holers and D. R. Karp, Complement opsonization is required for presentation of immune complexes by resting peripheral blood B cells. J. Immunol. 161, 6537–6543. (1998).PubMedGoogle Scholar
  85. 85.
    B. P. Thornton, V. Vetvieka and G. D. Ross, Natural antibody and complement-mediated antigen processing and presentation by B lymphocytes. J. Immunol. 152, 1727–1737. (1994).PubMedGoogle Scholar
  86. 86.
    A. Cherukuri, P. C. Cheng and S. K. Pierce, The role of the CD19/CD21 complex in B cell processing and presentation of complement-tagged antigens. J. Immunol. 167, 163–172. (2001).PubMedGoogle Scholar
  87. 87.
    F. Martin, A. M. Oliver and J. F. Keamey, Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14, 617–629. (2001).PubMedCrossRefGoogle Scholar
  88. 88.
    A. M. Oliver, F. Martin and J. F. Kearney, IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J. Immunol. 162, 7198–7207 (1999).PubMedGoogle Scholar
  89. 89.
    J. C. Poe, M. Hasegawa and T. F. Tedder, CD19, CD21 and CD22: multifaceted response regulators of B lymphocyte signal transduction. Int. Rev. Immunol. 20, 739–762 (2001).PubMedGoogle Scholar
  90. 90.
    R. M. Perlmutter, D. Hansburg, D. E. Briles, R. A. Nicolotti and J. M. Davie, Subclass restriction of murine anti-carbohydrate antibodies. J. Immunol. 121, 566–572. (1978).PubMedGoogle Scholar
  91. 91.
    J. McLay, E. Leonard, S. Petersen, D. Shapiro, N. S. Greenspan and J. R. Schreiber, Gamma-3 gene-distrupted mice selectively deficient in the dominant IgG subclass made to bacterial polysaccharides. II. Increased susceptibility to fatal pneumococcal sepsis due to absence of anti-polysaccharide IgG3 is corrected by induction of anti-polysaccharide IgG1. J. Immunol. 168, 3437–3443. (2002).PubMedGoogle Scholar
  92. 92.
    D. E. Briles, W. H. Benjamin, Jr., W. J. Huster and B. Posey, Genetic approaches to the study of disease resistance: with special emphasis on the use of recombinant inbred mice. Curr. Top. Microbiol. Immunol. 124, 21–35 (1986).PubMedGoogle Scholar
  93. 93.
    P. G. Shackelford, S. J. Nelson, A. T. Palma and M. H. Nahm, Human antibodies to group A streptococcal carbohydrate. Ontogeny, subclass restriction, and clonal diversity. J. Immunol. 140, 3200–3205. (1988).PubMedGoogle Scholar
  94. 94.
    T. W. Kuijpers, R. S. Weening and T. A. Out, IgG subclass deficiencies and recurrent pyogenic infections: unresponsiveness against bacterial polysaccharide antigens. Allergol. Immunopathol. 20, 28–34, (1992).Google Scholar
  95. 95.
    N. S. Greenspan and L. J. Cooper, Cooperative binding by mouse IgG3 antibodies: implications for functional affinity, effector function, and isotype restriction. Springer Semin. Immunopathol. 15, 275–291 (1993).PubMedCrossRefGoogle Scholar
  96. 96.
    H. Wardemann, T. Boehm, N. Dear and R. Carsetti, B-1a B cells that link the innate and adaptive immune responses are lacking in the absence of the spleen. J. Exp. Med. 195, 771–780 (2002).PubMedCrossRefGoogle Scholar
  97. 97.
    R. R. Hardy, C. E. Carmack, Y. S. Li and K. Hayakawa, Distinctive developmental origins and specificities of murine CD5+ B cells. Immunol. Rev. 137, 91–118 (1994).PubMedCrossRefGoogle Scholar
  98. 98.
    T. M. Ross, Y. Xu, T. D. Green, D. C. Montefiori and H. L. Robinson, Enhanced avidity maturation of antibody to human immunodeficiency virus envelope: DNA vaccination with gp120-C3d fusion proteins. AIDS Res. and Human Retroviruses 17, 829–835 (2001).CrossRefGoogle Scholar
  99. 99.
    T. D. Green, D. C. Montefiori and T. M. Ross, Enhancement of antibodies to the human immunodeficiency virus type 1 envelope by using the molecular adjuvant C3d. J. Virology 77, 2046–2055 (2003).PubMedCrossRefGoogle Scholar
  100. 100.
    J. A. Mitchell, T. D. Green, R. A. Bright and T. M. Ross, Induction of heterosubtypic immunity to influenza A virus using a DNA vaccine expressing hemagglutinin-C3d fusion proteins. Vaccine 21, 902–914 (2003).PubMedCrossRefGoogle Scholar
  101. 101.
    T. D. Green, B. R. Newton, P. Rota, Y. Xu, H. L. Robinson and T. M. Ross, Immune responses in mice to measles hemagglutin-C3d DNA vaccinations. Vaccine 20, 242–248 (2002).CrossRefGoogle Scholar
  102. 102.
    T. M. Ross, Y. Xu, R. A. Bright and H. L. Robinson, C3d enhancement of antibodies to hemagglutinin accelerates protection against influenza challenge. Nature Immunol. 1, 127–131 (2000).CrossRefGoogle Scholar
  103. 103.
    I. Walanabe, T. M. Ross, S. I. Tamura, T. Ichinohe, S. Ito, H. Takahashi, H. Sawa, J. Chiba, T. Kurala, T. Sata and H. Hasegawa, Protection against influenza virus infection by intranasal administration of C3d-fused hemagglutinin. Vaccine 21, 4532–4538. (2003).CrossRefGoogle Scholar
  104. 104.
    S. T. Test, J. Mitsuyoshi, C. C. Connolly and A. H. Lucas, Increased immunogenicity and induction of class switching by conjugation of complement C3d to pneumococcal serotype 14 capsular polysaccharide. Infect. Immun. 69, 3031–3040. (2001).PubMedCrossRefGoogle Scholar
  105. 105.
    R. H. Carter, M. O. Spycher, Y. C. Ng, R. Hoffman and D. T. Fearon, Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes. J. Immunol. 141, 457–463 (1988).PubMedGoogle Scholar
  106. 106.
    J. D. Fingeroth, M. A. Benedict, D. N. Levy and J. L. Strominger, Identification of murine complement receptor type 2. Proc. Natl. Acad. Sci. USA 86, 242–246 (1989).PubMedCrossRefGoogle Scholar
  107. 107.
    K. M. Haas, F. R. Toapanta, J. A. Oliver, J. C. Poe, J. H. Weis, D. R. Karp, J. F. Bower, T. M. Ross and T. F. Tedder, C3d functions as a molecular adjuvant in the absence of CD21/35 expression. (submitted).Google Scholar
  108. 108.
    F. R. Vogel Improving vaccine performance with adjuvants. Clinical Infectious Diseases 30Suppl 3, S266–270 (2000).PubMedCrossRefGoogle Scholar
  109. 109.
    M. Bennett and T. Leanderson, Was it there all the time? Scand. J. of Immunol. 57, 499–505 (2003).CrossRefGoogle Scholar
  110. 110.
    S. Sato, M. Hasegawa, M. Fujimoto, T. F. Tedder and K. Takehara, Quantitative genetic variation in CD19 expression correlates with autoimmunity in mice and humans. J. Immunol. 165, 6635–6643 (2000).PubMedGoogle Scholar
  111. 111.
    Y. Okano Antinuclear antibody in systemic sclerosis (scleroderma). Rheum. Dis. Clin. North Am. 22, 709–735 (1996).PubMedCrossRefGoogle Scholar
  112. 112.
    E. Saito, M. Fujimoto, M. Hasegawa, K. Komura, Y. Hamaguchi, Y. Kaburagi, T. Nagaoka, K. Takehara, T. F. Tedder and S. Sato, CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J. Clin. Invest 109, 1453–1462 (2002).PubMedCrossRefGoogle Scholar
  113. 113.
    S. A. Boackle, V. M. Hoters, X. Chen, G. Szakonyi, D. R. Karp, E. K. Wakeland and L. Morel, Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. Immunity 15, 775–785. (2001).PubMedCrossRefGoogle Scholar
  114. 114.
    A. P. Prodeus, S. Goerg, L. M. Shen, O. O. Pozdnyakova, L. Chu, E. M. Alicot, C. C. Goodnow and M. C. Carroll, A critical role for complement in maintenance of self-tolerance. Immunity 9, 721–731 (1998).PubMedCrossRefGoogle Scholar
  115. 115.
    M. Carroll, The role of complement in B cell activation and tolerance. Adv. Immunol. 74, 61–88 (2000).PubMedCrossRefGoogle Scholar
  116. 116.
    Z. Chen, S. B. Koralov and G. Kelsoe, Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J. Exp. Med. 192, 1339–1351 (2000).PubMedCrossRefGoogle Scholar
  117. 117.
    J. P. Atkinson, in: Systemic Lupus Erythematosus. edited R. G. Lahita (Churehill Livingston, Edinburgh; 1992), pp. 87–102.Google Scholar
  118. 118.
    M. Fujimoto, J. C. Poe, M. Hasegawa and T. F. Tedder, CD19 amplification of B lymphocyte Ca2+ responses: A role for Lyn sequestration in extinguishing negative regulation. J. Biol. Chem. 276, 44820–44827 (2001).PubMedCrossRefGoogle Scholar
  119. 119.
    L. Chakravarty, M. D. Zabel, J. J. Weis and J. H. Weis, Depletion of Lyn kinase from the BCR complex and inhibition of B cell activation by excess CD21 ligation. Intl. Immunol. 14, 139–146 (2002).CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Karen M. Haas
  • Thomas F. Tedder
    • 1
  1. 1.Duke University Medical CenterDurham

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