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Departments of
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Medicine and Immunology, and
Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, CO 80262;
Protein Chemistry Laboratory, University of Pennsylvania, Philadelphia, PA 19104;
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
¶ Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and
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Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, University College, London, United Kingdom
Complement receptor type 2 (CR2)/CD21 is a B lymphocyte cell membrane C3d/iC3b receptor that plays a central role in the immune response. Human CR2 is also the receptor for the EBV viral membrane glycoprotein gp350/220. Both C3d and gp350/220 bind CR2 within the first two of 15–16 repetitive domains that have been designated short consensus/complement repeats. Many mAbs react with human CR2; however, only one currently available mAb is known to block both C3d/iC3b and gp350/220 binding. We have used a recombinant form of human CR2 containing the short consensus/complement repeat 1-2 ligand-binding fragment to immunize Cr2-/- mice. Following fusion, we identified and further characterized four new anti-CR2 mAbs that recognize this fragment. Three of these inhibited binding of CR2 to C3d and gp350/220 in different forms. We have determined the relative inhibitory ability of the four mAbs to block ligand binding, and we have used overlapping peptide-based approaches to identify linear epitopes recognized by the inhibitory mAbs. Placement of these epitopes on the recently solved crystal structure of the CR2-C3d complex reveals that each inhibitory mAb recognizes a site either within or adjacent to the CR2-C3d contact site. One new mAb, designated 171, blocks CR2 receptor-ligand interactions with the greatest efficiency and recognizes a portion of the C3d contact site on CR2. Thus, we have created an anti-human CR2 mAb that blocks the C3d ligand by direct contact with its interaction site, and we have provided confirmatory evidence that the C3d binding site seen in its crystal structure exists in solution.
This article has been cited by other articles:
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  J. M. Kovacs, J. P. Hannan, E. Z. Eisenmesser, and V. M. Holers Mapping of the C3d Ligand Binding Site on Complement Receptor 2 (CR2/CD21) Using Nuclear Magnetic Resonance and Chemical Shift Analysis J. Biol. Chem., April 3, 2009; 284(14): 9513 - 9520. [Abstract] [Full Text] [PDF]
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 K. A. Young, A. P. Herbert, P. N. Barlow, V. M. Holers, and J. P. Hannan Molecular Basis of the Interaction between Complement Receptor Type 2 (CR2/CD21) and Epstein-Barr Virus Glycoprotein gp350 J. Virol., November 15, 2008; 82(22): 11217 - 11227. [Abstract] [Full Text] [PDF]
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K. A. Young, X. S. Chen, V. M. Holers, and J. P. Hannan Isolating the Epstein-Barr Virus gp350/220 Binding Site on Complement Receptor Type 2 (CR2/CD21) J. Biol. Chem., December 14, 2007; 282(50): 36614 - 36625. [Abstract] [Full Text] [PDF]
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 A. M. Lenderink, K. Liegel, D. Ljubanovic, K. E. Coleman, G. S. Gilkeson, V. M. Holers, and J. M. Thurman The alternative pathway of complement is activated in the glomeruli and tubulointerstitium of mice with adriamycin nephropathy Am J Physiol Renal Physiol, August 1, 2007; 293(2): F555 - F564. [Abstract] [Full Text] [PDF]
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 J. Ho, S. Moir, L. Kulik, A. Malaspina, E. T. Donoghue, N. J. Miller, W. Wang, T.-W. Chun, A. S. Fauci, and V. M. Holers Role for CD21 in the Establishment of an Extracellular HIV Reservoir in Lymphoid Tissues J. Immunol., June 1, 2007; 178(11): 6968 - 6974. [Abstract] [Full Text] [PDF]
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F. C. Hsiao, M. Lin, A. Tai, G. Chen, and B. T. Huber Cutting Edge: Epstein-Barr Virus Transactivates the HERV-K18 Superantigen by Docking to the Human Complement Receptor 2 (CD21) on Primary B Cells J. Immunol., August 15, 2006; 177(4): 2056 - 2060. [Abstract] [Full Text] [PDF]
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R. Asokan, J. Hua, K. A. Young, H. J. Gould, J. P. Hannan, D. M. Kraus, G. Szakonyi, G. J. Grundy, X. S. Chen, M. K. Crow, et al. Characterization of Human Complement Receptor Type 2 (CR2/CD21) as a Receptor for IFN-{alpha}: A Potential Role in Systemic Lupus Erythematosus J. Immunol., July 1, 2006; 177(1): 383 - 394. [Abstract] [Full Text] [PDF]
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L. Birrell, L. Kulik, B. P. Morgan, V. M. Holers, and K. J. Marchbank B Cells from Mice Prematurely Expressing Human Complement Receptor Type 2 Are Unresponsive to T-Dependent Antigens J. Immunol., June 1, 2005; 174(11): 6974 - 6982. [Abstract] [Full Text] [PDF]
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D. Morikis and J. D. Lambris The Electrostatic Nature of C3d-Complement Receptor 2 Association J. Immunol., June 15, 2004; 172(12): 7537 - 7547. [Abstract] [Full Text] [PDF]
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A. Cherukuri, T. Shoham, H. W. Sohn, S. Levy, S. Brooks, R. Carter, and S. K. Pierce The Tetraspanin CD81 Is Necessary for Partitioning of Coligated CD19/CD21-B Cell Antigen Receptor Complexes into Signaling-Active Lipid Rafts J. Immunol., January 1, 2004; 172(1): 370 - 380. [Abstract] [Full Text] [PDF]
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M. A. Lindorfer, H. B. Jinivizian, P. L. Foley, A. D. Kennedy, M. D. Solga, and R. P. Taylor B Cell Complement Receptor 2 Transfer Reaction J. Immunol., April 1, 2003; 170(7): 3671 - 3678. [Abstract] [Full Text] [PDF]
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K. J. Marchbank, L. Kulik, M. G. Gipson, B. P. Morgan, and V. M. Holers 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 J. Immunol., October 1, 2002; 169(7): 3526 - 3535. [Abstract] [Full Text] [PDF]
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M. T. McClain, P. A. Ramsland, K. M. Kaufman, and J. A. James Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens J. Immunol., February 15, 2002; 168(4): 2054 - 2062. [Abstract] [Full Text] [PDF]
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