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Proc Natl Acad Sci U S A. 1996 April 16; 93(8): 3357–3361.
PMCID: PMC39612
Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2.
H Molina, V M Holers, B Li, Y Fung, S Mariathasan, J Goellner, J Strauss-Schoenberger, R W Karr, and D D Chaplin
Department of Internal Medicine and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract
Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1- and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B- and T-cell development are overtly normal. Nevertheless, B-cell responses to low and high doses of a T-cell-dependent antigen are impaired with decreased titers of antigen-specific IgM and IgG isotypes. This defect is not complete because there is still partial activation of B lymphocytes during the primary immune response, with generation of splenic germinal centers and a detectable, although reduced, secondary antibody response. These data suggest that certain T-dependent antigens manifest an absolute dependence on complement receptors for the initiation of a normally robust immune response.
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  • Weigle WO, Goodman MG, Morgan EL, Hugli TE. Regulation of immune response by components of the complement cascade and their activated fragments. Springer Semin Immunopathol. 1983;6(2-3):173–194. [PubMed]
  • Hourcade D, Holers VM, Atkinson JP. The regulators of complement activation (RCA) gene cluster. Adv Immunol. 1989;45:381–416. [PubMed]
  • Ahearn JM, Fearon DT. Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21). Adv Immunol. 1989;46:183–219. [PubMed]
  • Hivroz C, Fischer E, Kazatchkine MD, Grillot-Courvalin C. Differential effects of the stimulation of complement receptors CR1 (CD35) and CR2 (CD21) on cell proliferation and intracellular Ca2+ mobilization of chronic lymphocytic leukemia B cells. J Immunol. 1991 Mar 15;146(6):1766–1772. [PubMed]
  • Aubry JP, Pochon S, Graber P, Jansen KU, Bonnefoy JY. CD21 is a ligand for CD23 and regulates IgE production. Nature. 1992 Aug 6;358(6386):505–507. [PubMed]
  • Holers VM, Kinoshita T, Molina H. The evolution of mouse and human complement C3-binding proteins: divergence of form but conservation of function. Immunol Today. 1992 Jun;13(6):231–236. [PubMed]
  • Molina H, Brenner C, Jacobi S, Gorka J, Carel JC, Kinoshita T, Holers VM. Analysis of Epstein-Barr virus-binding sites on complement receptor 2 (CR2/CD21) using human-mouse chimeras and peptides. At least two distinct sites are necessary for ligand-receptor interaction. J Biol Chem. 1991 Jul 5;266(19):12173–12179. [PubMed]
  • Kinoshita T, Lavoie S, Nussenzweig V. Regulatory proteins for the activated third and fourth components of complement (C3b and C4b) in mice. II. Identification and properties of complement receptor type 1 (CR1). J Immunol. 1985 Apr;134(4):2564–2570. [PubMed]
  • Molina H, Wong W, Kinoshita T, Brenner C, Foley S, Holers VM. Distinct receptor and regulatory properties of recombinant mouse complement receptor 1 (CR1) and Crry, the two genetic homologues of human CR1. J Exp Med. 1992 Jan 1;175(1):121–129. [PubMed]
  • Kurtz CB, O'Toole E, Christensen SM, Weis JH. The murine complement receptor gene family. IV. Alternative splicing of Cr2 gene transcripts predicts two distinct gene products that share homologous domains with both human CR2 and CR1. J Immunol. 1990 May 1;144(9):3581–3591. [PubMed]
  • Kinoshita T, Takeda J, Hong K, Kozono H, Sakai H, Inoue K. Monoclonal antibodies to mouse complement receptor type 1 (CR1). Their use in a distribution study showing that mouse erythrocytes and platelets are CR1-negative. J Immunol. 1988 May 1;140(9):3066–3072. [PubMed]
  • Heyman B, Wiersma EJ, Kinoshita T. In vivo inhibition of the antibody response by a complement receptor-specific monoclonal antibody. J Exp Med. 1990 Aug 1;172(2):665–668. [PubMed]
  • Wiersma EJ, Kinoshita T, Heyman B. Inhibition of immunological memory and T-independent humoral responses by monoclonal antibodies specific for murine complement receptors. Eur J Immunol. 1991 Oct;21(10):2501–2506. [PubMed]
  • Thyphronitis G, Kinoshita T, Inoue K, Schweinle JE, Tsokos GC, Metcalf ES, Finkelman FD, Balow JE. Modulation of mouse complement receptors 1 and 2 suppresses antibody responses in vivo. J Immunol. 1991 Jul 1;147(1):224–230. [PubMed]
  • Hebell T, Ahearn JM, Fearon DT. Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science. 1991 Oct 4;254(5028):102–105. [PubMed]
  • Gustavsson S, Kinoshita T, Heyman B. Antibodies to murine complement receptor 1 and 2 can inhibit the antibody response in vivo without inhibiting T helper cell induction. J Immunol. 1995 Jun 15;154(12):6524–6528. [PubMed]
  • Molina H, Kinoshita T, Inoue K, Carel JC, Holers VM. A molecular and immunochemical characterization of mouse CR2. Evidence for a single gene model of mouse complement receptors 1 and 2. J Immunol. 1990 Nov 1;145(9):2974–2983. [PubMed]
  • De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J, et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science. 1994 Apr 29;264(5159):703–707. [PubMed]
  • Mansour SL, Thomas KR, Capecchi MR. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988 Nov 24;336(6197):348–352. [PubMed]
  • Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R, Berns A. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 1991 Aug 11;19(15):4293. [PubMed]
  • Heyman B, Holmquist G, Borwell P, Heyman U. An enzyme-linked immunosorbent assay for measuring anti-sheep erythrocyte antibodies. J Immunol Methods. 1984 Mar 30;68(1-2):193–204. [PubMed]
  • Wiersma EJ, Nose M, Heyman B. Evidence of IgG-mediated enhancement of the antibody response in vivo without complement activation via the classical pathway. Eur J Immunol. 1990 Dec;20(12):2585–2589. [PubMed]
  • Fearon DT. The CD19-CR2-TAPA-1 complex, CD45 and signaling by the antigen receptor of B lymphocytes. Curr Opin Immunol. 1993 Jun;5(3):341–348. [PubMed]
  • Tedder TF, Zhou LJ, Engel P. The CD19/CD21 signal transduction complex of B lymphocytes. Immunol Today. 1994 Sep;15(9):437–442. [PubMed]
  • Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity. 1995 Jul;3(1):39–50. [PubMed]
  • Rickert RC, Rajewsky K, Roes J. Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature. 1995 Jul 27;376(6538):352–355. [PubMed]
  • Tuveson DA, Ahearn JM, Matsumoto AK, Fearon DT. Molecular interactions of complement receptors on B lymphocytes: a CR1/CR2 complex distinct from the CR2/CD19 complex. J Exp Med. 1991 May 1;173(5):1083–1089. [PubMed]
  • Frade R, Gauffre A, Hermann J, Barel M. EBV/C3d receptor (CR2) interacts by its intracytoplasmic carboxy-terminal domain and two distinct binding sites with the p53 anti-oncoprotein and the p68 calcium-binding protein. J Immunol. 1992 Nov 15;149(10):3232–3238. [PubMed]
  • Kozono Y, Duke RC, Schleicher MS, Holers VM. Co-ligation of mouse complement receptors 1 and 2 with surface IgM rescues splenic B cells and WEHI-231 cells from anti-surface IgM-induced apoptosis. Eur J Immunol. 1995 Apr;25(4):1013–1017. [PubMed]