Search tips
Search criteria 


Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. 1995 February 1; 181(2): 599–606.
PMCID: PMC2191878

Human immunoglobulin (IgG) induced deletion of IgM rheumatoid factor B cells in transgenic mice


The singular ability of immunoglobulin genes to hypermutate their variable regions, while permitting the generation of high-affinity antibodies against foreign antigens, poses a problem in terms of maintenance of immunological self-tolerance. Immunoglobulin gene hypermutation driven by a foreign antigen has the potential to generate antibodies that cross-react with self-components. Consequently, there must exist a mechanism in the periphery for inactivation of mature autoreactive B cell clones. The classical experimental system used to address this problem is the induction of tolerance to soluble, deaggregated human IgG. We have analyzed the mechanism of induction of tolerance to human IgG using transgenic mice that express a human IgM rheumatoid factor (IgM RF) on a large proportion of their B cells. Injection of deaggregated human IgG caused a specific deletion of those B cells that express an intact IgM RF on their cell surface. The degree of RF B cell deletion was proportional to the reduction in the proliferative response of splenocytes to antigen (aggregated human IgG), or to F(ab')2 fragments of anti-human IgM antibodies. Control experiments showed that IgG administration had little effect on the numbers of mouse Ig-bearing cells or their ability to proliferate to a nonspecific mitogen. Thus, the effects of IgG on the human IgM RF B cell are antigen specific and are not due to nonspecific toxic effects of the human IgG preparation. These experiments demonstrate that peripheral exposure to IgG induces deletion of reactive B cells, without any evidence for anergy, and differ from data obtained by other investigators studying tolerance to soluble protein antigens. The results imply that human Igs have distinct properties as soluble antigens, and that peripheral nonresponsiveness to IgG may be due to lymphocyte deletion.

Full Text

The Full Text of this article is available as a PDF (3.0M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Weigle WO. Analysis of autoimmunity through experimental models of thyroiditis and allergic encephalomyelitis. Adv Immunol. 1980;30:159–273. [PubMed]
  • Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Brink RA, Pritchard-Briscoe H, Wotherspoon JS, Loblay RH, Raphael K, et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 1988 Aug 25;334(6184):676–682. [PubMed]
  • Goodnow CC, Crosbie J, Jorgensen H, Brink RA, Basten A. Induction of self-tolerance in mature peripheral B lymphocytes. Nature. 1989 Nov 23;342(6248):385–391. [PubMed]
  • Hartley SB, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature. 1991 Oct 24;353(6346):765–769. [PubMed]
  • Adams E, Basten A, Goodnow CC. Intrinsic B-cell hyporesponsiveness accounts for self-tolerance in lysozyme/anti-lysozyme double-transgenic mice. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5687–5691. [PubMed]
  • Nemazee DA, Bürki K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature. 1989 Feb 9;337(6207):562–566. [PubMed]
  • Russell DM, Dembić Z, Morahan G, Miller JF, Bürki K, Nemazee D. Peripheral deletion of self-reactive B cells. Nature. 1991 Nov 28;354(6351):308–311. [PubMed]
  • Tighe H, Chen PP, Tucker R, Kipps TJ, Roudier J, Jirik FR, Carson DA. Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice. J Exp Med. 1993 Jan 1;177(1):109–118. [PMC free article] [PubMed]
  • Chiller JM, Habicht GS, Weigle WO. Kinetic differences in unresponsiveness of thymus and bone marrow cells. Science. 1971 Feb 26;171(3973):813–815. [PubMed]
  • Louis JA, Chiller JM, Weigle WO. The ability of bacterial lipopolysaccharide to modulate the induction of unresponsiveness to a state of immunity. Cellular parameters. J Exp Med. 1973 Dec 1;138(6):1481–1495. [PMC free article] [PubMed]
  • Axelrod O, Silverman GJ, Dev V, Kyle R, Carson DA, Kipps TJ. Idiotypic cross-reactivity of immunoglobulins expressed in Waldenström's macroglobulinemia, chronic lymphocytic leukemia, and mantle zone lymphocytes of secondary B-cell follicles. Blood. 1991 Apr 1;77(7):1484–1490. [PubMed]
  • Louis J, Chiller JM, Weigle WO. Fate of antigen-binding cells in unresponsive and immune mice. J Exp Med. 1973 Feb 1;137(2):461–469. [PMC free article] [PubMed]
  • Parks DE, Weigle WO. Maintenance of immunologic unresponsiveness to human gamma-globulin: evidence for irreversible inactivation in B lymphocytes. J Immunol. 1980 Mar;124(3):1230–1236. [PubMed]
  • Golub ES, Weigle WO. Studies on the induction of immunologic unresponsiveness. II. Kinetics. J Immunol. 1967 Sep;99(3):624–628. [PubMed]
  • Jirik FR, Sorge J, Fong S, Heitzmann JG, Curd JG, Chen PP, Goldfien R, Carson DA. Cloning and sequence determination of a human rheumatoid factor light-chain gene. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2195–2199. [PubMed]
  • Chen PP, Robbins DL, Jirik FR, Kipps TJ, Carson DA. Isolation and characterization of a light chain variable region gene for human rheumatoid factors. J Exp Med. 1987 Dec 1;166(6):1900–1905. [PMC free article] [PubMed]
  • Roudier J, Silverman GJ, Chen PP, Carson DA, Kipps TJ. Intraclonal diversity in the VH genes expressed by CD5- chronic lymphocytic leukemia-producing pathologic IgM rheumatoid factor. J Immunol. 1990 Feb 15;144(4):1526–1530. [PubMed]
  • Silberstein LE, Jefferies LC, Goldman J, Friedman D, Moore JS, Nowell PC, Roelcke D, Pruzanski W, Roudier J, Silverman GJ. Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens. Blood. 1991 Nov 1;78(9):2372–2386. [PubMed]
  • Sanz I, Kelly P, Williams C, Scholl S, Tucker P, Capra JD. The smaller human VH gene families display remarkably little polymorphism. EMBO J. 1989 Dec 1;8(12):3741–3748. [PubMed]
  • Murakami M, Tsubata T, Okamoto M, Shimizu A, Kumagai S, Imura H, Honjo T. Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice. Nature. 1992 May 7;357(6373):77–80. [PubMed]
  • Carsetti R, Köhler G, Lamers MC. A role for immunoglobulin D: interference with tolerance induction. Eur J Immunol. 1993 Jan;23(1):168–178. [PubMed]
  • Bijsterbosch MK, Klaus GG. Crosslinking of surface immunoglobulin and Fc receptors on B lymphocytes inhibits stimulation of inositol phospholipid breakdown via the antigen receptors. J Exp Med. 1985 Dec 1;162(6):1825–1836. [PMC free article] [PubMed]
  • Rigley KP, Harnett MM, Klaus GG. Co-cross-linking of surface immunoglobulin Fc gamma receptors on B lymphocytes uncouples the antigen receptors from their associated G protein. Eur J Immunol. 1989 Mar;19(3):481–485. [PubMed]
  • Sidman CL, Unanue ER. Control of B-lymphocyte function. I. Inactivation of mitogenesis by interactions with surface immunoglobulin and Fc-receptor molecules. J Exp Med. 1976 Oct 1;144(4):882–896. [PMC free article] [PubMed]
  • Tony HP, Schimpl A. Stimulation of murine B cells with anti-Ig antibodies: dominance of a negative signal mediated by the Fc receptor. Eur J Immunol. 1980 Sep;10(9):726–729. [PubMed]
  • Wilson HA, Greenblatt D, Taylor CW, Putney JW, Tsien RY, Finkelman FD, Chused TM. The B lymphocyte calcium response to anti-Ig is diminished by membrane immunoglobulin cross-linkage to the Fc gamma receptor. J Immunol. 1987 Mar 15;138(6):1712–1718. [PubMed]
  • Phillips NE, Parker DC. Fc-dependent inhibition of mouse B cell activation by whole anti-mu antibodies. J Immunol. 1983 Feb;130(2):602–606. [PubMed]
  • Phillips NE, Parker DC. Cross-linking of B lymphocyte Fc gamma receptors and membrane immunoglobulin inhibits anti-immunoglobulin-induced blastogenesis. J Immunol. 1984 Feb;132(2):627–632. [PubMed]
  • Gottschalk AR, Joseph LJ, Quintáns J. Fc gamma RII cross-linking inhibits anti-Ig-induced erg-1 and erg-2 expression in BCL1. J Immunol. 1994 Mar 1;152(5):2115–2122. [PubMed]
  • Nossal GJ. Cellular mechanisms of immunologic tolerance. Annu Rev Immunol. 1983;1:33–62. [PubMed]
  • Fulcher DA, Basten A. Reduced life span of anergic self-reactive B cells in a double-transgenic model. J Exp Med. 1994 Jan 1;179(1):125–134. [PMC free article] [PubMed]
  • Shlomchik MJ, Zharhary D, Saunders T, Camper SA, Weigert MG. A rheumatoid factor transgenic mouse model of autoantibody regulation. Int Immunol. 1993 Oct;5(10):1329–1341. [PubMed]
  • Carson DA, Chen PP, Fox RI, Kipps TJ, Jirik F, Goldfien RD, Silverman G, Radoux V, Fong S. Rheumatoid factor and immune networks. Annu Rev Immunol. 1987;5:109–126. [PubMed]
  • Harindranath N, Goldfarb IS, Ikematsu H, Burastero SE, Wilder RL, Notkins AL, Casali P. Complete sequence of the genes encoding the VH and VL regions of low- and high-affinity monoclonal IgM and IgA1 rheumatoid factors produced by CD5+ B cells from a rheumatoid arthritis patient. Int Immunol. 1991 Sep;3(9):865–875. [PubMed]
  • Roosnek E, Lanzavecchia A. Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells. J Exp Med. 1991 Feb 1;173(2):487–489. [PMC free article] [PubMed]
  • Cooke MP, Heath AW, Shokat KM, Zeng Y, Finkelman FD, Linsley PS, Howard M, Goodnow CC. Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. J Exp Med. 1994 Feb 1;179(2):425–438. [PMC free article] [PubMed]
  • Eris JM, Basten A, Brink R, Doherty K, Kehry MR, Hodgkin PD. Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4392–4396. [PubMed]
  • Nemazee DA. Immune complexes can trigger specific, T cell-dependent, autoanti-IgG antibody production in mice. J Exp Med. 1985 Jan 1;161(1):242–256. [PMC free article] [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press