Skip to main content

Advertisement

SpringerLink
Log in

Models for the dynamics and order of immunoglobulin isotype switching

  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Experiments show that class switch recombination (CSR) depends on the number of divisions that the cell has performed rather than on the time since stimulation. Using computer simulations of CSR dynamics in B cell populations, we addressed the following questions. How does the probability of CSR depend on the number of divisions that a cell has performed? How does the cell decide which isotype to switch to? Does this decision depend on the distance between the genes of the pre-switch and the post-switch isotype? Our results indicate that post-switch isotype choice may be determined indirectly by the probabilities of division (which is fixed) and of switching per division (which increases as a function of the number of divisions that a cell performs), and more directly by a bias in the choice of the post-switch C gene segment towards those proximal to the pre-switch C gene.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CSR:

class switch recombination

AID:

activation-induced cytidine deaminase

References

  • Armitage, R.J. et al., 1992. Molecular and biological characterization of a murine ligand for CD40. Nature 357, 80–82.

    Article  Google Scholar 

  • Avery, D.T., Kalled, S.L., Ellyard, J.I., Ambrose, C., Bixler, S.A., Thien, M., Brink, R., Mackay, F., Hodgkin, P.D., Tangye, S.G., 2003. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J. Clin. Invest. 112, 286–297.

    Article  Google Scholar 

  • Coffman, R.L., Lebman, D.A., Shrader, B., 1989. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J. Exp. Med. 170, 1039–1044.

    Article  Google Scholar 

  • Daniels, G.A., Lieber, M.R., 1995. RNA-DNA complex formation upon transcription of immunoglobulin switch region: implications for the mechanism and regulation of class switch recombination. Nucleic Acids Res. 23, 5006–5011.

    Google Scholar 

  • Deenick, E.K., Hasbold, J., Hodgkin, P.D., 1999. Switching to IgG3, IgG2b, and IgA is division linked and independent, revealing a stochastic framework for describing differentiation. J. Immunol. 63, 4707–4714.

    Google Scholar 

  • Durandy, A., Honjo, T., 2001. Human genetic defects in class-switch recombination (hyper-IgM syndromes). Curr. Opin. Immunol. 13, 543–548.

    Article  Google Scholar 

  • Ehrenstein, M.R., O’Keefe, T.L., Davies, S.L., Neuberger, M.S., 1998. Targeted gene disruption reveals a role for natural secretory IgM in the maturation of the primary immune response. Proc. Natl. Acad. Sci. USA 95, 10089–10093.

    Google Scholar 

  • Gould, H.J., Sutton, B.J., Beavil, A.J., Beavil, R.L., McCloskey, N., Coker, H.A., Fear, D., Smurthwaite, L., 2003. The biology of IgE and the basis of allergic disease. Annu. Rev. Immunol. 21, 579–628.

    Article  Google Scholar 

  • Gregorek, H., Madalinski, K., Woynarowski, M., Mikolajewicz, J., Syczewska, M., Socha, J., 2000. IgG subclass distribution of hepatitis B surface antigen antibodies induced in children with chronic hepatitis B infection after interferon-alpha therapy. J. Infect. Dis. 181, 2059–5062.

    Article  Google Scholar 

  • Hasbold, J., Gett, A.V., Rush, J.S., Deenick, E., Avery, D., Jun, J., Hodgkin, P.D., 1999. Quantitative analysis of lymphocyte differentiation and proliferation in vitro using carboxyfluorescein diacetate succinimidyl ester. Immunol. Cell. Biol. 77, 516–522.

    Article  Google Scholar 

  • Hasbold, J., Lyons, A.B., Kehry, M.R., Hodgkin, P.D., 1998. Cell division number regulates IgG1 and IgE switching of B cells following stimulation by CD40 ligand and IL-4. Eur. J. Immunol. 28, 1040–1051.

    Article  Google Scholar 

  • Hodgkin, P.D., Lee, J.H., Lyons, A.B., 1996. B cell differentiation and isotype switching is related to division cycle number. J. Exp. Med. 184, 277–281.

    Article  Google Scholar 

  • Jones, S., Chen, Y.W., Isakson, P., Layton, J., Pure, E., Word, C., Krammer, P.H., Tucker, P., Vitetta, E.S., 1983. Effect of T cell-derived lymphokines containing B cell differentiation factor(s) for IgG (BCDF gamma) on gamma-specific mRNA in murine B cells. J. Immunol. 131, 3049–3051.

    Google Scholar 

  • Kinoshita, K., Lee, C.G., Tashiro, J., Muramatsu, M., Chen, X.C., Yoshikawa, K., Honjo, T., 1999. Molecular mechanism of immunoglobulin class switch recombination. Cold. Spring. Harbor. Symp. Quant. Biol. 64, 217–226.

    Article  Google Scholar 

  • Kinoshita, K., Tashiro, J., Tomita, S., Lee, C.G., Honjo, T., 1998. Target specificity of immunoglobulin class switch recombination is not determined by nucleotide sequences of S regions. Immunity 9, 849–858.

    Article  Google Scholar 

  • Kunimoto, D.Y., Harriman, G.R., Strober, W., 1988. Regulation of IgA differentiation in CH12LX B cells by lymphokines. IL-4 induces membrane IgM-positive CH12LX cells to express membrane IgA and IL-5 induces membrane IgA-positive CH12LX cells to secrete IgA. J. Immunol. 141, 713–720.

    Google Scholar 

  • Kuppers, R., Klein, U., Hansmann, M.L., Rajewsky, K., 1999. Cellular origin of human B-cell lymphomas. N. Engl. J. Med. 341, 1520–1529.

    Article  Google Scholar 

  • Liu, Y.J., Zhang, J., Lane, P.J., Chan, E.Y., MacLennan, I.C., 1991. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur. J. Immunol. 21, 2951–2962.

    Google Scholar 

  • Maizels, N., 1999. Immunoglobulin class switch recombination: will genetics provide new clues to mechanism? Am. J. Hum. Gene. 64, 1270–1275.

    Article  Google Scholar 

  • Maliszewski, C.R., Grabstein, K., Fanslow, W.C., Armitage, R., Spriggs, M.K., Sato, T.A., 1993. Recombinant CD40 ligand stimulation of murine B cell growth and differentiation: cooperative effects of cytokines. Eur. J. Immunol. 23, 1044–1049.

    Google Scholar 

  • McCall, M.N., Hodgkin, P.D., 1999. Switch recombination and germ-line transcription are division-regulated events in B lymphocytes. Biochim. Biophys. Acta. 1447, 43–50.

    Google Scholar 

  • McIntyre, T.M., Kehry, M.R., Snapper, C.M., 1995. Novel in vitro model for high-rate IgA class switching. J. Immunol. 154, 3156–3161.

    Google Scholar 

  • McIntyre, T.M., Klinman, D.R., Rothman, P., Lugo, M., Dasch, J.R., Mond, J.J., Snapper, C.M., 1993. Transforming growth factor β1 selectivity stimulates IgG2b secretion by LipoPolySaccharide murine B cells. J. Exp. Med. 177, 1031–1037.

    Article  Google Scholar 

  • Mehr, R., Perelson, A.S., Fridkis-Hareli, M., Globerson, A., 1997. Regulatory feedback pathways in the thymus. Immunol. Today 18, 581–585.

    Article  Google Scholar 

  • Mehr, R., Shahaf, G., Sah, A., Cancro, M., 2003. Asynchronous differentiation models explain bone marrow labeling kinetics and predict reflux between the pre-and immature B cell pools. Int. Immunol. 15, 301–312.

    Article  Google Scholar 

  • Mehr, R., Shannon, M., Litwin, S., 1999. Biased receptor editing in B cells implications for allelic exclusion. J. Immunol. 163, 1793–1798.

    Google Scholar 

  • Moon, H.B., Severinson, E., Heusser, C., Johansson, S.G., Moller, G., Persson, U., 1989. Regulation of IgG1 and IgE synthesis by interleukin 4 in mouse B cells. Scand. J. Immunol. 30, 355–361.

    Google Scholar 

  • Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y., Honjo, T., 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563.

    Article  Google Scholar 

  • Mussmann, R., Courtet, M., Schwager, J., Du Pasquier, L., 1997. Microsites for immunoglobulin-switch recombination breakpoints from Xenopus to mammals. Eur. J. Immunol. 27, 2610–2619.

    Google Scholar 

  • Nagaoka, H., Muramatsu, M., Yamamura, N., Kinoshita, K., Honjo, T., 2002. Activation-induced deaminase (AID)-directed hypermutation in the immunoglobulin Smu region: implication of AID involvement in a common step of class switch recombination and somatic hypermutation. J. Exp. Med. 195, 529–534.

    Article  Google Scholar 

  • Pecanha, L.M., Yamaguchi, H., Lees, A., Noelle, R.J., Mond, J.J., Snapper, C.M., 1993. Dextran-conjugated anti-IgD antibodies inhibit T cell-mediated IgE production but augment the synthesis of IgM and IgG. J. Immunol. 150, 2160–2168.

    Google Scholar 

  • Petersen-Mahrt, S.K., Harris, R.S., Neuberger, M.S., 2002. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418, 99–103.

    Article  Google Scholar 

  • Phan, T.G., Amesbury, M., Gardam, S., Crosbie, J., Hasbold, J., Hodgkin, P.D., Basten, A., Brink, R., 2003. B cell receptor-independent stimuli trigger immunoglobulin (Ig) class switch recombination and production of IgG autoantibodies by anergic self-reactive B cells. J. Exp. Med. 197, 845–860.

    Article  Google Scholar 

  • Reaban, M.E., Griffin, J.A., 1990. Induction of RNA-stabilized DNA conformers by transcription of an immunoglobulin switch region. Nature 348, 342–344.

    Article  Google Scholar 

  • Revy, P. et al., 2000. Activation induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper IgM syndrome (HIGM2). Cell 102, 565–575.

    Article  Google Scholar 

  • Rush, J.S., Hasbold, J., Hodgkin, P.D., 2002. Cross-linking surface Ig delays CD40 ligand-and IL-4-induced B cell Ig class switching and reveals evidence for independent regulation of B cell proliferation and differentiation. J. Immunol. 168, 2676–2682.

    Google Scholar 

  • Rush, J.S., Hodgkin, P.D., 2001. B cells activated via CD40 and IL-4 undergo a division burst but require continued stimulation to maintain division, survival and differentiation. Eur. J. Immunol. 4, 1150–1159.

    Article  Google Scholar 

  • Shannon, M., Mehr, R., 1999. Reconciling repertoire shift with affinity maturation: the role of deleterious mutations. J. Immunol. 162, 3950–3956.

    Google Scholar 

  • Shimoda, M., Nakamura, T., Takahashi, Y., Asanuma, H., Tamura, S., Kurata, T., Mizuochi, T., Azuma, N., Kanno, C., Takemori, T., 2001. Isotype-specific selection of high affinity memory B cells in nasal-associated lymphoid tissue. J. Exp. Med. 194, 1597–1607.

    Article  Google Scholar 

  • Snapper, C.M., Finkelman, F.D., Paul, W.E., 1988a. Differential regulation of IgG1 and IgE synthesis by interleukin 4. J. Exp. Med. 167, 183–196.

    Article  Google Scholar 

  • Snapper, C.M., Finkelman, F.D., Paul, W.E., 1988b. Regulation of IgG1 and IgE production by interleukin 4. Immunol. Rev. 102, 51–75.

    Article  Google Scholar 

  • Snapper, C.M., Kehry, M.R., Castle, B.E., Mond, J.J., 1995. Multivalent, but not divalent, antigen receptor crosslinkers synergize with CD40 ligand for induction of Ig synthesis and class switching in normal murine B cells. A redefinition of the TI-2 vs T cell-dependent antigen dichotomy. J. Immunol. 154, 1177–1187.

    Google Scholar 

  • Snapper, C.M., Marcu, K.B., Zelazowski, P., 1997. The immunoglobulin class switch: beyond ‘accessibility’. Immunity 6, 217–223.

    Article  Google Scholar 

  • Snapper, C.M., McIntyre, T.M., Mandler, R., Pecanha, L.M., Finkelman, F.D., Lees, A., Mond, J.J., 1992. Induction of IgG3 secretion by Interferon γ: a model for T cell-independent class switching in response to T cell-independent type 2 antigens. J. Exp. Med. 175, 1367–1371.

    Article  Google Scholar 

  • Snapper, C.M., Mond, J.J., 1993. Towards a comprehensive view of immunoglobulin class switching. Immunol. Today 14, 15–17.

    Article  Google Scholar 

  • Snapper, C.M., Paul, W.E., 1987. IFN-γ and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 236, 944–947.

    Google Scholar 

  • Snapper, C.M., Pecanha, L.M., Levine, A.D., Mond, J.J., 1991. IgE class Switching is critically dependent upon the nature of the B cell activator, in addition to the presence of IL-4. J. Immunol. 147, 1163–1170.

    Google Scholar 

  • Snapper, C.M., Peschel, C., Paul, W.E., 1988c. IFN-α stimulates IgG2a secretion by murine B cells stimulated with bacterial Lipopolysaccharide. J. Immunol. 140, 2121–2127.

    Google Scholar 

  • Sonoda, E., Matsumoto, R., Hitoshi, Y., Ishii, T., Sugimoto, M., Araki, S., Tominaga, A., Yamaguchi, N., Takatsu, K., 1989. Transforming growth factor beta induces IgA production and acts additively with interleukin 5 for IgA production. J. Exp. Med. 170, 1415–1420.

    Article  Google Scholar 

  • Stavnezer, J., 1996. Immunoglobulin class switch. Curr. Opin. Immunol. 8, 199–205.

    Article  Google Scholar 

  • Stavnezer, J., 2000. Molecular processes that regulate class switching. Curr. Top. Microbiol. Immunol. 245, 127–168.

    Google Scholar 

  • Stavnezer, J., Radcliffe, G., Lin, Y.C., Nietupski, J., Berggren, L., Sitia, R., Severinson, E., 1988. Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes. Proc. Natl. Acad. Sci. 85, 7704–7708.

    Article  Google Scholar 

  • Tangye, S.G., Avery, D.T., Deenick, E.K., Hodgkin, P.D., 2003a. Intrinsic differences in the proliferation of naïve and memory B cells as a mechanism for enhanced secondary immune responses. J. Immunol. 170, 686–694.

    Google Scholar 

  • Tangye, S.G., Avery, D.T., Hodgkin, P.D., 2003b. A division-linked mechanism for the rapid generation of Ig-secreting cells from human memory B cells. J. Immunol. 170, 261–269.

    Google Scholar 

  • Tangye, S.G., Ferguson, A., Avery, D.T., Ma, C.S., Hodgkin, P.D., 2002. Isotype switching by human B cells is division-associated and regulated by cytokines. J. Immunol. 169, 4298–4306.

    Google Scholar 

  • White, H., Gray, D., 2000. Analysis of immunoglobulin (Ig) isotype diversity and IgM/D memory in the response to phenyl-oxazolone. J. Exp. Med. 191, 2209–2220.

    Article  Google Scholar 

  • Wrammert, J., Kallberg, E., Agace, W.W., Leanderson, T., 2002. Ly6C expression differentiates plasma cells from other B cell subsets in mice. Eur. J. Immunol. 32, 97–103.

    Article  Google Scholar 

  • Xu, L., Rothman, P., 1994. IFN-gamma represses epsilon germline transcription and subsequently down-regulates switch recombination to epsilon. Int. Immunol. 6, 515–521.

    Google Scholar 

  • Yuan, D., Dang, T., Bibi, R., 2001. Inappropriate expression of IgD from a transgene inhibits the function of antigen-specific memory B cells. Cell Immunol. 211, 61–70.

    Article  Google Scholar 

  • Zelazowski, P., Collins, J.T., Dunnick, W., Snapper, C.M., 1995. Antigen receptor cross-linking differentially regulates germ-line CH ribonucleic acid expression in murine B cells. J. Immunol 154, 1223–1231.

    Google Scholar 

  • Zhang, K., 2000. Immunoglobulin class switch recombination machinery: progress and challenges. Clin. Immunol. 95, 1–8.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 52900, Israel

    Barak Yaish & Ramit Mehr

Authors
  1. Barak Yaish
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ramit Mehr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramit Mehr.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yaish, B., Mehr, R. Models for the dynamics and order of immunoglobulin isotype switching. Bull. Math. Biol. 67, 15–32 (2005). https://doi.org/10.1016/j.bulm.2004.05.007

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.bulm.2004.05.007

Keywords

Search

Navigation