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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2000 Mar 29;355(1395):357–360. doi: 10.1098/rstb.2000.0573

Memory in the B-cell compartment: antibody affinity maturation.

M S Neuberger 1, M R Ehrenstein 1, C Rada 1, J Sale 1, F D Batista 1, G Williams 1, C Milstein 1
PMCID: PMC1692737  PMID: 10794054

Abstract

In the humoral arm of the immune system, the memory response is not only more quickly elicited and of greater magnitude than the primary response, but it is also different in quality. In the recall response to antigen, the antibodies produced are of higher affinity and of different isotype (typically immunoglobulin G rather than immunoglobulin M). This maturation rests on the antigen dependence of B-cell maturation and is effected by programmed genetic modifications of the immunoglobulin gene loci. Here we consider how the B-cell response to antigen depends on the affinity of the antigen receptor interaction. We also compare and draw parallels between the two processes, which underpin the generation of secondary-response antibodies: V gene somatic hypermutation and immunoglobulin heavy-chain class switching.

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Selected References

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  1. Batista F. D., Neuberger M. S. Affinity dependence of the B cell response to antigen: a threshold, a ceiling, and the importance of off-rate. Immunity. 1998 Jun;8(6):751–759. doi: 10.1016/s1074-7613(00)80580-4. [DOI] [PubMed] [Google Scholar]
  2. Berek C., Milstein C. Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev. 1987 Apr;96:23–41. doi: 10.1111/j.1600-065x.1987.tb00507.x. [DOI] [PubMed] [Google Scholar]
  3. Betz A. G., Rada C., Pannell R., Milstein C., Neuberger M. S. Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2385–2388. doi: 10.1073/pnas.90.6.2385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boyden S. V. Natural antibodies and the immune response. Adv Immunol. 1966;5:1–28. doi: 10.1016/s0065-2776(08)60271-0. [DOI] [PubMed] [Google Scholar]
  5. Carter R. H., Fearon D. T. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science. 1992 Apr 3;256(5053):105–107. doi: 10.1126/science.1373518. [DOI] [PubMed] [Google Scholar]
  6. Casellas R., Nussenzweig A., Wuerffel R., Pelanda R., Reichlin A., Suh H., Qin X. F., Besmer E., Kenter A., Rajewsky K. Ku80 is required for immunoglobulin isotype switching. EMBO J. 1998 Apr 15;17(8):2404–2411. doi: 10.1093/emboj/17.8.2404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. EISEN H. N., SISKIND G. W. VARIATIONS IN AFFINITIES OF ANTIBODIES DURING THE IMMUNE RESPONSE. Biochemistry. 1964 Jul;3:996–1008. doi: 10.1021/bi00895a027. [DOI] [PubMed] [Google Scholar]
  8. Ehrenstein M. R., Neuberger M. S. Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation. EMBO J. 1999 Jun 15;18(12):3484–3490. doi: 10.1093/emboj/18.12.3484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Frey S., Bertocci B., Delbos F., Quint L., Weill J. C., Reynaud C. A. Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process. Immunity. 1998 Jul;9(1):127–134. doi: 10.1016/s1074-7613(00)80594-4. [DOI] [PubMed] [Google Scholar]
  10. Gellert M. Recent advances in understanding V(D)J recombination. Adv Immunol. 1997;64:39–64. doi: 10.1016/s0065-2776(08)60886-x. [DOI] [PubMed] [Google Scholar]
  11. Goodnow C. C. Transgenic mice and analysis of B-cell tolerance. Annu Rev Immunol. 1992;10:489–518. doi: 10.1146/annurev.iy.10.040192.002421. [DOI] [PubMed] [Google Scholar]
  12. JERNE N. K. A study of avidity based on rabbit skin responses to diphtheria toxin-antitoxin mixtures. Acta Pathol Microbiol Scand Suppl. 1951;87:1–183. [PubMed] [Google Scholar]
  13. Jerne N. K. THE NATURAL-SELECTION THEORY OF ANTIBODY FORMATION. Proc Natl Acad Sci U S A. 1955 Nov 15;41(11):849–857. doi: 10.1073/pnas.41.11.849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jolly C. J., Wagner S. D., Rada C., Klix N., Milstein C., Neuberger M. S. The targeting of somatic hypermutation. Semin Immunol. 1996 Jun;8(3):159–168. doi: 10.1006/smim.1996.0020. [DOI] [PubMed] [Google Scholar]
  15. Klaus G. G., Humphrey J. H., Kunkl A., Dongworth D. W. The follicular dendritic cell: its role in antigen presentation in the generation of immunological memory. Immunol Rev. 1980;53:3–28. doi: 10.1111/j.1600-065x.1980.tb01038.x. [DOI] [PubMed] [Google Scholar]
  16. Manis J. P., Gu Y., Lansford R., Sonoda E., Ferrini R., Davidson L., Rajewsky K., Alt F. W. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J Exp Med. 1998 Jun 15;187(12):2081–2089. doi: 10.1084/jem.187.12.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Milstein C., Neuberger M. S., Staden R. Both DNA strands of antibody genes are hypermutation targets. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8791–8794. doi: 10.1073/pnas.95.15.8791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Neuberger M. S., Ehrenstein M. R., Klix N., Jolly C. J., Yélamos J., Rada C., Milstein C. Monitoring and interpreting the intrinsic features of somatic hypermutation. Immunol Rev. 1998 Apr;162:107–116. doi: 10.1111/j.1600-065x.1998.tb01434.x. [DOI] [PubMed] [Google Scholar]
  19. Neuberger M. S., Milstein C. Somatic hypermutation. Curr Opin Immunol. 1995 Apr;7(2):248–254. doi: 10.1016/0952-7915(95)80010-7. [DOI] [PubMed] [Google Scholar]
  20. O'Keefe T. L., Williams G. T., Batista F. D., Neuberger M. S. Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J Exp Med. 1999 Apr 19;189(8):1307–1313. doi: 10.1084/jem.189.8.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rada C., Ehrenstein M. R., Neuberger M. S., Milstein C. Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting. Immunity. 1998 Jul;9(1):135–141. doi: 10.1016/s1074-7613(00)80595-6. [DOI] [PubMed] [Google Scholar]
  22. Rogozin I. B., Kolchanov N. A. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochim Biophys Acta. 1992 Nov 15;1171(1):11–18. doi: 10.1016/0167-4781(92)90134-l. [DOI] [PubMed] [Google Scholar]
  23. Rolink A., Melchers F., Andersson J. The SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching. Immunity. 1996 Oct;5(4):319–330. doi: 10.1016/s1074-7613(00)80258-7. [DOI] [PubMed] [Google Scholar]
  24. SEGRE D., KAEBERLE M. L. The immunologic behavior of baby pigs. I. Production of antibodies in three-week-old pigs. J Immunol. 1962 Dec;89:782–789. [PubMed] [Google Scholar]
  25. Sale J. E., Neuberger M. S. TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. Immunity. 1998 Dec;9(6):859–869. doi: 10.1016/s1074-7613(00)80651-2. [DOI] [PubMed] [Google Scholar]
  26. Stavnezer J. Antibody class switching. Adv Immunol. 1996;61:79–146. doi: 10.1016/s0065-2776(08)60866-4. [DOI] [PubMed] [Google Scholar]
  27. Wagner S. D., Milstein C., Neuberger M. S. Codon bias targets mutation. Nature. 1995 Aug 31;376(6543):732–732. doi: 10.1038/376732a0. [DOI] [PubMed] [Google Scholar]
  28. Wuerffel R. A., Du J., Thompson R. J., Kenter A. L. Ig Sgamma3 DNA-specifc double strand breaks are induced in mitogen-activated B cells and are implicated in switch recombination. J Immunol. 1997 Nov 1;159(9):4139–4144. [PubMed] [Google Scholar]

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