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Somatic Diversification of Immune Responses pp 33–44Cite as

Characteristics of Somatic Hypermutation of Human Immunoglobulin Genes

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 229))

Abstract

Affinity maturation of antibodies after immunization is a result of hypermutation of the variable region of immunoglobulin genes and an antigen selection process that preserves those B lymphocytes with mutated surface immunoglobulin (Ig) expressing an increased affinity for the immunogen (French et al. 1989; Kocks and Rajewsky 1989; Wagner and Neuberger 1996). The surviving B cells then give rise to memory B cells and antibody secreting cells. Hypermutation is the predominant mechanism for diversification of the secondary antibody response. The hypermutation process is not only lineage-specific but is site- and stage-specific. Hypermutation of Ig genes is prominent in B cells in the germinal centers of secondary lymphoid organs from approximately 1–3 weeks after immunization (Levy et al. 1989; Berek et al. 1991; Jacob et al. 1991; MacLennan 1994; Pascual et al. 1994). The mutations are primarily single point substitutions that are targeted to 2 kb of DNA of rearranged heavy and light chain V gene segments with a sharp upstream boundary in the middle of the leader intron and an imprecise downstream boundary in the J-C intron that are introduced at approximately 10-3-10-4 mutations per base pair per generation, which is the highest rate of mutation observed in the eukaryotic genome (Kocks and Rajewsky 1989; Lebeque and Gearhart 1990; Wagner and Neuberger 1996).

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References

  • Bachi J, Wabl M (1996) An immunoglobulin mutator that targets G -C pairs. Proc Natl Acad Sci USA 93:851–855

    Article  Google Scholar 

  • Berek C, Berger A, Apel M (1991) Maturation of the immune response in germinal centers. Cell 67: 1121–1129

    Article  PubMed  CAS  Google Scholar 

  • Betz AG, Rada C, Pannell R, Milstein C, Neuberger MS (1993a) Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots. Proc Natl Acad Sci USA 90:2385–2388

    Article  PubMed  CAS  Google Scholar 

  • Betz AG, Neuberger MS, Milstein C (1993b) Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol Today 14:405–411

    Article  PubMed  CAS  Google Scholar 

  • Brenner S, Milstein C (1966) Origin of antibody variation. Nature 211:242–243

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Roberts VA, Rittenberg MB (1992) Generation and analysis of random point mutations in an antibody CDR2 sequence: many mutated antibodies lose their ability to bind antigen. J Exp Med 176:855–866

    Article  PubMed  CAS  Google Scholar 

  • Ellis RW, Granoff DM (1994) Development and clinical uses of Haemophilus b conjugate vaccines. Dekker, New York, pp 19–35

    Google Scholar 

  • French DL, Laskov R, Scharff MD (1989) The role of somatic hypermutation in the generation of antibody diversity. Science 244:1152–1157

    Article  PubMed  CAS  Google Scholar 

  • Golding GB, Gearhart PJ, Glickman BW (1987) Patterns of somatic mutations in immunoglobulin variable genes. Genetics 115:169–177

    PubMed  CAS  Google Scholar 

  • Hu B, Lee S, Marin E, Ryan D, Insel R (1997) Telomerase is upregulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J Immunol 159:1068–1071

    PubMed  CAS  Google Scholar 

  • Insel RA, Varade WS (1994) Bias in somatic hypermutation of human VH genes. Int Immunol 6: 1437–1443

    Article  PubMed  CAS  Google Scholar 

  • Insel RA, Adderson EE, Carroll WL (1992) The repertoire of human antibody to the Haemophilus influenzae type b capsular polysaccharide. Int Rev Immunol 9:25–42

    Article  PubMed  CAS  Google Scholar 

  • Insel RA, Marin E, Varade WS (1994) Human splenic IgM immunoglobulin transcripts are mutated at high frequency. Mol Immunol 31:383–392

    Article  PubMed  CAS  Google Scholar 

  • Insel RA, Marin E, Chu Y-W (to be published) Immunization induced diversification and mutation of a human antibody repertoire

    Google Scholar 

  • Jacob J, Kelsoe G, Rajewsky K, Weiss U (1991) Intraclonal generation of antibody mutants in germinal centres. Nature 354:389–392

    Article  PubMed  CAS  Google Scholar 

  • Jacob J, Przylepa J, Miller C, Kelsoe G (1993) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells. J Exp Med 178:1293–1307

    Article  PubMed  CAS  Google Scholar 

  • Klein R, Jaenichen R, Zachau HG (1993) Expressed human immunoglobulin genes and their hyper-mutation. Eur J Immunol 23:3248–3271

    Article  PubMed  CAS  Google Scholar 

  • Kocks C, Rajewsky K (1989) Stable expression and somatic hypermutation of antibody V regions in B cell developmental pathways. Annu Rev Immunol 7:537–559

    Article  PubMed  CAS  Google Scholar 

  • Kolchanov NA, Solovyov VV, Rogozin IB (1987) Peculiarities of immunoglobulin gene structures as a basis for somatic mutation emergence. FEBS Lett 214:87–90

    Article  PubMed  CAS  Google Scholar 

  • Lebecque SG, Gearhart PJ (1990) Boundaries of somatic mutation in rearrangement immunoglobulin genes: 5′ boundary is near the promoter, and 3′ boundary is 1 kb from V(D)J gene. J Exp Med 172:1717–1727

    Article  PubMed  CAS  Google Scholar 

  • Levy NS, Malipiero UV, Lebecque SG, Gearhart PJ (1989) Early onset of somatic mutation in immunoglobulin VH genes during the primary immune response. J Exp Med 169:2007–2019

    Article  PubMed  CAS  Google Scholar 

  • Liu YJ, Malisan F, de Bouteiller O, Guret C, Lebecque S, Banchereau J, Mills FC, Max EE, Martinez-Valdez H (1996) Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 4:241–250

    Article  PubMed  CAS  Google Scholar 

  • MacLennan ICM (1994) Germinal centers. Annu Rev Immunol 12:117–139

    Article  PubMed  CAS  Google Scholar 

  • Manser T (1990) The efficiency of antibody affinity maturation: can the rate of B-cell division be limiting? Immunol Today 11:305–307

    Article  PubMed  CAS  Google Scholar 

  • McKean D, Huppi K, Bell M, Staudt L, Gerhard W, Weigert M (1984) Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci USA 81:3180–3184

    Article  PubMed  CAS  Google Scholar 

  • Meek K, Eversole T, Capra JD (1991) Conservation of the most JH proximal Ig VH gene segment (VHVI) throughout primate evolution. J Immunol 146:2434–2438

    PubMed  CAS  Google Scholar 

  • Motoyama N, Miwa T, Suzuki Y, Okada H, Azumal (1994) Comparison of somatic mutation frequency among immunoglobulin genes. J Exp Med 179:395–403

    Article  PubMed  CAS  Google Scholar 

  • Munoz JL, Insel RA (1987) In vitro human antibody production to the Haemophilus influenzae type b capsular polysaccharide. J Immunol 139:2026–2031

    PubMed  CAS  Google Scholar 

  • Pascual V, Liu YJ, Magalski A, de Bouteiller O, Banchereau J, Capra JD (1994) Analysis of somatic mutation in five B cell subsets of human tonsil. J Exp Med 180:329–339

    Article  PubMed  CAS  Google Scholar 

  • Peters A, Storb U (1996) Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 4:57–65

    Article  PubMed  CAS  Google Scholar 

  • Reynaud CA, Garcia C, Hein WR, Weill J-C (1995) Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process. Cell 80:115–125

    Article  PubMed  CAS  Google Scholar 

  • Roes J, Huppi K, Rajewsky K, Sablitzky F (1989) V gene rearrangement is required to fully activate the hypermutation mechanism in B cells. J Immunol 142:1022–1026

    PubMed  CAS  Google Scholar 

  • Rogerson B, Hackett J, Peters A, Haasch D, Storb U (1991) Mutation pattern of immunoglobulin transgenes is compatible with a model of somatic hypermutation in which targeting of the mutator is linked to the direction of DNA replication. EMBO J 10:4331–4341

    PubMed  CAS  Google Scholar 

  • Rogozin IB, Kolchanov NA (1992) Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochim Biophys Acta 1171:11–18

    PubMed  CAS  Google Scholar 

  • Smith DS, Creadon G, Jena PK, Portanova JP, Kotzin BL, Wysocki LJ (1996) Di- and trinucleotide target preferences of somatic mutagenesis in normal and autoreactive B cells. J Immunol 156:2642–2652

    PubMed  CAS  Google Scholar 

  • Umar A, Schweitzer PA, Levy NS, Gearhart JD, Gearhart PJ (1991) Mutation in a reporter gene depends on proximity to and transcription of immunoglobulin variable transgenes. Proc Natl Acad Sci USA 88:4902–4906

    Article  PubMed  CAS  Google Scholar 

  • Varade WS, Insel RA (1993) Isolation of germinal center-like events from human spleen RNA: somatic hypermutation of a clonally related VH6DJH rearrangement expressed with IgM, IgG, and IgA. J Clin Invest 91:1838–1842

    Article  PubMed  CAS  Google Scholar 

  • Varade WS, Marin E, Kittelberger AM, Insel RA (1993) Use of the most JH-proximal human immunoglobulin heavy chain variable region gene, VH6, in the expressed immune repertoire. J Immunol 150:4985–4995

    PubMed  CAS  Google Scholar 

  • Varade WS, Carnahan J, Kingsley P, Insel RA (1997) Inherent properties of somatic hypermutation as revealed by human nonproductive VH6 immunoglobulin rearrangements (submitted for publication)

    Google Scholar 

  • Wagner SD, Neuberger MS (1996) Somatic hypermutation of immunoglobulin genes. Annu Rev Immunol 14:441–457

    Article  PubMed  CAS  Google Scholar 

  • Wilson M, Hsu E, Marcuz A, Courtet M, DuPasquier L, Steinberg C (1992) What limits affinity maturation of antibodies in Xenopus — the rate of somatic mutation or the ability to select mutants? EMBO J 11:4337–4347

    PubMed  CAS  Google Scholar 

  • Wu H, Kaartinen M (1996) Distribution and nucleotide biases of the somatic hypermutations in the functional k light chain gene of a human follicular lymphoma line. Scand J Immunol 43:193–201

    Article  PubMed  CAS  Google Scholar 

  • Yélamos J, Klix N, Goyenechea B, Lozano F, Chui YL, Gonzalez Fernandez A, Pannell R, Neuberger MS, Milstein C (1995) Targeting of non-Ig sequences in place of the V segment by somatic hypermutation. Nature 376:225–228

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Rochester School of Medicine, 601 Elmwood Avenue, P.O. Box 777, Rochester, NY, 14642, USA

    R. A. Insel & W. S. Varade

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  1. R. A. Insel
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  2. W. S. Varade
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Editors and Affiliations

  1. Department of Microbiology and Immunology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD, 21201, USA

    Garnett Kelsoe D. Sc.

  2. Department of Microbiology and Immunology, University of Miami School of Medicine, 1600 NW 10th Avenue, Miami, FL, 33136, USA

    Martin F. Flajnik Ph.D.

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© 1998 Springer-Verlag Berlin Heidelberg

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Insel, R.A., Varade, W.S. (1998). Characteristics of Somatic Hypermutation of Human Immunoglobulin Genes. In: Kelsoe, G., Flajnik, M.F. (eds) Somatic Diversification of Immune Responses. Current Topics in Microbiology and Immunology, vol 229. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-71984-4_4

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  • DOI: https://doi.org/10.1007/978-3-642-71984-4_4

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-71986-8

  • Online ISBN: 978-3-642-71984-4

  • eBook Packages: Springer Book Archive

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