On the Possible Role of Natural Reverse Genetics in the V Gene Loci

  • R. V. Blanden
  • H. S. Rothenfluth
  • E. J. Steele
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 229)

Abstract

The immune system of higher vertebrates has evolved to mount destructive responses which eliminate infectious agents. These responses depend upon a large population of mobile cells (lymphocytes) each of which expresses multiple copies of a particular receptor for antigen. The receptors are encoded by large multigene families in germline DNA, but before expression of receptor proteins in lymphocytes (each with a heterodimeric binding site for antigen) the germline genes undergo a unique rearrangement process in which two or three separate genetic elements are brought together to form the final coding sequence for the variable (V) portion of each of the two receptor protein chains (Tonegawa 1983). Another separate element encodes the constant (C) region of the receptor protein which, in the case of the heavy chains of immunoglobulins and both chains of T cell receptors, spans the cell membrane and is an integral part of the signalling mechanism which activates lymphocyte responses to antigen. In the case of B lymphocytes, soluble immunoglobulins are secreted which have the same antigen-binding specificity as the receptor on each individual cell and which mediate effector functions through the constant region of the secreted antibody molecule.

Keywords

Hydroxyl Recombination Germinal Acetyl Tated 

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References

  1. Arakawa H, Furusawa S, Ekino S, Yamagishi H (1996) Immunoglobulin gene hyperconversion ongoing in the chicken splenic germinal centers. EMBO J 15:2540–2546PubMedGoogle Scholar
  2. Azuma T, Motoyama N, Fields LE, Loh DY (1993) Mutations of the chloramphenicol acetyl transferase transgene driven by the immunoglobulin promoter and intron enhancer. Int Immunol 5:121–130PubMedCrossRefGoogle Scholar
  3. Berek C, Berger A, Apel M (1991) Maturation of the immune response in germinal centers. Cell 67:1121–1129PubMedCrossRefGoogle Scholar
  4. Betz AG, Neuberger MS, Milstein C (1993) Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol Today 14:404–411CrossRefGoogle Scholar
  5. Betz AG, Milstein C, Gonzalez-Fernandez A, Pannell R, Larson T, Neuberger MS (1994) Elements regulating somatic hypermutation of an immunoglobulin κ gene: critical role of the intron enhancer/matrix attachment region. Cell 77:239–248PubMedCrossRefGoogle Scholar
  6. Blackburn EH (1992) Telomerases. Annu Rev Biochem 61:113–129CrossRefGoogle Scholar
  7. Both GW, Taylor L, Pollard JW, Steele EJ (1990) Distribution of mutations around rearranged heavy-chain antibody variable-region genes. Mol Cell Biol 10:5187–5196PubMedGoogle Scholar
  8. Carlson LM, McCormack WT, Postema CE, Humphries EH, Thompson CB (1990) Templated insertions in the rearranged chicken IgL V gene segment arise by intrachromosomal gene conversion. Genes Dev 4:536–547PubMedCrossRefGoogle Scholar
  9. 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 176:855–866PubMedCrossRefGoogle Scholar
  10. Chen C, Roberts VA, Stevens S, Brown M, Stenzel-Poore MP, Rittenberg MB (1995) Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled by V gene combinatorial associations. EMBO J 14:2784–2794PubMedGoogle Scholar
  11. Chien NC, Pollock RR, Desaymard C, Scharff MD (1988) Point mutations cause the somatic diversification of IgM and IgG2a anti-phosphorylcholine antibodies. J Exp Med 167:954–973PubMedCrossRefGoogle Scholar
  12. Giusti AM, Manser T (1993) Hypermutation is observed only in antibody H chain V region transgenes that have recombined with endogenous immunoglobulin H DNA: implications for the location of exacting elements required for somatic mutation. J Exp Med 177:797–809PubMedCrossRefGoogle Scholar
  13. Gonzalez-Fernandez A, Milstein C (1993) Analysis of somatic hypermutation in mouse Peyer’s patches using immunoglobulin κ light-chain transgenes. Proc Natl Acad Sci USA 90:9862–9866PubMedCrossRefGoogle Scholar
  14. Hackett J, Stebbins C, Rogerson B, Davis MM, Storb U (1992) Analysis of a T cell receptor gene as a target of the somatic hypermutational mechanism. J Exp Med 176:225–231PubMedCrossRefGoogle Scholar
  15. Jacob J, Kelsoe G, Rajewsky K, Weiss U (1991) Intraclonal generation of antibody mutants in germinal centres. Nature 354:389–392PubMedCrossRefGoogle Scholar
  16. Knight KL (1992) Restricted VH gene usage and generation of antibody diversity in rabbit. Annu Rev Immunol 10:593–616PubMedCrossRefGoogle Scholar
  17. Lebecque SG, Gearhart PJ (1990) Boundaries of somatic mutation in rearranged immunoglobulin genes: 5′ boundary is near the promoter, and 3′ boundary is approximately 1 kb from V-D-J gene. J Exp Med 172:1717–1727PubMedCrossRefGoogle Scholar
  18. Luan DD, Korman MH, Jakubczak JL, Eickbush TH (1993) Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell 72:595–605PubMedCrossRefGoogle Scholar
  19. Manser T (1990) The efficiency of antibody affinity maturation: can the rate of B-cell division be limiting? Immunol Today 11:305–308PubMedCrossRefGoogle Scholar
  20. McCormack WT, Thompson CB (1990a) Somatic diversification of the chicken immunoglobulin light-chain gene. Adv Immunol 48:41–67PubMedCrossRefGoogle Scholar
  21. McCormack WT, Thompson CB (1990b) Chicken IgL variable gene conversion display pseudogene donor preference and 5′ to 3′ polarity. Genes Dev 4:548–558PubMedCrossRefGoogle Scholar
  22. Motoyama N, Okada H, Azuma T (1991) Somatic mutation in constant regions of mouse 11 light chains. Proc Natl Acad Sci USA 88:7933–7937PubMedCrossRefGoogle Scholar
  23. Peters A, Storb U (1996) Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 4:57–65PubMedCrossRefGoogle Scholar
  24. Rada C, Gonzalez-Fernandez A, Jarvis, JM, Milstein C (1994) The 5′ boundary of somatic hypermutation in a Vκ gene is in the leader intron. Eur J Immunol 24:1453–1457PubMedCrossRefGoogle Scholar
  25. Reynaud C-A, Anquez V, Grimal H, Weill J-C (1987) A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 48:379–388PubMedCrossRefGoogle Scholar
  26. Rogerson BJ (1994) Mapping the upstream boundary of somatic mutations in rearranged immunoglobulin transgenes and endogenous genes. Mol Immunol 31:83–98PubMedCrossRefGoogle Scholar
  27. Rothenfluh HS, Taylor L, Bothwell ALM, Both GW, Steele EJ (1993) Somatic hypermutation in 5′ flanking regions of heavy chain antibody variable genes. Eur J Immunol 23:2152–2159PubMedCrossRefGoogle Scholar
  28. Sohn J, Gerstein RM, Hsieh C-L, Lemer M, Seising E (1993) Somatic hypermutation of an immunoglobulin u heavy chain transgene. J Exp Med 177:493–504PubMedCrossRefGoogle Scholar
  29. Steele EJ (1991) (ed) Somatic hypermutation in V-regions. CRC Press, Boca Raton, FloridaGoogle Scholar
  30. Steele EJ, Pollard JW (1987) Hypothesis: somatic hypermutation by gene conversion via the error prone DNA → RNA → DNA information loop. Mol Immunol 24:667–673PubMedCrossRefGoogle Scholar
  31. Steele EJ, Rothenfluh HS, Both GW (1992) Defining the nucleic acid substrate for somatic hypermutation. Immunol Cell Biol 70:129–144PubMedCrossRefGoogle Scholar
  32. Steele EJ, Rothenfluh HS, Blanden RV (1997) Mechanism of antigen-driven somatic hypermutation of rearranged immunoglobulin V(D)J genes in the mouse. Immunol Cell Biol 75:82–95PubMedCrossRefGoogle Scholar
  33. Tonegawa S (1983) Somatic generation of antibody diversity. Nature 302:575–581PubMedCrossRefGoogle Scholar
  34. Umar A, Gearhart PJ (1995) Reciprocal homologous recombination in or near antibody VDJ. Eur J Immunol 25:2392–2400PubMedCrossRefGoogle Scholar
  35. 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 88:4902–4906PubMedCrossRefGoogle Scholar
  36. Weber JS, Berry J, Manser T, Claflin JL (1991) Position of the rearranged Vκ and its 5′ flanking sequences determines the location of somatic mutations in the Jκ locus. J Immunol 146:3652–3655PubMedGoogle Scholar
  37. Xu B, Seising E (1994) Analysis of sequence transfers resembling gene conversion in a mouse antibody transgene. Science 265:1590–1593PubMedCrossRefGoogle Scholar
  38. Yang J, Zimmerly S, Perlman PS, Lambowitz AM (1996) Efficient integration of an intron RNA into double-stranded DNA by reverse splicing. Nature 381:332–335PubMedCrossRefGoogle Scholar
  39. Yang X, Stedra J, Cerny J (1996) Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice. J Exp Med 183:959–970PubMedCrossRefGoogle Scholar
  40. Yelamos 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 376:225–229PubMedCrossRefGoogle Scholar
  41. Zimmerly S, Guo H, Perlman PS, Lambowitz AM (1995) Group II intron mobility occurs by target DNA-primed reverse transcription. Cell 82:545–554PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • R. V. Blanden
    • 1
  • H. S. Rothenfluth
    • 1
    • 2
  • E. J. Steele
    • 1
    • 2
  1. 1.Division of Immunology and Cell Biology, John Curtin School of Medical ResearchThe Australian National UniversityCanberraAustralia
  2. 2.Department of Biological SciencesUniversity of WollongongWollongongAustralia

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