▪ Abstract 

Autoreactive antibodies are etiologic agents in a number of autoimmune diseases. Like all other antibodies these antibodies are produced in developing B cells by V(D)J recombination in the bone marrow. Three mechanisms regulate autoreactive B cells: deletion, receptor editing, and anergy. Here we review the prevalence of autoantibodies in the initial antibody repertoire, their regulation by receptor editing, and the role of the recombinase proteins (RAG1 and RAG2) in this process.


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Literature Cited

  1. Tonegawa S. 1.  1983. Somatic generation of antibody diversity. Nature 302:575–81 [Google Scholar]
  2. Silverstein AM. 2.  2001. Autoimmunity versus horror autotoxicus: the struggle for recognition. Nat. Immunol. 2:279–81 [Google Scholar]
  3. Burnet MF. 3.  1959. The Clonal Selection Theory of Acquired Immunity. Cambridge, UK: Cambridge Univ. Press [Google Scholar]
  4. Talmage DW. 4.  1959. Tumor development in immunologically deficient nude mice after exposure to chemical carcinogens. Science 129:1643–48 [Google Scholar]
  5. Lederberg J. 5.  1959. Genes and antibodies. Science 129:1649–53 [Google Scholar]
  6. Gay D, Saunders T, Camper S, Weigert M. 6.  1993. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177:999–1008 [Google Scholar]
  7. Tiegs SL, Russell DM, Nemazee D. 7.  1993. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177:1009–20 [Google Scholar]
  8. Nemazee DA, Burki K. 8.  1989. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337:562–66 [Google Scholar]
  9. Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ. 9.  et al. 1988. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334:676–82 [Google Scholar]
  10. Landsteiner K. 10.  1936. The Specificity of Serological Reactions. New York: Dover [Google Scholar]
  11. Sidman CL, Unanue ER. 11.  1975. Receptor-mediated inactivation of early B lymphocytes. Nature 257:149–51 [Google Scholar]
  12. Teale JM, Klinman NR. 12.  1980. Tolerance as an active process. Nature 288:385–87 [Google Scholar]
  13. Nossal GJ. 13.  1983. Cellular mechanisms of immunologic tolerance. Annu. Rev. Immunol. 1:33–62 [Google Scholar]
  14. Allman DM, Ferguson SE, Lentz VM, Cancro MP. 14.  1993. Peripheral B cell maturation. II. Heat-stable antigen (hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells J. Immunol. 151:4431–44 [Google Scholar]
  15. Norvell A, Mandik L, Monroe JG. 15.  1995. Engagement of the antigen-receptor on immature murine B lymphocytes results in death by apoptosis. J. Immunol. 154:4404–13 [Google Scholar]
  16. Rolink AG, Andersson J, Melchers F. 16.  1998. Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity. Eur. J. Immunol. 28:3738–48 [Google Scholar]
  17. Forster I, Rajewsky K. 17.  1990. The bulk of the peripheral B-cell pool in mice is stable and not rapidly renewed from the bone marrow. Proc. Natl. Acad. Sci. USA 87:4781–84 [Google Scholar]
  18. Hao Z, Rajewsky K. 18.  2001. Homeostasis of peripheral B cells in the absence of B cell influx from the bone marrow. J. Exp. Med. 194:1151–64 [Google Scholar]
  19. Raff MC, Owen JJ, Cooper MD, Lawton ARd, Megson M. 19.  et al. 1975. Differences in susceptibility of mature and immature mouse B lymphocytes to anti-immunoglobulin-induced immunoglobulin suppression in vitro. Possible implications for B-cell tolerance to self J. Exp. Med. 142:1052–64 [Google Scholar]
  20. Gu H, Tarlinton D, Muller W, Rajewsky K, Forster I. 20.  1991. Most peripheral B cells in mice are ligand selected. J. Exp. Med. 173:1357–71 [Google Scholar]
  21. Sandel PC, Monroe JG. 21.  1999. Negative selection of immature B cells by receptor editing or deletion is determined by site of antigen encounter. Immunity 10:289–99 [Google Scholar]
  22. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. 22.  2003. Predominant autoantibody production by early human B cell precursors. Science 301:(5638)1374–77 [Google Scholar]
  23. Schatz DG, Oettinger MA, Baltimore D. 23.  1989. The V(D)J recombination activating gene, RAG-1. Cell 59:1035–48 [Google Scholar]
  24. Oettinger MA, Schatz DG, Gorka C, Baltimore D. 24.  1990. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248:1517–23 [Google Scholar]
  25. McBlane JF, van Gent DC, Ramsden DA, Romeo C, Cuomo CA. 25.  et al. 1995. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell 83:387–95 [Google Scholar]
  26. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S. 26.  et al. 1992. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68:869–77 [Google Scholar]
  27. Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V. 27.  et al. 1992. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68:855–67 [Google Scholar]
  28. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z. 28.  et al. 1996. RAG mutations in human B cell-negative SCID. Science 274:97–99 [Google Scholar]
  29. Wilson A, Held W, MacDonald HR. 29.  1994. Two waves of recombinase gene expression in developing thymocytes. J. Exp. Med. 179:1355–60 [Google Scholar]
  30. Grawunder U, Leu TM, Schatz DG, Werner A, Rolink AG. 30.  et al. 1995. Down-regulation of RAG1 and RAG2 gene expression in preB cells after functional immunoglobulin heavy chain rearrangement. Immunity 3:601–8 [Google Scholar]
  31. Allman D, Li J, Hardy RR. 31.  1999. Commitment to the B lymphoid lineage occurs before DH-JH recombination. J. Exp. Med. 189:735–40 [Google Scholar]
  32. Yu W, Misulovin Z, Suh H, Hardy RR, Jankovic M. 32.  et al. 1999. Coordinate regulation of RAG1 and RAG2 by cell type-specific DNA elements 5′ of RAG2. Science 285:1080–84 [Google Scholar]
  33. Igarashi H, Gregory SC, Yokota T, Sakaguchi N, Kincade PW. 33.  2002. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17:117–30 [Google Scholar]
  34. Alt FW, Yancopoulos GD, Blackwell TK, Wood C, Thomas E. 34.  et al. 1984. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J. 3:1209–19 [Google Scholar]
  35. Li YS, Hayakawa K, Hardy RR. 35.  1993. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J. Exp. Med. 178:951–60 [Google Scholar]
  36. Ehlich A, Martin V, Muller W, Rajewsky K. 36.  1994. Analysis of the B-cell progenitor compartment at the level of single cells. Curr. Biol. 4:573–83 [Google Scholar]
  37. Nussenzweig MC, Shaw AC, Sinn E, Danner DB, Holmes KL. 37.  et al. 1987. Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin mu. Science 236:816–19 [Google Scholar]
  38. Manz J, Denis K, Witte O, Brinster R, Storb U. 38.  1988. Feedback inhibition of immunoglobulin gene rearrangement by membrane mu, but not by secreted mu heavy chains [published erratum appears in J. Exp. Med. 1989 June 1. 169(6):2269] J. Exp. Med. 168:1363–81 [Google Scholar]
  39. Kitamura D, Rajewsky K. 39.  1992. Targeted disruption of mu chain membrane exon causes loss of heavy-chain allelic exclusion. Nature 356:154–56 [Google Scholar]
  40. Melchers F, Rolink A, Grawunder U, Winkler TH, Karasuyama H. 40.  et al. 1995. Positive and negative selection events during B lymphopoiesis. Curr. Opin. Immunol. 7:214–27 [Google Scholar]
  41. Bassing CH, Swat W, Alt FW. 41.  2002. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109:(Suppl.)S45–55 [Google Scholar]
  42. Chowdhury D, Sen R. 42.  2001. Stepwise activation of the immunoglobulin mu heavy chain gene locus. EMBO J. 20:6394–403 [Google Scholar]
  43. Melchers F. 43.  1995. The role of B cell and pre-B cell receptors in development and growth control of the B-lymphocyte lineage. In Immunoglobulin Genes ed. T Honjo, FW Alt pp. 33–56 London: London Academic Ltd, 3rd ed.. [Google Scholar]
  44. Monroe RJ, Seidl KJ, Gaertner F, Han S, Chen F. 44.  et al. 1999. RAG2:GFP knockin mice reveal novel aspects of RAG2 expression in primary and peripheral lymphoid tissues. Immunity 11:201–12 [Google Scholar]
  45. Li Z, Dordai DI, Lee J, Desiderio S. 45.  1996. A conserved degradation signal regulates RAG-2 accumulation during cell division and links V(D)J recombination to the cell cycle. Immunity 5:575–89 [Google Scholar]
  46. Ehlich A, Schaal S, Gu H, Kitamura D, Muller W. 46.  et al. 1993. Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development. Cell 72:695–704 [Google Scholar]
  47. Carsetti R, Kohler G, Lamers MC. 47.  1995. Transitional B cells are the target of negative selection in the B cell compartment. J. Exp. Med. 181:2129–40 [Google Scholar]
  48. Melamed D, Benschop RJ, Cambier JC, Nemazee D. 48.  1998. Developmental regulation of B lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection. Cell 92:173–82 [Google Scholar]
  49. Radic MZ, Erikson J, Litwin S, Weigert M. 49.  1993. B lymphocytes may escape tolerance by revising their antigen receptors. J. Exp. Med. 177:1165–73 [Google Scholar]
  50. Feddersen RM, Van Ness BG. 50.  1985. Double recombination of a single immunoglobulin kappa-chain allele: implications for the mechanism of rearrangement. Proc. Natl. Acad. Sci. USA 82:4793–97 [Google Scholar]
  51. Levy S, Campbell MJ, Levy R. 51.  1989. Functional immunoglobulin light chain genes are replaced by ongoing rearrangements of germline V kappa genes to downstream J kappa segment in a murine B cell line. J. Exp. Med. 170:1–13 [Google Scholar]
  52. Kleinfield R, Hardy RR, Tarlinton D, Dangl J, Herzenberg LA. 52.  et al. 1986. Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphoma. Nature 322:843–46 [Google Scholar]
  53. Ritchie KA, Brinster RL, Storb U. 53.  1984. Allelic exclusion and control of endogenous immunoglobulin gene rearrangement in kappa transgenic mice. Nature 312:517–20 [Google Scholar]
  54. Rusconi S, Kohler G. 54.  1985. Transmission and expression of a specific pair of rearranged immunoglobulin mu and kappa genes in a transgenic mouse line. Nature 314:330–34 [Google Scholar]
  55. Erikson J, Radic MZ, Camper SA, Hardy RR, Carmack C. 55.  et al. 1991. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349:331–34 [Google Scholar]
  56. Prak EL, Trounstine M, Huszar D, Weigert M. 56.  1994. Light chain editing in kappa-deficient animals: a potential mechanism of B cell tolerance. J. Exp. Med. 180:1805–15 [Google Scholar]
  57. Li H, Jiang Y, Prak EL, Radic M, Weigert M. 57.  2001. Editors and editing of anti-DNA receptors. Immunity 15:947–57 [Google Scholar]
  58. Pelanda R, Schwers S, Sonoda E, Torres RM, Nemazee D. 58.  et al. 1997. Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification. Immunity 7:765–75 [Google Scholar]
  59. Chen C, Prak EL, Weigert M. 59.  1997. Editing disease-associated autoantibodies. Immunity 6:97–105 [Google Scholar]
  60. Kleinfield RW, Weigert MG. 60.  1989. Analysis of VH gene replacement events in a B cell lymphoma. J. Immunol. 142:4475–82 [Google Scholar]
  61. Reth M, Gehrmann P, Petrac E, Wiese P. 61.  1986. A novel VH to VHDJH joining mechanism in heavy-chain-negative (null) pre-B cells results in heavy-chain production. Nature 322:840–42 [Google Scholar]
  62. Wilson PC, Wilson K, Liu YJ, Banchereau J, Pascual V. 62.  et al. 2000. Receptor revision of immunoglobulin heavy chain variable region genes in normal human B lymphocytes. J. Exp. Med. 191:1881–94 [Google Scholar]
  63. Chen C, Nagy Z, Prak EL, Weigert M. 63.  1995. Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. Immunity 3:747–55 [Google Scholar]
  64. Pewzner-Jung Y, Friedmann D, Sonoda E, Jung S, Rajewsky K. 64.  et al. 1998. B cell deletion, anergy, and receptor editing in “knock in” mice targeted with a germline-encoded or somatically mutated anti-DNA heavy chain. J. Immunol. 161:4634–45 [Google Scholar]
  65. Itoh K, Meffre E, Albesiano E, Farber A, Dines D. 65.  et al. 2000. Immunoglobulin heavy chain variable region gene replacement as a mechanism for receptor revision in rheumatoid arthritis synovial tissue B lymphocytes. J. Exp. Med. 192:1151–64 [Google Scholar]
  66. Sonoda E, Pewzner-Jung Y, Schwers S, Taki S, Jung S. 66.  et al. 1997. B cell development under the condition of allelic inclusion. Immunity 6:225–33 [Google Scholar]
  67. Cascalho M, Ma A, Lee S, Masat L, Wabl M. 67.  1996. A quasi-monoclonal mouse. Science 272:1649–52 [Google Scholar]
  68. Zhang Z ZM, Wang YH, Munfus D, Huye LE, Findley HW. 68.  et al. 2003. Contribution of Vh gene replacement to the primary B cell repertoire. Immunity 19:21–31 [Google Scholar]
  69. Hertz M, Nemazee D. 69.  1997. BCR ligation induces receptor editing in IgM+IgD- bone marrow B cells in vitro. Immunity 6:429–36 [Google Scholar]
  70. Melamed D, Nemazee D. 70.  1997. Self-antigen does not accelerate immature B cell apoptosis, but stimulates receptor editing as a consequence of developmental arrest. Proc. Natl. Acad. Sci. USA 94:9267–72 [Google Scholar]
  71. Nemazee D, Buerki K. 71.  1989. Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. Proc. Natl. Acad. Sci. USA 86:8039–43 [Google Scholar]
  72. Yu W, Nagaoka H, Jankovic M, Misulovin Z, Suh H. 72.  et al. 1999. Continued RAG expression in late stages of B cell development and no apparent re-induction after immunization. Nature 400:682–87 [Google Scholar]
  73. Casellas R, Shih TA, Kleinewietfeld M, Rakonjac J, Nemazee D. 73.  et al. 2001. Contribution of receptor editing to the antibody repertoire. Science 291:1541–44 [Google Scholar]
  74. Oberdoerffer P, Novobrantseva TI, Rajewsky K. 74.  2003. Expression of a targeted lambda 1 light chain gene is developmentally regulated and independent of Ig kappa rearrangements. J. Exp. Med. 197:1165–72 [Google Scholar]
  75. Prak EL, Weigert M. 75.  1995. Light chain replacement: a new model for antibody gene rearrangement. J. Exp. Med. 182:541–48 [Google Scholar]
  76. Brauninger A, Goossens T, Rajewsky K, Kuppers R. 76.  2001. Regulation of immunoglobulin light chain gene rearrangements during early B cell development in the human. Eur. J. Immunol. 31:3631–37 [Google Scholar]
  77. Retter MW, Nemazee D. 77.  1998. Receptor editing occurs frequently during normal B cell development. J. Exp. Med. 188:1231–38 [Google Scholar]
  78. Blackwell TK, Moore MW, Yancopoulos GD, Suh H, Lutzker S. 78.  et al. 1986. Recombination between immunoglobulin variable region gene segments is enhanced by transcription. Nature 324:585–89 [Google Scholar]
  79. Schlissel MS, Baltimore D. 79.  1989. Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell 58:1001–7 [Google Scholar]
  80. Yancopoulos GD, Alt FW. 80.  1985. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell 40:271–81 [Google Scholar]
  81. Chen J, Young F, Bottaro A, Stewart V, Smith RK. 81.  et al. 1993. Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus. EMBO J. 12:4635–45 [Google Scholar]
  82. Serwe M, Sablitzky F. 82.  1993. V(D)J recombination in B cells is impaired but not blocked by targeted deletion of the immunoglobulin heavy chain intron enhancer. EMBO J. 12:2321–27 [Google Scholar]
  83. Xu Y, Davidson L, Alt FW, Baltimore D. 83.  1996. Deletion of the Ig kappa light chain intronic enhancer/matrix attachment region impairs but does not abolish V kappa J kappa rearrangement. Immunity 4:377–85 [Google Scholar]
  84. Whitehurst CE, Schlissel MS, Chen J. 84.  2000. Deletion of germline promoter PD beta 1 from the TCR beta locus causes hypermethylation that impairs D beta 1 recombination by multiple mechanisms. Immunity 13:703–14 [Google Scholar]
  85. Corcoran AE, Riddell A, Krooshoop D, Venkitaraman AR. 85.  1998. Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor. Nature 391:904–7 [Google Scholar]
  86. Romanow WJ, Langerak AW, Goebel P, Wolvers-Tettero IL, van Dongen JJ. 86.  et al. 2000. E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in nonlymphoid cells. Mol. Cell 5:343–53 [Google Scholar]
  87. Alvarez JD, Anderson SJ, Loh DY. 87.  1995. V(D)J recombination and allelic exclusion of a TCR beta-chain minilocus occurs in the absence of a functional promoter. J. Immunol. 155:1191–202 [Google Scholar]
  88. Okada A, Mendelsohn M, Alt F. 88.  1994. Differential activation of transcription versus recombination of transgenic T cell receptor beta variable region gene segments in B and T lineage cells. J. Exp. Med. 180:261–72 [Google Scholar]
  89. Cherry SR, Baltimore D. 89.  1999. Chromatin remodeling directly activates V(D)J recombination. Proc. Natl. Acad. Sci. USA 96:10788–93 [Google Scholar]
  90. Angelin-Duclos C, Calame K. 90.  1998. Evidence that immunoglobulin VH-DJ recombination does not require germ line transcription of the recombining variable gene segment. Mol. Cell Biol. 18:6253–64 [Google Scholar]
  91. Hesslein DG, Pflugh DL, Chowdhury D, Bothwell AL, Sen R. 91.  et al. 2003. Pax5 is required for recombination of transcribed, acetylated, 5′ IgH V gene segments. Genes Dev. 17:37–42 [Google Scholar]
  92. Gstaiger M, Knoepfel L, Georgiev O, Schaffner W, Hovens CM. 92.  1995. A B-cell coactivator of octamer-binding transcription factors. Nature 373:360–62 [Google Scholar]
  93. Strubin M, Newell JW, Matthias P. 93.  1995. OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins. Cell 80:497–506 [Google Scholar]
  94. Luo Y, Fujii H, Gerster T, Roeder RG. 94.  1992. A novel B cell-derived coactivator potentiates the activation of immunoglobulin promoters by octamer-binding transcription factors. Cell 71:231–41 [Google Scholar]
  95. Staudt LM, Lenardo MJ. 95.  1991. Immunoglobulin gene transcription. Annu. Rev. Immunol. 9:373–98 [Google Scholar]
  96. Luo Y, Roeder RG. 96.  1995. Cloning, functional characterization, and mechanism of action of the B-cell-specific transcriptional coactivator OCA-B. Mol. Cell Biol. 15:4115–24 [Google Scholar]
  97. Schubart DB, Rolink A, Kosco-Vilbois MH, Botteri F, Matthias P. 97.  1996. B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation. Nature 383:538–42 [Google Scholar]
  98. Casellas R, Jankovic M, Meyer G, Gazumyan A, Luo Y. 98.  et al. 2002. OcaB is required for normal transcription and V(D)J recombination of a subset of immunoglobulin κ genes. Cell 110:575–85 [Google Scholar]
  99. Han S, Zheng B, Schatz DG, Spanopoulou E, Kelsoe G. 99.  1996. Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Science 274:2094–97 [Google Scholar]
  100. Hikida M, Mori M, Takai T, Tomochika K, Hamatani K. 100.  et al. 1996. Reexpression of RAG-1 and RAG-2 genes in activated mature mouse B cells. Science 274:2092–94 [Google Scholar]
  101. Giachino C, Padovan E, Lanzavecchia A. 101.  1998. Re-expression of RAG-1 RAG-2 genes and evidence for secondary rearrangements in human germinal center B lymphocytes. Eur. J. Immunol. 28:3506–13 [Google Scholar]
  102. Girschick HJ, Grammer AC, Nanki T, Mayo M, Lipsky PE. 102.  2001. RAG1 and RAG2 expression by B cell subsets from human tonsil and peripheral blood. J. Immunol. 166:377–86 [Google Scholar]
  103. Hikida M, Ohmori H. 103.  1998. Rearrangement of lambda light chain genes in mature B cells in vitro and in vivo. Function of reexpressed recombination-activating gene (RAG) products J. Exp. Med. 187:795–99 [Google Scholar]
  104. Meffre E, Papavasiliou F, Cohen P, de Bouteiller O, Bell D. 104.  et al. 1998. Antigen receptor engagement turns off the V(D)J recombination machinery in human tonsil B cells. J. Exp. Med. 188:765–72 [Google Scholar]
  105. Meffre E, Davis E, Schiff C, Cunningham-Rundles C, Ivashkiv LB. 105.  et al. 2000. Circulating human B cells that express surrogate light chains edited receptors. Nat. Immunol. 1:207–13 [Google Scholar]
  106. Hikida M, Nakayama Y, Yamashita Y, Kumazawa Y, Nishikawa SI. 106.  et al. 1998. Expression of recombination activating genes in germinal center B cells: involvement of interleukin 7 (IL-7) and the IL-7 receptor. J. Exp. Med. 188:365–72 [Google Scholar]
  107. Papavasiliou F, Casellas R, Suh H, Qin XF, Besmer E. 107.  et al. 1997. V(D)J recombination in mature B cells: a mechanism for altering antibody responses. Science 278:298–301 [Google Scholar]
  108. Han S, Dillon SR, Zheng B, Shimoda M, Schlissel MS. 108.  et al. 1997. V(D)J recombinase activity in a subset of germinal center B lymphocytes. Science 278:301–5 [Google Scholar]
  109. Gartner F, Alt FW, Monroe RJ, Seidl KJ. 109.  2000. Antigen-independent appearance of recombination activating gene (RAG)-positive bone marrow B cells in the spleens of immunized mice. J. Exp. Med. 192:1745–54 [Google Scholar]
  110. Nagaoka H, Gonzalez-Aseguinolaza G, Tsuji M, Nussenzweig MC. 110.  2000. Immunization and infection change the number of recombination activating gene (RAG)-expressing B cells in the periphery by altering immature lymphocyte production. J. Exp. Med. 191:2113–20 [Google Scholar]
  111. Lawton AR 3rd, Asofsky R, Hylton MB, Cooper MD. 111.  1972. Suppression of immunoglobulin class synthesis in mice. I. Effects of treatment with antibody to μ-chain J. Exp. Med. 135:277–97 [Google Scholar]
  112. Chen C, Nagy Z, Radic MZ, Hardy RR, Huszar D. 112.  et al. 1995. The site and stage of anti-DNA B-cell deletion. Nature 373:252–55 [Google Scholar]
  113. Hartley SB, Cooke MP, Fulcher DA, Harris AW, Cory S. 113.  et al. 1993. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72:325–35 [Google Scholar]
  114. Okamoto M, Murakami M, Shimizu A, Ozaki S, Tsubata T. 114.  et al. 1992. A transgenic model of autoimmune hemolytic anemia. J. Exp. Med. 175:71–79 [Google Scholar]
  115. Spanopoulou E, Roman CA, Corcoran LM, Schlissel MS, Silver DP. 115.  et al. 1994. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev. 8:1030–42 [Google Scholar]
  116. Xu H, Li H, Suri-Payer E, Hardy RR, Weigert M. 116.  1998. Regulation of anti-DNA B cells in recombination-activating gene-deficient mice. J. Exp. Med. 188:1247–54 [Google Scholar]
  117. Sandel PC, Gendelman M, Kelsoe G, Monroe JG. 117.  2001. Definition of a novel cellular constituent of the bone marrow that regulates the response of immature B cells to B cell antigen receptor engagement. J. Immunol. 166:5935–44 [Google Scholar]
  118. Fugmann SD, Lee AI, Shockett PE, Villey IJ, Schatz DG. 118.  2000. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18:495–527 [Google Scholar]
  119. Flajnik MF. 119.  1998. Churchill and the immune system of ectothermic vertebrates. Immunol. Rev. 166:5–14 [Google Scholar]
  120. Hiom K, Melek M, Gellert M. 120.  1998. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 94:463–70 [Google Scholar]
  121. Agrawal A, Eastman QM, Schatz DG. 121.  1998. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394:744–51 [Google Scholar]
  122. Zarrin AA, Fong I, Malkin L, Marsden PA, Berinstein NL. 122.  1997. Cloning and characterization of the human recombination activating gene 1 (RAG1) and RAG2 promoter regions. J. Immunol. 159:4382–94 [Google Scholar]
  123. Kurioka H, Kishi H, Isshiki H, Tagoh H, Mori K. 123.  et al. 1996. Isolation and characterization of a TATA-less promoter for the human RAG-1 gene. Mol. Immunol. 33:1059–66 [Google Scholar]
  124. Kitagawa T, Mori K, Kishi H, Tagoh H, Nagata T. 124.  et al. 1996. Chromatin structure and transcriptional regulation of human RAG-1 gene. Blood 88:3785–91 [Google Scholar]
  125. Fuller K, Storb U. 125.  1997. Identification and characterization of the murine Rag1 promoter. Mol. Immunol. 34:939–54 [Google Scholar]
  126. Brown ST, Miranda GA, Galic Z, Hartman IZ, Lyon CJ. 126.  et al. 1997. Regulation of the RAG-1 promoter by the NF-Y transcription factor. J. Immunol. 158:5071–74 [Google Scholar]
  127. Lauring J, Schlissel MS. 127.  1999. Distinct factors regulate the murine RAG-2 promoter in B- and T-cell lines. Mol. Cell. Biol. 19:2601–12 [Google Scholar]
  128. Kishi H, Wei XC, Jin ZX, Fujishiro Y, Nagata T. 128.  et al. 2000. Lineage-specific regulation of the murine RAG-2 promoter: GATA-3 in T cells and Pax-5 in B cells. Blood 95:3845–52 [Google Scholar]
  129. Hsu LY, Lauring J, Liang HE, Greenbaum S, Cado D. 129.  et al. 2003. A conserved transcriptional enhancer regulates RAG gene expression in developing B cells. Immunity 19:105–17 [Google Scholar]
  130. Monroe RJ, Chen F, Ferrini R, Davidson L, Alt FW. 130.  1999. RAG2 is regulated differentially in B and T cells by elements 5′ of the promoter. Proc. Natl. Acad. Sci. USA 96:12713–18 [Google Scholar]
  131. Yannoutsos N, Wilson P, Yu W, Chen HT, Nussenzweig A. 131.  et al. 2001. The role of recombination activating gene (RAG) reinduction in thymocyte development in vivo. J. Exp. Med. 194:471–80 [Google Scholar]
  132. Grosveld F, van Assendelft GB, Greaves DR, Kollias G. 132.  1987. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell 51:975–85 [Google Scholar]
  133. Li Q, Peterson KR, Fang X, Stamatoyannopoulos G. 133.  2002. Locus control regions. Blood 100:3077–86 [Google Scholar]
  134. Godfrey D, Kennedy J, Mombaerts P, Tonegawa S, Zlotnik A. 134.  1994. Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8-thymocyte differentiation. J. Immunol. 152:4783–92 [Google Scholar]
  135. von Boehmer H, Fehling HJ. 135.  1997. Structure and function of the pre-T cell receptor. Annu. Rev. Immunol. 15:433–52 [Google Scholar]
  136. Kruisbeek AM, Haks MC, Carleton M, Wiest DL, Michie AM. 136.  et al. 2000. Branching out to gain control: how the pre-TCR is linked to multiple functions. Immunol. Today 21:637–44 [Google Scholar]
  137. Petrie H, Livak F, Schatz D, Strasser A, Crispe I. 137.  et al. 1993. Multiple rearrangements in T cell receptor alpha chain genes maximize the production of useful thymocytes. J. Exp. Med. 178:615–22 [Google Scholar]
  138. Shinkai Y, Koyasu S, Nakayama K, Murphy KM, Loh DY. 138.  et al. 1993. Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. Science 259:822–25 [Google Scholar]
  139. Guo J, Hawwari A, Li H, Sun Z, Mahanta SK. 139.  et al. 2002. Regulation of the TCRalpha repertoire by the survival window of CD4(+)CD8(+) thymocytes. Nat. Immunol. 3:469–76 [Google Scholar]
  140. Turka LA, Schatz DG, Oettinger MA, Chun JJ, Gorka C. 140.  et al. 1991. Thymocyte expression of RAG-1 and RAG-2: termination by T cell receptor cross-linking. Science 16:778–81 [Google Scholar]
  141. Borgulya P, Kishi H, Uematsu Y, von Boehmer H. 141.  1992. Exclusion and inclusion of α and β T cell receptor alleles. Cell 69:529–37 [Google Scholar]

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