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Bulletin of Mathematical Biology

, Volume 68, Issue 5, pp 1073–1094 | Cite as

Feedback Loops, Reversals and Nonlinearities in Lymphocyte Development

  • Ramit Mehr
Original Article

Abstract

Systems of differentiating cells are often regarded by experimental biologists as unidirectional processes, in which cells spend a fixed time at each successive developmental stage. However, mathematical modeling has in several cases revealed that differentiating cell systems are more complex than previously believed. For example, non-linear transitions, feedback effects, and even apparent reversals have been suggested by our studies on models for the development of lymphocytes and their receptor repertoires, and are reviewed in this paper. These studies have shown that cell population growth in developing lymphocyte subsets is usually nonlinear, as it depends on the density of cells in each compartment. Additionally, T cell development has been shown to be subject to feedback regulation by mature T cell subsets, and B cell development has been shown to include a phenotypic reflux from an advanced to an earlier developmental stage. The challenges we face in our efforts to understand how the repertoires of these cells are generated and regulated are also discussed here.

Keywords

B and T lymphocytes Natural killer cells Cellular proliferation Cellular differentiation Repertoire development Computational modeling Simulations 

Abbreviations:

BCR

B cell receptor

BM

bone marrow

DN

double-negative

DP

double positive

FTOC

fetal thymus organ culture

MHC

major histocompatibility complex

NK

natural killer

TCR

T cell receptor

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References

  1. 1.
    Agenes, F., Rosado, M.M., Freitas, A.A., 1999. Independent homeostatic regulation of B cell compartments. Eur. J. Immunol. 27, 1801–1807.Google Scholar
  2. 3.
    Allman, D., Lindsley, R.C., DeMuth, W., Rudd, K., Shinton, S.A., Hardy, R.R., 2001. Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J. Immunol. 167, 6834–6840.Google Scholar
  3. 4.
    Allman, D.M., Ferguson, S.E., Cancro, M.P., 1992. Peripheral B cell maturation. I. immature peripheral B cells in adults are heat-stable antigenhi and exhibit unique signaling characteristics. J. Immunol. 149, 2533–2540.Google Scholar
  4. 6.
    Baron, C., Penit, C., 1990. Study of the thymocyte cell cycle by bivariate analysis of incorporated bromodeoxyuridine and DNA content. Eur. J. Immunol. 20, 1231–1236.Google Scholar
  5. 7.
    Benschop, R., Brandl, E., Chan, A., Cambier, J., 2001. Unique signaling properties of B cell antigen receptor in mature and immature B cells. J. Immunol. 167, 4172–4179.Google Scholar
  6. 9.
    Bonhoeffer, S., Mohri, H., Ho, D., Perelson, A.S., 2000. Quantification of cell turnover kinetics using 5-Bromo-2′-deoxyuridine. J. Immunol. 164, 5049–5054.Google Scholar
  7. 10.
    Boyd, R., Hugo, P., 1991. Towards an integrated view of thymopoiesis. Immunol. Today 12, 71–79.Google Scholar
  8. 11.
    Boyd, R.L., Tucek, C.L., Godfrey, D.I., Izon, D.J., Wilson, T.J., Davidson, N.J., et al., 1993. The thymic microenvironment. Immunol. Today 14, 445–459.Google Scholar
  9. 12.
    Bradl, H., Jack, H., 2001. Surrogate light chain-mediated interaction of a soluble pre-B cell receptor with adherent cell lines. J. Immunol. 167, 6403–6411.Google Scholar
  10. 14.
    Carsetti, R., 2000. The development of B cells in the bone marrow is controlled by the balance between cell-autonomous mechanisms and signals from the microenvironment. J. Exp. Med. 191, 5–8.Google Scholar
  11. 15.
    Carsetti, R., Kohler, G., Lamers, M.C., 1995. Transitional B cells are the target of negative selection in the B cell compartment. J. Exp. Med. 181, 2129–2140.Google Scholar
  12. 16.
    Casellas, R., Yang Shih, T.A., Kleinewietfeld, M., Rakonjac, J., Nemazee, D., Rajewsky, K., Nussenzweig, M.C., 2001. Contribution of receptor editing to the antibody repertoire. Science 291, 1541–1544.Google Scholar
  13. 18.
    Chen, C., Luning-Prak, E., Weigert, M., 1997. Editing in disease-associated autoantibodies. Immunity 6, 97–105.Google Scholar
  14. 19.
    Clevers, H., Owen, M., 1991. Towards a molecular understanding of T cell differentiation. Immunol. Today 12, 86–92.Google Scholar
  15. 20.
    Detours, V., Mehr, R., Perelson, A., 1999. A quantitative theory of affinity-driven T cell repertoire selection. J. Theor. Biol. 200, 389–403.Google Scholar
  16. 21.
    Detours, V., Mehr, R., Perelson, A., 2000. Deriving quantitative constrains under which T cell selection operates from data on the mature T cell repertoire. J. Immunol. 164, 121–128.Google Scholar
  17. 22.
    Dunn-Walters, D.K., Belelovsky, A., Edelman, H., Banerjee, M., Mehr, R., 2002. The dynamics of germinal centre selection as measured by graph-theoretical analysis of mutational lineage trees. Dev. Immunol. 9, 233–245.Google Scholar
  18. 23.
    Dunn-Walters, D.K., Edelman, H., Mehr, R., 2004. Immune system learning and memory quantified by graphical analysis of B-lymphocyte phylogenetic trees. Biosystems 76, 141–155.Google Scholar
  19. 24.
    Egerton, M., Scollay, R., Shortman, K., 1990a. Kinetics of mature T cell development in the thymus. Proc. Natl. Acad. Sci. 87, 2579–2582.Google Scholar
  20. 25.
    Egerton, M., Shortman, K., Scollay, R., 1990b. The kinetics of immature murine thymocyte development in vivo. Intl. Immunol. 2, 501–507.Google Scholar
  21. 26.
    Eren, R., Abel, L., Globerson, A., 1989. Syngeneic preference manifested by thymic stroma during development of thymocytes from bone marrow cells. Eur. J. Immunol. 19, 2087–2092.Google Scholar
  22. 27.
    Fang, W., Mueller, D.L., Pennell, C.A., Rivard, J.J., Li, Y.S., Hardy, R.R., Schlissel, M.S., Behrens, T.W., 1996. Frequent aberrant immunoglobulin gene rearrangements in Pro-B cells revealed by a bcl-XL transgene. Immunity 4, 291–299.Google Scholar
  23. 28.
    Finkel, T., Cambier, J., Kubo, R., Born, W., Marrack, P., Kappler, J., 1989. The thymus has two functionally distinct populations of immature αβ+ T cells, One population is deleted by ligation of αβ TCR. Cell 58, 1047–1054.Google Scholar
  24. 29.
    Finkel, T., Kappler, J., Marrack, P., 1992. Immature thymocytes are protected from deletion early in ontogeny. Proc. Natl. Acad. Sci. 89, 3372–3374.Google Scholar
  25. 30.
    Finkel, T., Kubo, R., Cambier, J., 1991. T cell development and transmembrane signaling, Changing biological responses through an unchanging receptor. Immunol. Today 12, 79–85.Google Scholar
  26. 31.
    Fridkis-Hareli, M., 1993. Differentiation of Mouse T Lymphocytes in the Thymus. PhD thesis, Department of Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.Google Scholar
  27. 32.
    Fridkis-Hareli, M., Eren, R., Sharp, A., Abel, L., Kululansky, T., Globerson, A., 1993. MHC recognition in colonization of the thymus by bone marrow cells. Cell. Immunol. 149, 91–98.Google Scholar
  28. 33.
    Fridkis-Hareli, M., Mehr, R., Abel, L., Globerson, A., 1994. Developmental interactions of CD4+ T cells and thymocytes, age-related differential effects. Mech. Age. Dev. 73, 169–178.Google Scholar
  29. 34.
    Gay, D., Saunders, T., Camper, S., Weigert, M., 1993. Receptor editing, an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999–1008.Google Scholar
  30. 35.
    Ghia, P., ten Boekel, E., Rolink, A.G., Melchers, F., 1998. B cell development: A comparison between mouse and man. Immunol. Today 19, 480–485.Google Scholar
  31. 37.
    Gossmann, J., Lohler, J., Lehmann-Grube, F., 1991. Entry of antivirally active T lymphocytes into the thymus of virus-infected mice. J. Immunol. 146, 293–297.Google Scholar
  32. 38.
    Hardy, R.R., Carmack, C.E., Shinton, S.A., Kemp, J.D., Hayakawa, K., 1991. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173, 1213–1225.Google Scholar
  33. 39.
    Hardy, R.R., Li, Y.S., Allman, D., Asano, M., Gui, M., Hayakawa, K., 2000. B cell commitment, development and selection. Immunol. Rev. 175, 23–32.Google Scholar
  34. 40.
    Hess, J., Werner, A., Wirth, T., Melchers, F., Jack, H.M., Winkler, T.H., 2001. Induction of pre-B cell proliferation after de novo synthesis of the pre-B cell receptor. Proc. Natl. Acad. Sci. USA 98, 1745–1750.Google Scholar
  35. 42.
    Horesh, Y., Mehr, R., Unger, R., 2005. Designing an A* Algorithm for calculating edit distance between rooted-unlabeled trees. J. Comp. Biol., in press.Google Scholar
  36. 44.
    Hugo, P., Boyd, R., Waanders, G., Petrie, H., Scollay, R., 1991a. Timing of deletion of autoreactive Vβ6+ cells and down-modulation of either CD4+ or CD8+ on phenotypically distinct CD4+8+ subsets of thymocytes expressing intermediate or high levels of T cell receptor. Intl. Immunol. 3, 265–272.Google Scholar
  37. 47.
    Janeway, C.A., 1994. Thymic selection, two pathways to life and two to death. Immunity 1, 3–6.Google Scholar
  38. 48.
    Kalmanovich, G., Mehr, R., 2003. Models for antigen receptor gene rearrangement. III. Heavy and light chain allelic exclusion. J. Immunol. 170, 182–193.Google Scholar
  39. 50.
    Kincade, P.W., Medina, K., Payne, K., Yamashita, Y., 1998. The transition of stem cells to B lymphocytes. The Immunologist 6, 43–47Google Scholar
  40. 51.
    Kirschner, D., Mehr, R., Perelson, A., 1998. The role of the thymus in pediatric HIV-1 infection. J AIDS Hum. Retrovirol. 18(2), 95–109Google Scholar
  41. 52.
    Kline, G.H., Hayden, T.A., Riegert, P., 2001. The initiation of B cell clonal expansion occurs independently of pre-B cell receptor formation. J. Immunol. 167, 5136–5142.Google Scholar
  42. 53.
    LeBien, T.W., 1998. B cell lymphopoiesis in mouse and man. Curr. Opin. Immunol. 10, 188–195.Google Scholar
  43. 54.
    Levine, M.H., Haberman, A.M., Sant'Angelo, D.B., Hannum, L.G., Cancro, M.P., Janeway, C.A., Schlomchik, M.J., 2000. A B cell receptor-specific selection step governs immature to mature B cell differentiation. Proc. Natl. Acad. Sci. 97, 2743–2748.Google Scholar
  44. 55.
    Li, Y.S., Hayakawa, K., Hardy, R.R., 1993. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J. Exp. Med. 178, 951–960.Google Scholar
  45. 56.
    Loder, F., Mutschler, B., Ray, R.J., Paige, C.J., Sideras, P., Lamers, M.C., Carsetti, R., 1999. B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J. Exp. Med. 190, 75–89.Google Scholar
  46. 57.
    Loffert, D., Schaal, S., Ehlich, A., Hardy, R.R., Zou, Y.R., Muller, W., Rajewsky, K., 1994. Early B cell development in the mouse, insights from mutations introduced by gene targeting. Immunol. Rev. 137, 135–153.Google Scholar
  47. 58.
    Lu, L., Chappel, M.S., Humphries, R.K., Osmond, D.G., 1997. Regulation of cell survival during B lymphopoiesis: increased pre-B cell apoptosis in CD24-transgenic mouse bone marrow. Eur. J. Immunol. 30, 2686–2691.Google Scholar
  48. 59.
    Lu, L., Chaudhury, P., Osmond, D.G., 1999. Regulation of cell survival during B lymphopoiesis: apoptosis and Bcl-2/Bax content of precursor B cells in bone marrow of mice with altered expression of IL-7 and recombinase-activating gene-2. J. Immunol. 162, 1931–1940.Google Scholar
  49. 60.
    Lu, L., Osmond, D.G., 1997. Apoptosis during B lymphopoiesis in mouse bone marrow. J. Immunol. 158, 5136–5145.Google Scholar
  50. 61.
    Luning-Prak, E., Trounstine, M., Huszar, D., Weigert, M., 1994. Light chain editing in k-deficient animals: a potential mechanism of B cell tolerance. J. Exp. Med. 180, 1805–1815.Google Scholar
  51. 62.
    Luning-Prak, E., Weigert, M., 1995. Light chain replacement: a new model for antibody gene rearrangement. J. Exp. Med. 182, 541–548.Google Scholar
  52. 63.
    Martensson, I.L., Ceredig, R., 2000. Role of the surrogate light chain and the pre-B cell receptor in mouse B cell development. Immunology 101, 435–441.Google Scholar
  53. 64.
    Mehr, R., Abel, L., Ubezio, P., Globerson, A., Agur, Z., 1993. A mathematical model of the effect of aging on bone marrow cells colonizing the thymus. Mech. Age. Dev. 67, 159–172.Google Scholar
  54. 65.
    Mehr, R., Edelman, H., Sehgal, D., Mage, R., 2004. Analysis of mutational lineage trees from sites of primary and secondary immunoglobulin gene diversification in rabbits and chickens. J. Immunol. 172, 4790–4796.Google Scholar
  55. 66.
    Mehr, R., Fridkis-Hareli, M., Abel, L., Segel, L., Globerson, A., 1995a. Lymphocyte development in irradiated thymuses: Dynamics of colonisation by progenitor cells and regeneration of resident cells. J. Theor. Biol. 177, 181–192.Google Scholar
  56. 67.
    Mehr, R., Globerson, A., Perelson, A., 1995b. Models for selection processes in the thymus. J. Appl. Sci. Comp. 3, 1–19.Google Scholar
  57. 68.
    Mehr, R., Globerson, A., Perelson, A., 1996c. Modeling positive and negative selection and differentiation processes in the thymus. J. Theor. Biol. 175, 103–126.Google Scholar
  58. 69.
    Mehr, R., Perelson, A., 1997. Blind Homeostasis and the CD4:CD8 Ratio in the thymus and peripheral blood. J. AIDS Hum. Retrovirol. 14, 387–398Google Scholar
  59. 70.
    Mehr, R., Perelson, A., Fridkis-Hareli, M., Globerson, A., 1996a. Feedback regulation of T cell development in the thymus. J. Theor. Biol. 181, 157–167.Google Scholar
  60. 71.
    Mehr, R., Perelson, A., Fridkis-Hareli, M., Globerson, A., 1996b. Feedback regulation of T cell development: Manifestations in aging. Mech. Age. Dev. 91, 195–210.Google Scholar
  61. 72.
    Mehr, R., Perelson, A., Globerson, A., 1997. Feedback regulatory pathways in the thymus. Immunol. Today 18, 581–585.Google Scholar
  62. 73.
    Mehr, R., Segel, L., Perelson, A., Globerson, A., 1998. MHC-linked syngeneic developmental preference in thymic lobes colonized with bone marrow cells–-a mathematical model. Dev. Immunol. 5(4), 303–318.CrossRefGoogle Scholar
  63. 74.
    Mehr, R., Segel, L., Sharp, A., Globerson, A., 1994. Colonization of the thymus by T cell progenitors: Models for cell–cell interaction. J. Theor. Biol. 170, 247–257.Google Scholar
  64. 75.
    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. Intl. Immunol. 15, 301–312Google Scholar
  65. 76.
    Mehr, R., Shannon, M., Litwin, S., 1999. Models for antigen receptor gene rearrangement. I. biased receptor editing in B cells–-implications for allelic exclusion. J. Immunol. 163, 1793–1798.Google Scholar
  66. 77.
    Mehr, R., Ubezio, P., Kukulansky, T., Globerson, A., 1995c. Differential effects of aging on various cell-cycle parameters in the T cell compartment. AGING: Immunol. Infect. Dis. 6, 133–140.Google Scholar
  67. 78.
    Melchers, F., ten Boekel, E., Seidl, T., Kong, X.C., Yamagami, T., Onishi, K., Shimizu, T., Rolink, A.G., Andersson, J., 2000. Repertoire selection by pre-B-cell receptors and B-cell receptors, and genetic control of B-cell development from immature to mature B cells. Immunol. Rev. 175, 33–46.Google Scholar
  68. 79.
    Melchers, F., ten Boekel, Yamagami, T., Andersson, J., Rolink, A.G., 1999. The roles of pre-B and B cell receptors in the stepwise allelic exclusion of mouse IgH and L chain gene loci. Semin. Immunol. 11, 307–317.Google Scholar
  69. 80.
    Metcalf, D., 1963. The autonomous behavior of normal thymus grafts. Austral. J. Exp. Biol. 41, 437–448.Google Scholar
  70. 81.
    Mundt, C., Licence, S., Shimizu, T., Melchers, F., Martensson, I., 2001. Loss of precursor B cell expansion but not allelic exclusion in VpreB1/VpreB2 double-deficient mice. J. Exp. Med. 193, 435–445Google Scholar
  71. 83.
    Nemazee, D., 2000a. Receptor selection in B and T lymphocytes. Annu. Rev. Immunol. 18, 19–51.Google Scholar
  72. 84.
    Nemazee, D., 2000b. Receptor editing in B cells. Adv. Immunol. 74, 89–126.CrossRefGoogle Scholar
  73. 86.
    NikolićŽugić, J., Moore, M., Bevan, M., 1989. Characterization of the subset of immature thymocytes which can undergo rapid in vitro differentiation. Eur. J. Immunol. 19, 649–653.Google Scholar
  74. 87.
    Opstelten, D., Osmond, D.G., 1983. Pre-B cells in bone marrow: Immunofluorescence stathmokinetic studies of the proliferation of cytoplasmic μ-chain-bearing cells in normal mice. J. Immunol. 131, 2635–2640.Google Scholar
  75. 88.
    Osmond, D.G., Rolink, A., Melchers, F., 1998. Murine B lymphopoiesis: Towards a unified model. Immunol. Today 19, 65–68Google Scholar
  76. 90.
    Petrie, H., Hugo, P., Scollay, R., Shortman, K., 1990. Lineage relationships and developmental kinetics of immature thymocytes: CD3+, CD4+, and CD8+ acquisition in vivo and in vitro. J. Exp. Med. 172, 1583–1588.Google Scholar
  77. 91.
    Piper, H., Litwin, S., Mehr, R., 1999. Models for antigen receptor gene rearrangement. II. T Cell receptor editing: Allelic exclusion or inclusion? J. Immunol. 163, 1799–1808.Google Scholar
  78. 92.
    Radic, M.Z., Zouali, M., 1996. Receptor editing, immune diversification, and self-tolerance. Immunity 5, 505–511.Google Scholar
  79. 93.
    Reichlin, A., Hu, Y., Meffre, E., Nagaoka, H., Gong, S., Kraus, M., Rajewsky, K., Nussenzweig, M.C., 2001. B cell development is arrested at the immature B cell stage in mice carrying a mutation in the cytoplasmic domain of immunoglobulin β. J. Exp. Med. 193, 13–23.Google Scholar
  80. 94.
    Rico-Vargas, S.A., Potter, M., Osmond, D.G., 1995. Perturbation of B cell genesis in the bone marrow of pristane-treated mice. implications for plasmacytoma induction. J. Immunol. 154, 2082–2091.Google Scholar
  81. 95.
    Rico-Vargas, S.A., Weiskopf, B., Nishikawa, S.I., Osmond, D.G., 1994. c-ki expression by B cell precursors in mouse bone marrow. J. Immunol. 152, 2845–2852.Google Scholar
  82. 96.
    Ritter, M.A., Boyd, R.L., 1993. Development in the thymus: It takes two to tango. Immunol. Today 14, 462–469.Google Scholar
  83. 97.
    Rolink, A., Karasuyama, H., Haasner, D., Grawunder, U., Maartenson, I.L., Kudo, A., Melchers, F., 1994. Two pathways of b-lymphocyte development in mouse bone marrow and the roles of surrogate L chain in this development. Immunol. Rev. 137, 185–201.Google Scholar
  84. 98.
    Rolink, A., Melchers, F., 1991. Molecular and cellular origins of B lymphocyte diversity. Cell 66, 1081–1094.Google Scholar
  85. 99.
    Rolink, A., Melchers, F., 1993. generation and regeneration of cells in the B-lymphocyte lineage. Curr. Opin. Immunol. 5, 207–217.Google Scholar
  86. 100.
    Rolink, A., Winkler, T.H., Melchers, F., Andersson, J., 2000. Precursor B cell receptor-dependent B cell proliferation and differentiation does not require the bone marrow or fetal liver environment. J. Exp. Med. 191, 23–32.Google Scholar
  87. 101.
    Salmon-Divon, M., Höglund, P., Johansson, M., Johansson, S., Mehr, R., 2004. Computational modeling of human natural killer cell development suggests a selection process regulating coexpression of KIR with CD94/NKG2A. Mol. Immunol. 42, 397–403.Google Scholar
  88. 102.
    Salmon-Divon, M., Höglund, P., Mehr, R., 2003a. Models for natural killer cell repertoire formation. Clin. Dev. Immunol. 10, 183–192.Google Scholar
  89. 103.
    Salmon-Divon, M., Höglund, P., Mehr, R., 2003b. Generation of the natural killer cell repertoire: The sequential vs. the two-step selection model. Bull. Math. Biol. 65, 199–218.Google Scholar
  90. 104.
    Scollay, R., 1991. T cell subset relationships in thymocyte development. Curr. Opin. Immunol. 3, 204–209.Google Scholar
  91. 105.
    Shahaf, G., Allman, D., Cancro, M.P., Mehr, R., 2004. Screening of alternative models for transitional B cell maturation. Intl. Immunol. 16, 1081–1090.Google Scholar
  92. 106.
    Shahaf, G., Johnson, K., Mehr, R., 2006. B cell development in aging mice: Lessons from mathematical modeling. Intl. Immunol. 18, 31–39.Google Scholar
  93. 107.
    Shannon, M., Mehr, R., 1999. Reconciling repertoire shift with affinity maturation: The role of deleterious mutations. J. Immunol. 162, 3950–3956.Google Scholar
  94. 108.
    Sharp, A., Fridkis-Hareli, M., Eren, R., Kukulansky, T., Abel, L., Globerson, A., 1995. MHC-linked colonization of the thymus and thymocyte development: Effects of mature T lymphocytes. Intl. Arch. Allergy Immunol. 106, 13–19.Google Scholar
  95. 109.
    Sharp, A., Kukulansky, T., Globerson, A., 1991. Interactions of bone marrow cells from young and old mice with syngeneic and allogeneic thymic tissue. Cell. Immunol. 138, 280–288.Google Scholar
  96. 110.
    Shortman, K., Egerton, M., Spangrude, G., Scollay, R., 1990. The generation and fate of thymocytes. Semin. Immunol. 2, 3–12.Google Scholar
  97. 111.
    Smith, D.J., Forrest, S., Ackley, D.H., Perelson, A.S., 1998. Using lazy evaluation to simulate realistic-size repertoires in models of the immune system. Bull. Math. Biol. 60, 647–658.zbMATHGoogle Scholar
  98. 112.
    Spangrude, G., Scollay, R., 1990. Differentiation of hematopoietic stem cells in irradiated mouse thymic lobes. Kinetics and phenotype of progeny. J. Immunol. 145, 3661–3668.Google Scholar
  99. 113.
    Steiman-Shimony, A., Edelman, H., Barak, M., Shahaf, G., Dunn-Walters, D., Stott, D., Abraham, R.S., Mehr, R., 2006. Immunoglobulin variable-region gene mutational lineage tree analysis: Application to autoimmune diseases. Autoimmun. Rev. 5(4), 242–251.Google Scholar
  100. 116.
    Tiegs, S.L., Russell, D.M., Nemazee, D., 1993. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177, 1009–1020.Google Scholar
  101. 117.
    Townsend, S.E., Weintraub, B.C., Goodnow, C.C., 1999. Growing up on the streets: Why B-cell development differs from T cell development. Immunol. Today 20, 217–220.Google Scholar
  102. 118.
    Tze, L.E., Baness, E.A., Hippen, K.L., Behrens, T.W., 2000. Ig light chain receptor editing in anergic B cells. J. Immunol. 165, 6796–6802.Google Scholar
  103. 119.
    Ubezio, P., Tagliabue, G., Schechter, B., Agur, Z., 1994. Increasing 1-beta-d-arabinofur- anosylcytosine efficacy by scheduled dosing intervals based on direct measurements of bone marrow cell kinetics. Cancer Res. 54, 6446–6451.Google Scholar
  104. 120.
    van Ewijk, W., Shores, E.W., Singer, A., 1994. Crosstalk in the mouse thymus. Immunol. Today 15, 214–217.Google Scholar
  105. 122.
    von Boehmer, H., 1992. Thymic selection: A matter of life and death. Immunol. Today 13, 454–458.Google Scholar
  106. 123.
    von Boehmer, H., 1994. Positive selection of lymphocytes. Cell 76, 219–228.Google Scholar
  107. 124.
    Wasserman, R., Li, Y.S., Hardy, R.R., 1997. Down-regulation of terminal deoxynucleotidyl transferase by Ig heavy chain in B lineage cells. J. Immunol. 158, 1133–1138.Google Scholar
  108. 125.
    Weissman, I.L., 1994. Developmental switches in the immature system. Cell 76, 207–218.Google Scholar
  109. 126.
    Yaish, B., Mehr, R., 2005. Models for the dynamics and order of immunoglobulin isotype switch. Bull. Math. Biol. 67, 15–32.Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.The Mina & Everard Goodman Faculty of Life SciencesBar-Ilan UniversityRamat-GanIsrael

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