Bulletin of Mathematical Biology

, Volume 71, Issue 6, pp 1432–1462 | Cite as

Exploration of Factors Affecting the Onset and Maturation Course of Follicular Lymphoma through Simulations of the Germinal Center

  • Michael K. Fenwick
  • Fernando A. EscobedoEmail author
Original Article


Genetic mutations frequently observed in human follicular lymphoma (FL) B-cells result in aberrant expression of the anti-apoptotic protein bcl-2 and surface immunoglobulins (Igs) which display one or more novel variable (V) region N-glycosylation motifs. In the present study, we develop a simulation model of the germinal center (GC) to explore how these mutations might influence the emergence and clonal expansion of key mutants which provoke FL development. The simulations employ a stochastic method for calculating the cellular dynamics, which incorporates actual IgV region sequences and a simplified hypermutation scheme. We first bring our simulations into agreement with experimental data for well-characterized normal and bcl-2+ anti-hapten GC responses in mice to provide a model for understanding how bcl-2 expression leads to permissive selection and memory cell differentiation of weakly competitive B-cells. However, as bcl-2 expression in the GC alone is thought to be insufficient for FL development, we next monitor simulated IgV region mutations to determine the emergence times of key mutants displaying aberrant N-glycosylation motifs recurrently observed in human FL IgV regions. Simulations of 26 germline VH gene segments indicate that particular IgV regions have a dynamical selective advantage by virtue of the speed with which one or more of their key sites can generate N-glycosylation motifs upon hypermutation. Separate calculations attribute the high occurrence frequency of such IgV regions in FL to an ability to produce key mutants at a fast enough rate to overcome stochastic processes in the GC that hinder clonal expansion. Altogether, these simulations characterize three pathways for FL maturation through positively selected N-glycosylations, namely, via one of two key sites within germline VH region gene segments, or via a site in the third heavy chain complementarity-determining region (CDR-H3) that is generated from VDJ recombination.


Apoptosis Affinity maturation Non-Hodgkin’s lymphoma 


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  1. Aarts, W.M., Bende, R.J., Steenbergen, E.J., Kluin, P.M., Ooms, E.C.M., Pals, S.T., Van Noesel, C.J.M., 2000. Variable heavy chain gene analysis of follicular lymphomas: correlation between heavy chain isotype expression and somatic mutation load. Blood 95, 2922–2929. Google Scholar
  2. Alabyev, B., Manser, T., 2002. Bcl-2 rescues the germinal center response but does not alter the V gene somatic hypermutation spectrum in MSH2-deficient mice. J. Immunol. 169, 3819–3824. Google Scholar
  3. Allen, D., Simon, T., Sablitzky, F., Rajewsky, K., Cumano, A., 1988. Antibody engineering for the analysis of affinity maturation of an anti-hapten response. EMBO J. 7, 1995–2001. Google Scholar
  4. Allen, C.D.C., Okada, T., Cyster, J.G., 2007a. Germinal-center organization and cellular dynamics. Immunity 27, 190–202. doi: 10.1016/j.immuni.2007.07.009. Google Scholar
  5. Allen, C.D.C., Okada, T., Tang, H.L., Cyster, J.G., 2007b. Imaging of germinal center selection events during affinity maturation. Science 315, 528–531. doi: 10.1126/science.1136736. Google Scholar
  6. Armitage, R.J., Sato, T.A., Macduff, B.M., Clifford, K.N., Alpert, A.R., Smith, C.A., Fanslow, W.C., 1992. Identification of a source of biologically active CD40 ligand. Eur. J. Immunol. 22, 2071–2076. doi: 10.1002/eji.1830220817. Google Scholar
  7. Batista, F.D., Neuberger, M.S., 1998. Affinity dependence of the B-cell response to antigen: a threshold, a ceiling, and the importance of off-rate. Immunity 8, 751–759. doi: 10.1016/S1074-7613(00)80580-4. Google Scholar
  8. Benson, M.J., Erickson, L.D., Gleeson, M.W., Noelle, R.J., 2007. Affinity of antigen encounter and other early B-cell signals determine B-cell fate. Curr. Opin. Immunol. 19, 275–280. doi: 10.1016/j.coi.2007.04.009. Google Scholar
  9. Bernasconi, N.L., Traggiai, E., Lanzavecchia, A., 2002. Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298, 2199–2202. doi: 10.1126/science.1076071. Google Scholar
  10. Betz, A.G., Neuberger, M.S., Milstein, C., 1993. Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol. Today 14, 405–411. doi: 10.1016/0167-5699(93)90144-A. Google Scholar
  11. Bothwell, A.L.M., Paskind, M., Reth, M., Imanishi-Kari, T., Rajewsky, K., Baltimore, D., 1981. Heavy chain variable region contribution to the NPb family of antibodies—somatic mutation evident in a γ2a variable region. Cell 24, 625–637. doi: 10.1016/0092-8674(81)90089-1. Google Scholar
  12. Brezinschek, H.P., Brezinschek, R.I., Lipsky, P.E., 1995. Analysis of the heavy chain repertoire of human peripheral B cells using single-cell polymerase chain reaction. J. Immunol. 155, 190–202. Google Scholar
  13. Brezinschek, H.P., Foster, S.J., Brezinschek, R.I., Dorner, T., Domiati-Saad, R., Lipsky, P.E., 1997. Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(−)/IgM+ B cells. J. Clin. Invest. 99, 2488–2501. doi: 10.1172/JCI119433. Google Scholar
  14. Carbone, A., Gloghini, A., Gruss, H.J., Pinto, A., 1995. CD40 ligand is constitutively expressed in a subset of T-cell lymphomas and on the microenvironmental reactive T cells of follicular lymphomas and Hodgkin’s disease. Am. J. Pathol. 147, 912–922. Google Scholar
  15. Cleary, M.L., Smith, S.D., Sklar, J., 1986. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47, 19–28. doi: 10.1016/0092-8674(86)90362-4. Google Scholar
  16. Cong, P., Raffeld, M., Teruya-Feldstein, J., Sorbara, L., Pittaluga, S., Jaffe, E.S., 2002. In situ localization of follicular lymphoma: description and analysis by laser capture microdissection. Blood 99, 3376–3382. doi: 10.1182/blood.V99.9.3376. Google Scholar
  17. Cumano, A., Rajewsky, K., 1985. Structure of primary anti-(4-hydroxy-3-nitro-phenyl)acetyl (NP) antibodies in normal and idiotypically suppressed C57BL/6 mice. Eur. J. Immunol. 15, 512–520. doi: 10.1002/eji.1830150517. Google Scholar
  18. Cyster, J.G., Hartley, S.B., Goodnow, C.C., 1994. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 371, 389–395. doi: 10.1038/371389a0. Google Scholar
  19. Dal Porto, J.M., Haberman, A.M., Kelsoe, G., Shlomchik, M.J., 2002. Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced. J. Exp. Med. 195, 1215–1221. doi: 10.1084/jem.20011550. Google Scholar
  20. de Wildt, R.M.T., Hoet, R.M.A., Van Venrooij, W.J., Tomlinson, I.M., Winter, G., 1999. Analysis of heavy and light chain pairings indicates that receptor editing shapes the human antibody repertoire. J. Mol. Biol. 285, 895–901. doi: 10.1006/jmbi.1998.2396. Google Scholar
  21. Dighiero, G., Hart, S., Lim, A., Borche, L., Levy, R., Miller, R.A., 1991. Autoantibody activity of immunoglobulins isolated from B-cell follicular lymphomas. Blood 78, 581–585. Google Scholar
  22. Dogan, A., Du, M.Q., Aiello, A., Diss, T.C., Ye, H.T., Pan, L.X., Isaacson, P.G., 1998. Follicular lymphomas contain a clonally linked but phenotypically distinct neoplastic B-cell population in the interfollicular zone. Blood 91, 4708–4714. Google Scholar
  23. Downing, I., Koch, C., Kilpatrick, D.C., 2003. Immature dendritic cells possess a sugar-sensitive receptor for human mannan-binding lectin. Immunology 109, 360–364. doi: 10.1046/j.1365-2567.2003.01675.x. Google Scholar
  24. Egle, A., Harris, A.W., Bath, M.L., O’Reilly, L., Cory, S., 2004. VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103, 2276–2283. doi: 10.1182/blood-2003-07-2469. Google Scholar
  25. Fenwick, M.K., 2005. PhD Thesis: Modeling and Simulation of Antibody Structure and the Role Antibodies Play in the Onset of Follicular Lymphoma. Cornell University, Ithaca. Google Scholar
  26. Freedman, A.S., Munro, J.M., Rice, G.E., Bevilacqua, M.P., Morimoto, C., McIntyre, B.W., Rhynhart, K., Pober, J.S., Nadler, L.M., 1990. Adhesion of human B-cells to germinal centers in vitro involves VLA-4 and INCAM-110. Science 249, 1030–1033. doi: 10.1126/science.1697696. Google Scholar
  27. Freedman, A.S., Munro, J.M., Morimoto, C., McIntyre, B.W., Rhynhart, K., Lee, N., Nadler, L.M., 1992. Follicular non-Hodgkin’s lymphoma cell adhesion to normal germinal centers and neoplastic follicles involves very late antigen-4 and vascular cell adhesion molecule-1. Blood 79, 206–212. Google Scholar
  28. Frizzera, G., Anaya, J.S., Banks, P.M., 1986. Neoplastic plasma cells in follicular lymphomas—clinical and pathologic findings in six cases. Virchows Arch. [Pathol. Anat.] 409, 149–162. Google Scholar
  29. Fukuhara, S., Rowley, J.D., Variakojis, D., Golomb, H.M., 1979. Chromosome abnormalities in poorly differentiated lymphocytic lymphoma. Cancer Res. 39, 3119–3128. Google Scholar
  30. Furukawa, K., Akasako-Furukawa, A., Shirai, H., Nakamura, H., Azuma, T., 1999. Junctional amino acids determine the maturation pathway of an antibody. Immunity 11, 329–338. doi: 10.1016/S1074-7613(00)80108-9. Google Scholar
  31. Ghia, P., Caligaris-Cappio, F., 2000. The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms. Adv. Cancer Res. 79, 157–173. doi: 10.1016/S0065-230X(00)79005-1. Google Scholar
  32. Ghia, P., Boussiotis, V.A., Schultze, J.L., Cardoso, A.A., Dorfman, D.M., Gribben, J.G., Freedman, A.S., Nadler, L.M., 1998. Unbalanced expression of bcl-2 family proteins in follicular lymphoma: Contribution of CD40 signaling in promoting survival. Blood 91, 244–251. Google Scholar
  33. Gillespie, D.T., 1976. A general method for numerically simulating the stochastic time evolution of coupled chemical reactions. J. Comput. Phys. 22, 403–434. doi: 10.1016/0021-9991(76)90041-3. MathSciNetGoogle Scholar
  34. Gray, D., Skarvall, H., 1988. B-cell memory is short-lived in the absence of antigen. Nature 336, 70–73. doi: 10.1038/336070a0. Google Scholar
  35. Haberman, A.M., Shlomchik, M.J., 2003. Reassessing the function of immune-complex retention by follicular dendritic cells. Nat. Rev. Immunol. 3, 757–764. Google Scholar
  36. Hande, S., Notidis, E., Manser, T., 1998. Bcl-2 obstructs negative selection of autoreactive, hypermutated antibody V regions during memory B cell development. Immunity 8, 189–198. doi: 10.1016/S1074-7613(00)80471-9. Google Scholar
  37. Harris, N.L., 1997. Principles of the revised European-American lymphoma classification (from the international lymphoma study group). Ann. Onc. 8, 11–16. doi: 10.1023/A:1008297208776. Google Scholar
  38. Harris, N.L., Ferry, J.A., 1992. Follicular lymphoma and related disorders (germinal center lymphomas). In: Knowles, D.M. (Ed.), Neoplastic Hematopathology, pp. 645–674. Williams and Wilkins, Baltimore Google Scholar
  39. Harris, N.L., Jaffe, E.S., Stein, H., Banks, P.M., Chan, J.K.C., Cleary, M.L., Delsol, G., De Wolf-Peeters, C., Falini, B., Gatter, K.C., Grogan, T.M., Isaacson, P.G., Knowles, D.M., Mason, D.Y., Muller-Hermelink, H.K., Pileri, S.A., Piris, M.A., Ralfkiaer, E., Warnke, R.A., 1994. A revised European-American classification of lymphoid neoplasms—a proposal from the international lymphoma study group. Blood 84, 1361–1392. Google Scholar
  40. Hauser, A.E., Junt, T., Mempel, T.R., Sneddon, M.W., Kleinstein, S.H., Henrickson, S.E., Von Andrian, U.H., Shlomchik, M.J., Haberman, A.M., 2007. Definition of germinal-center B-cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26, 655–667. doi: 10.1016/j.immuni.2007.04.008. Google Scholar
  41. Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R.D., Korsmeyer, S.J., 1990. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334–336. doi: 10.1038/348334a0. Google Scholar
  42. Huang, S.C., Jiang, R., Glas, A.M., Milner, E.C.B., 1996. Non-stochastic utilization of Ig V region genes in unselected human peripheral B cells. Mol. Immunol. 33, 553–560. doi: 10.1016/0161-5890(95)00162-X. Google Scholar
  43. Iber, D., Maini, P.K., 2002. A mathematical model for germinal centre kinetics and affinity maturation. J. Theor. Biol. 219, 153–175. doi: 10.1006/jtbi.2002.3079. MathSciNetGoogle Scholar
  44. Jaffe, E.S., Shevach, E.M., Frank, M.M., Berard, C.W., Green, I., 1974. Nodular lymphoma—evidence for origin from follicular B lymphocytes. New Engl. J. Med. 290, 813–819. Google Scholar
  45. Johnson, P.W., Watt, S.M., Betts, D.R., Davies, D., Jordan, S., Norton, A.J., Lister, T.A., 1993. Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system. Blood 82, 1848–1857. Google Scholar
  46. Kepler, T.B., 1997. Codon bias and plasticity in immunoglobulins. Mol. Biol. Evol. 14, 637–643. Google Scholar
  47. Kepler, T.B., Bartl, S., 1998. Plasticity under somatic mutation in antigen receptors. Curr. Top. Microbiol. Immunol. 229, 149–162. Google Scholar
  48. Kepler, T.B., Perelson, A.S., 1993. Cyclic re-entry of germinal center B cells and the efficiency of affinity maturation. Immunol. Today 14, 412–415. doi: 10.1016/0167-5699(93)90145-B. Google Scholar
  49. Kesmir, C., De Boer, R.J., 2003. A spatial model of germinal center reactions: cellular adhesion based sorting of B cells results in efficient affinity maturation. J. Theor. Biol. 222, 9–22. doi: 10.1016/S0022-5193(03)00010-9. Google Scholar
  50. Kleinstein, S.H., Singh, J.P., 2003. Why are there so few key mutant clones? The influence of stochastic selection and blocking on affinity maturation in the germinal center. Int. Immunol. 15, 871–884. doi: 10.1093/intimm/dxg085.sgm. Google Scholar
  51. Kleinstein, S.H., Louzoun, Y., Shlomchik, M.J., 2003. Estimating hypermutation rates from clonal tree data. J. Immunol. 171, 4639–4649. Google Scholar
  52. Koopman, G., Keehnen, R.M., Lindhout, E., Newman, W., Shimizu, Y., Van Seventer, G.A., de Groot, C., Pals, S.T., 1994. Adhesion through the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and the VLA-4 (CD49d)-VCAM-1 (CD106) pathways prevents apoptosis of germinal center B cells. J. Immunol. 152, 3760–3767. Google Scholar
  53. Koopman, G., Keehnen, R.M.J., Lindhout, E., Zhou, D.F.H., de Groot, C., Pals, S.T., 1997. Germinal center B cells rescued from apoptosis by CD40 ligation or attachment to follicular dendritic cells, but not by engagement of surface immunoglobulin or adhesion receptors, become resistant to CD95-induced apoptosis. Eur. J. Immunol. 27, 1–7. doi: 10.1002/eji.1830270102. Google Scholar
  54. Kraj, P., Rao, S.P., Glas, A.M., Hardy, R.R., Milner, E.C., Silberstein, L.E., 1997. The human heavy chain Ig V region gene repertoire is biased at all stages of B-cell ontogeny, including early pre-B cells. J. Immunol. 158, 5824–5832. Google Scholar
  55. Kuo, P., Bynoe, M., Diamond, B., 1999. Crossreactive B cells are present during a primary but not secondary response in BALB/c mice expressing a bcl-2 transgene. Mol. Immunol. 36, 471–479. doi: 10.1016/S0161-5890(99)00052-8. Google Scholar
  56. Kuppers, R., Zhao, M., Hansmann, M.L., Rajewsky, K., 1993. Tracing B-cell development in human germinal centers by molecular analysis of single cells picked from histological sections. EMBO J. 12, 4955–4967. Google Scholar
  57. Kuppers, R., Klein, U., Hansmann, M.L., Rajewsky, K., 1999. Cellular origin of human B-cell lymphomas. New Engl. J. Med. 341, 1520–1529. doi: 10.1056/NEJM199911113412007. Google Scholar
  58. Lewis, S.M., 1994. The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses. Adv. Immunol. 56, 27–150. doi: 10.1016/S0065-2776(08)60450-2. Google Scholar
  59. Limpens, J., Stad, R., Vos, C., de Vlaam, C., de Jong, D., van Ommen, G.J., Schuuring, E., Kluin, P.M., 1995. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 85, 2528–2536. Google Scholar
  60. Lindhout, E., Mevissen, M.L.C.M., Kwekkeboom, J., Tager, J.M., de Groot, C., 1993. Direct evidence that human follicular dendritic cells (FDC) rescue germinal center B-cells from death by apoptosis. Clin. Exp. Immunol. 91, 330–336. Google Scholar
  61. Liu, Y.J., Joshua, D.E., Williams, G.T., Smith, C.A., Gordon, J., Maclennan, I.C.M., 1989. Mechanism of antigen-driven selection in germinal centres. Nature 342, 929–931. doi: 10.1038/342929a0. Google Scholar
  62. Liu, Y.J., Cairns, J.A., Holder, M.J., Abbot, S.D., Jansen, K.U., Bonnefoy, J.Y., Gordon, J., Maclennan, I.C.M., 1991a. Recombinant 25-kDa CD23 and interleukin 1 alpha promote the survival of germinal center B cells: evidence for bifurcation in the development of centrocytes rescued from apoptosis. Eur. J. Immunol. 21, 1107–1114. doi: 10.1002/eji.1830210504. Google Scholar
  63. Liu, Y.J., Zhang, J., Lane, P.J.L., Chan, E.Y.T., Maclennan, I.C.M., 1991b. Sites of specific B-cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur. J. Immunol. 21, 2951–2962. doi: 10.1002/eji.1830211209. Google Scholar
  64. Macallan, D.C., Wallace, D.L., Zhang, Y., Ghattas, H., Asquith, B., de Lara, C., Worth, A., Panayiotakopoulos, G., Griffin, G.E., Tough, D.F., Beverley, P.C.L., 2005. B-cell kinetics in humans: Rapid turnover of peripheral blood memory cells. Blood 105, 3633–3640. doi: 10.1182/blood-2004-09-3740. Google Scholar
  65. Manser, T., 2004. Textbook germinal centers? J. Immunol. 172, 3369–3375. Google Scholar
  66. Matsuda, F., Shin, E.K., Nagaoka, H., Matsumura, R., Haino, M., Fukita, Y., Taka-ishi, S., Imai, T., Riley, J.H., Anand, R., Soeda, E., Honjo, T., 1993. Structure and physical map of 64 variable segments in the 3’ 0.8-megabase region of the human immunoglobulin heavy chain locus. Nature Genet. 3, 88–94. doi: 10.1038/ng0193-88. Google Scholar
  67. McCann, K.J., Johnson, P.W.M., Stevenson, F.K., Ottensmeier, C.H., 2006. Universal N-glycosylation sites introduced into the B-cell receptor of follicular lymphoma by somatic mutation: a second tumorigenic event? Leukemia 20, 530–534. doi: 10.1038/sj.leu.2404095. Google Scholar
  68. 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. U.S.A. 81, 3180–3184. doi: 10.1073/pnas.81.10.3180. Google Scholar
  69. Meyer-Hermann, M., 2007a. A concerted action of B-cell selection mechanisms. Adv. Complex Syst. 10, 557–580. doi: 10.1142/S0219525907001276. zbMATHGoogle Scholar
  70. Meyer-Hermann, M.E., 2007b. Are T cells at the origin of B-cell lymphomas? J. Theor. Biol. 244, 656–669. doi: 10.1016/j.jtbi.2006.09.006. MathSciNetGoogle Scholar
  71. Meyer-Hermann, M., Deutsch, A., Or-Guil, M., 2001. Recycling probability and dynamical properties of germinal center reactions. J. Theor. Biol. 210, 265–285. doi: 10.1006/jtbi.2001.2297. Google Scholar
  72. Meyer-Hermann, M.E., Maini, P.K., Iber, D., 2006. An analysis of B-cell selection mechanisms in germinal centres. Math. Med. Biol. 23, 255–277. doi: 10.1093/imammb/dql012. zbMATHGoogle Scholar
  73. Notidis, E., Hande, S., Manser, T., 2001. Enforced expression of bcl-2 selectively perturbs negative selection of dual reactive antibodies. Dev. Immunol. 8, 223–234. doi: 10.1155/2001/83595. Google Scholar
  74. Notidis, E., Heltemes, L., Manser, T., 2002. Dominant, hierarchical induction of peripheral tolerance during foreign antigen-driven B-cell development. Immunity 17, 317–327. doi: 10.1016/S1074-7613(02)00392-8. Google Scholar
  75. O’Connor, B.P., Vogel, L.A., Zhang, W., Loo, W., Shnider, D., Lind, E.F., Ratliff, M., Noelle, R.J., Erickson, L.D., 2006. Imprinting the fate of antigen-reactive B cells through the affinity of the B-cell receptor. J. Immunol. 177, 7723–7732. Google Scholar
  76. Oeschger, S., Brauninger, A., Kuppers, R., Hansmann, M.L., 2002. Tumor cell dissemination in follicular lymphoma. Blood 99, 2192–2198. doi: 10.1182/blood.V99.6.2192. Google Scholar
  77. Ohm-Laursen, L., Barington, T., 2007. Analysis of 6912 unselected somatic hypermutations in human VDJ rearrangements reveals lack of strand specificity and correlation between phase II substitution rates and distance to the nearest 3’ activation-induced cytidine deaminase target. J. Immunol. 178, 4322–4334. Google Scholar
  78. Oprea, M., Perelson, A.S., 1997. Somatic mutation leads to efficient affinity maturation when centrocytes recycle back to centroblasts. J. Immunol. 158, 5155–5162. Google Scholar
  79. Paus, D., Phan, T.G., Chan, T.D., Gardam, S., Basten, A., Brink, R., 2006. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B-cell differentiation. J. Exp. Med. 203, 1081–1091. doi: 10.1084/jem.20060087. Google Scholar
  80. Petrasch, S., Kosco, M., Perez-Alvarez, C., Schmitz, J., Brittinger, G., 1992a. Proliferation of non-Hodgkin-lymphoma lymphocytes in vitro is dependent upon follicular dendritic cell-interactions. Br. J. Haematol. 80, 21–26. doi: 10.1111/j.1365-2141.1992.tb06395.x. Google Scholar
  81. Petrasch, S., Kosco, M., Schmitz, J., Wacker, H.H., Brittinger, G., 1992b. Follicular dendritic cells in non-Hodgkin-lymphoma express adhesion molecules complementary to ligands on neoplastic B-cells. Br. J. Haematol. 82, 695–700. doi: 10.1111/j.1365-2141.1992.tb06946.x. Google Scholar
  82. Petrescu, A.J., Milac, A.L., Petrescu, S.M., Dwek, R.A., Wormald, M.R., 2004. Statistical analysis of the protein environment of N-glycosylation sites: implications for occupancy, structure, and folding. Glycobiology 14, 103–114. doi: 10.1093/glycob/cwh008. Google Scholar
  83. Phan, T.G., Paus, D., Chan, T.D., Turner, M.L., Nutt, S.L., Basten, A., Brink, R., 2006. High affinity germinal center B cells are actively selected into the plasma cell compartment. J. Exp. Med. 203, 2419–2424. doi: 10.1084/jem.20061254. Google Scholar
  84. Radcliffe, C.M., Arnold, J.N., Suter, D.M., Wormald, M.R., Harvey, D.J., Royle, L., Mimura, Y., Kimura, Y., Sim, R.B., Inoges, S., Rodriguez-Calvillo, M., Zabalegui, N., de Cerio, A.L.D., Potter, K.N., Mockridge, C.I., Dwek, R.A., Bendandi, M., Rudd, P.M., Stevenson, F.K., 2007. Human follicular lymphoma cells contain oligomannose glycans in the antigen-binding site of the B-cell receptor. J. Biol. Chem. 282, 7405–7415. doi: 10.1074/jbc.M602690200. Google Scholar
  85. Radmacher, M.D., Kelsoe, G., Kepler, T.B., 1998. Predicted and inferred waiting times for key mutations in the germinal centre reaction: Evidence for stochasticity in selection. Immunol. Cell Biol. 76, 373–381. doi: 10.1046/j.1440-1711.1998.00753.x. Google Scholar
  86. Rao, S.P., Riggs, J.M., Friedman, D.F., Scully, M.S., Lebien, T.W., Silberstein, L.E., 1999. Biased VH gene usage in early lineage human B cells: Evidence for preferential Ig gene rearrangement in the absence of selection. J. Immunol. 163, 2732–2740. Google Scholar
  87. Retter, I., Althaus, H.H., Munch, R., Muller, W., 2005. VBASE2, an integrative V gene database. Nucl. Acids Res. 33, D671–D674. doi: 10.1093/nar/gki088. Google Scholar
  88. Sablitzky, F., Wildner, G., Rajewsky, K., 1985. Somatic mutation and clonal expansion of B cells in an antigen-driven immune response. EMBO J. 4, 345–350. Google Scholar
  89. Schatz, D.G., Oettinger, M.A., Schlissel, M.S., 1992. V(D)J recombination: Molecular biology and regulation. Annu. Rev. Immunol. 10, 359–383. Google Scholar
  90. Schwickert, T.A., Lindquist, R.L., Shakhar, G., Livshits, G., Skokos, D., Kosco-Vilbois, M.H., Dustin, M.L., Nussenzweig, M.C., 2007. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83–87. doi: 10.1038/nature05573. Google Scholar
  91. Shlomchik, M.J., Litwin, S., Weigert, M.G., 1990. In: Progress in Immunology. Proceedings of the Seventh International Congress of Immunology, vol. 7, p. 415. Google Scholar
  92. Smith, D.S., Creadon, G., Jena, P.K., Portanova, J.P., Kotzin, B.L., Wysocki, L.J., 1996. Di- and tri-nucleotide target preferences of somatic mutagenesis in normal and autoreactive B cells. J. Immunol. 156, 2642–2652. Google Scholar
  93. Smith, K.G.C., Weiss, U., Rajewsky, K., Nossal, G.J.V., Tarlinton, D.M., 1994. Bcl-2 increases memory B-cell recruitment but does not perturb selection in germinal centers. Immunity 1, 803–813. doi: 10.1016/S1074-7613(94)80022-7. Google Scholar
  94. Smith, K.G.C., Light, A., Nossal, G.J.V., Tarlinton, D.M., 1997. The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response. EMBO J. 16, 2996–3006. doi: 10.1093/emboj/16.11.2996. Google Scholar
  95. Smith, K.G.C., Light, A., O’Reilly, L.A., Ang, S.M., Strasser, A., Tarlinton, D., 2000. Bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells. J. Exp. Med. 191, 475–484. doi: 10.1084/jem.191.3.475. Google Scholar
  96. Stamatopoulos, K., Kosmas, C., Papadaki, T., Pouliou, E., Belessi, C., Afendaki, S., Anagnostou, D., Loukopoulos, D., 1997. Follicular lymphoma immunoglobulin kappa light chains are affected by the antigen selection process, but to a lesser degree than their partner heavy chains. Br. J. Haematol. 96, 132–146. doi: 10.1046/j.1365-2141.1997.8492477.x. Google Scholar
  97. Stein, H., Gerdes, J., Mason, D.Y., 1982. The normal and malignant germinal center. Clin. Haematol. 11, 531–559. Google Scholar
  98. Su, W., Spencer, J., Wotherspoon, A.C., 2001. Relative distribution of tumour cells and reactive cells in follicular lymphoma. J. Pathol. 193, 498–504. doi: 10.1002/path.820. Google Scholar
  99. Tan, T., Bogarad, L.D., Deem, M.W., 2004. Modulation of base-specific mutation and recombination rates enables functional adaptation within the context of the genetic code. J. Mol. Evol. 59, 385–399. doi: 10.1007/s00239-004-2633-8. Google Scholar
  100. Tomlinson, I.M., Walter, G., Marks, J.D., Llewelyn, M.B., Winter, G., 1992. The repertoire of human germline VH sequences reveals about 50 groups of VH segments with different hypervariable loops. J. Mol. Biol. 227, 776–798. doi: 10.1016/0022-2836(92)90223-7. Google Scholar
  101. Tsujimoto, Y., Finger, L.R., Yunis, J., Nowell, P.C., Croce, C.M., 1984. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226, 1097–1099. doi: 10.1126/science.6093263. Google Scholar
  102. Tsujimoto, Y., Cossman, J., Jaffe, E., Croce, C.M., 1985a. Involvement of the bcl-2 gene in human follicular lymphoma. Science 228, 1440–1443. doi: 10.1126/science.3874430. Google Scholar
  103. Tsujimoto, Y., Gorham, J., Cossman, J., Jaffe, E., Croce, C.M., 1985b. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229, 1390–1393. doi: 10.1126/science.3929382. Google Scholar
  104. Umetsu, D.T., Esserman, L., Donlon, T.A., Dekruyff, R.H., Levy, R., 1990. Induction of proliferation of human follicular (B type) lymphoma cells by cognate interaction with CD4+ T cell clones. J. Immunol. 144, 2550–2557. Google Scholar
  105. Weiss, U., Rajewsky, K., 1990. The repertoire of somatic antibody mutants accumulating in the memory compartment after primary immunization is restricted through affinity maturation and mirrors that expressed in the secondary response. J. Exp. Med. 172, 1681–1689. doi: 10.1084/jem.172.6.1681. Google Scholar
  106. Weiss, L.M., Strickler, J.G., Medeiros, L.J., Gerdes, J., Stein, H., Warnke, R.A., 1987. Proliferative rates of non-Hodgkin’s lymphomas as assessed by Ki-67 antibody. Hum. Pathol. 18, 1155–1159. doi: 10.1016/S0046-8177(87)80068-0. Google Scholar
  107. Yanez, R., Barrios, Y., Cabrera, R., Diaz-Espada, F., 2006. Intraclonal variability of VH genes in follicular lymphoma patients who have received anti-idiotypic immunotherapy. J. Immunother. 29, 61–66. doi: 10.1097/01.cji.0000182270.66506.e1. Google Scholar
  108. Yunis, J.J., Oken, M.M., Kaplan, M.E., Ensrud, K.M., Howe, R.R., Theologides, A., 1982. Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin’s lymphoma. New Engl. J. Med. 307, 1231–1236. CrossRefGoogle Scholar
  109. Zabalegui, N., de Cerio, A.L.D., Inoges, S., Rodriguez-Calvillo, M., Perez-Calvo, J., Hernandez, M., Garcia-Foncillas, J., Martin-Algarra, S., Rocha, E., Bendandi, M., 2004. Acquired potential N-glycosylation sites within the tumor-specific immunoglobulin heavy chains of B-cell malignancies. Haematologica 89, 541–546. Google Scholar
  110. Zhu, D., McCarthy, H., Ottensmeier, C.H., Johnson, P., Hamblin, T.J., Stevenson, F.K., 2002. Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma. Blood 99, 2562–2568. doi: 10.1182/blood.V99.7.2562. Google Scholar

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© Society for Mathematical Biology 2009

Authors and Affiliations

  1. 1.Department of Chemical and Biomolecular EngineeringCornell UniversityIthacaUSA

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