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

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Abstract

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.

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References

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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.

    MathSciNet  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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.

    MathSciNet  Google Scholar 

  • 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 

  • 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 

  • Kepler, T.B., 1997. Codon bias and plasticity in immunoglobulins. Mol. Biol. Evol. 14, 637–643.

    Google Scholar 

  • Kepler, T.B., Bartl, S., 1998. Plasticity under somatic mutation in antigen receptors. Curr. Top. Microbiol. Immunol. 229, 149–162.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • Kleinstein, S.H., Louzoun, Y., Shlomchik, M.J., 2003. Estimating hypermutation rates from clonal tree data. J. Immunol. 171, 4639–4649.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • Manser, T., 2004. Textbook germinal centers? J. Immunol. 172, 3369–3375.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • Meyer-Hermann, M., 2007a. A concerted action of B-cell selection mechanisms. Adv. Complex Syst. 10, 557–580. doi:10.1142/S0219525907001276.

    MATH  Google Scholar 

  • 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.

    MathSciNet  Google Scholar 

  • 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 

  • 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.

    MATH  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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.

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • Stein, H., Gerdes, J., Mason, D.Y., 1982. The normal and malignant germinal center. Clin. Haematol. 11, 531–559.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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.

    Article  Google Scholar 

  • 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 

  • 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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  1. Michael K. Fenwick

    Present address: Department of Molecular Medicine, Cornell University, Ithaca, NY, 14853, USA

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  1. Department of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, 14853, USA

    Michael K. Fenwick & Fernando A. Escobedo

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Fenwick, M.K., Escobedo, F.A. Exploration of Factors Affecting the Onset and Maturation Course of Follicular Lymphoma through Simulations of the Germinal Center. Bull. Math. Biol. 71, 1432–1462 (2009). https://doi.org/10.1007/s11538-009-9408-8

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