Terminal differentiation of B cells is an essential process for the humoral immune response in vertebrates and is achieved by the concerted action of several transcription factors in response to antigen recognition and extracellular signals provided by T-helper cells. While there is a wealth of experimental data regarding the molecular and cellular signals involved in this process, there is no general consensus regarding the structure and dynamical properties of the underlying regulatory network controlling this process. We developed a dynamical model of the regulatory network controlling terminal differentiation of B cells. The structure of the network was inferred from experimental data available in the literature, and its dynamical behavior was analyzed by modeling the network both as a discrete and a continuous dynamical systems. The steady states of these models are consistent with the patterns of activation reported for the Naive, GC, Mem, and PC cell types. Moreover, the models are able to describe the patterns of differentiation from the precursor Naive to any of the GC, Mem, or PC cell types in response to a specific set of extracellular signals. We simulated all possible single loss- and gain-of-function mutants, corroborating the importance of Pax5, Bcl6, Bach2, Irf4, and Blimp1 as key regulators of B cell differentiation process. The model is able to represent the directional nature of terminal B cell differentiation and qualitatively describes key differentiation events from a precursor cell to terminally differentiated B cells.
References
[1]
LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood. 2008;112(5):1570–80. doi: 10.1182/blood-2008-02-078071. pmid:18725575
[2]
Gatto D, Brink R. The germinal center reaction. J Allergy Clin Immunol. 2010;126(5):898–907; quiz 908–9. doi: 10.1016/j.jaci.2010.09.007. pmid:21050940
Moens L, Tangye SG. Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage. Front Immunol. 2014 jan;5(February):65. doi: 10.3389/fimmu.2014.00065. pmid:24600453
[5]
Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, Rosenwald A, et al. Blimp-1 Orchestrates Plasma Cell Differentiation by Extinguishing the Mature B Cell Gene Expression Program. Immunity. 2002 Jul;17(1):51–62. doi: 10.1016/S1074-7613(02)00335-7. pmid:12150891
[6]
Basso K, Saito M, Sumazin P, Margolin Aa, Wang K, Lim Wk, et al. Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells. Blood. 2010 feb;115(5):975–84. doi: 10.1182/blood-2009-06-227017. pmid:19965633
Delogu A, Schebesta A, Sun Q, Aschenbrenner K, Perlot T, Busslinger M. Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity. 2006 Mar;24(3):269–81. doi: 10.1016/j.immuni.2006.01.012. pmid:16546096
[9]
Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E, et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature. 2004 Jun;429(6991):566–71. doi: 10.1038/nature02596. pmid:15152264
[10]
Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007;8(5):463–70. doi: 10.1038/ni1454. pmid:17440452
[11]
Mora-López F, Reales E, Brieva JA, Campos-Caro A, Dc W, Mora-lo F, et al. Human BSAP and BLIMP1 conform an autoregulatory feedback loop. Blood. 2007;110(9):3150–7. doi: 10.1182/blood-2007-05-092262. pmid:17682124
[12]
Ochiai K, Katoh Y, Ikura T, Hoshikawa Y, Noda T, Karasuyama H, et al. Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells. J Biol Chem. 2006;281(50):38226–34. doi: 10.1074/jbc.M607592200. pmid:17046816
[13]
Toyama H, Okada S, Hatano M, Takahashi Y, Takeda N, Ichii H, et al. Memory B Cells without Somatic Hypermutation Are Generated from Bcl6-Deficient B Cells. Immunity. 2002 Sep;17(3):329–339. doi: 10.1016/S1074-7613(02)00387-4. pmid:12354385
[14]
Fukuda T, Yoshida T, Okada S, Hatano M, Miki T, Ishibashi K, et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J Exp Med. 1997;186(3):439–48. doi: 10.1084/jem.186.3.439. pmid:9236196
[15]
Dent aL, Shaffer AL, Yu X, Allman D, Staudt LM. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science. 1997;276(5312):589–92. doi: 10.1126/science.276.5312.589. pmid:9110977
[16]
Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, Bhagat G, et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell. 2007;12(3):280–92. doi: 10.1016/j.ccr.2007.08.011. pmid:17785208
[17]
Kuo TC, Shaffer AL, Haddad J, Choi YS, Staudt LM, Calame K. Repression of BCL-6 is required for the formation of human memory B cells in vitro. J Exp Med. 2007;204(4):819–30. doi: 10.1084/jem.20062104. pmid:17403935
[18]
Sciammas R, Shaffer aL, Schatz JH, Zhao H, Staudt LM, Singh H. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity. 2006;25(2):225–36. doi: 10.1016/j.immuni.2006.07.009. pmid:16919487
[19]
Muto A, Ochiai K, Kimura Y, Itoh-Nakadai A, Calame KL, Ikebe D, et al. Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch. EMBO J. 2010;29(23):4048–61. doi: 10.1038/emboj.2010.257. pmid:20953163
[20]
Sciammas R, Li Y, Warmflash A, Song Y, Dinner AR, Singh H. An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. Mol Syst Biol. 2011;7(495):495. doi: 10.1038/msb.2011.25. pmid:21613984
[21]
Bhattacharya S, Conolly RB, Kaminski NE, Thomas RS, Andersen ME, Zhang Q. A bistable switch underlying B-cell differentiation and its disruption by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci. 2010;115(1):51–65. doi: 10.1093/toxsci/kfq035. pmid:20123757
[22]
Zhang Q, Kline DE, Bhattacharya S, Crawford RB, Conolly RB, Thomas RS, et al. All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol. 2013;268(1):17–26. doi: 10.1016/j.taap.2013.01.015. pmid:23357550
[23]
Martínez MR, Corradin A, Klein U, álvarez MJ, Toffolo GM, di Camillo B, et al. Quantitative modeling of the terminal differentiation of B cells and mechanisms of lymphomagenesis. Proc Natl Acad Sci U S A. 2012;109(7):2672–7. doi: 10.1073/pnas.1113019109. pmid:22308355
[24]
Meyer-Hermann M. A mathematical model for the germinal center morphology and affinity maturation. J Theor Biol. 2002;p. 273–300.
[25]
Hawkins JB, Jones MT, Plassmann PE, Thorley-Lawson Da. Chemotaxis in densely populated tissue determines germinal center anatomy and cell motility: a new paradigm for the development of complex tissues. PLoS One. 2011;6(12):e27650. doi: 10.1371/journal.pone.0027650. pmid:22145018
[26]
Kestler Ha, Wawra C, Kracher B, Kühl M. Network modeling of signal transduction: Establishing the global view; 2008.
[27]
Morris MK, Saez-Rodriguez J, Sorger PK, Lauffenburger Da. Logic-based models for the analysis of cell signaling networks; 2010.
[28]
Albert R, Thakar J. Boolean modeling: A logic-based dynamic approach for understanding signaling and regulatory networks and for making useful predictions; 2014.
[29]
Huang S, Eichler G, Bar-Yam Y, Ingber DE. Cell fates as high-dimensional attractor states of a complex gene regulatory network. Phys Rev Lett. 2005 Apr;94(12):1–4. doi: 10.1103/PhysRevLett.94.128701.
[30]
Horcher M, Souabni A, Busslinger M. Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis. Immunity. 2001 Jun;14(6):779–90. doi: 10.1016/S1074-7613(01)00153-4. pmid:11420047
[31]
Schebesta A, Mcmanus S, Salvagiotto G, Delogu A, Busslinger GA, Busslinger M. Transcription factor Pax5 activates the chromatin of key genes involved in B cell signaling, adhesion, migration, and immune function. Immunity. 2007;27(1):49–63. doi: 10.1016/j.immuni.2007.05.019. pmid:17658281
[32]
Roessler S, Gy？ry I, Imhof S, Spivakov M, Williams RR, Busslinger M, et al. Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5. Mol Cell Biol. 2007 Jan;27(2):579–594. doi: 10.1128/MCB.01192-06. pmid:17101802
[33]
O’Riordan M, Grosschedl R. Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. Immunity. 1999 Jul;11(1):21–31. doi: 10.1016/S1074-7613(00)80078-3. pmid:10435576
[34]
Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti RSK, Dalla-Favera R. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood. 2003;101(8):2914–23. doi: 10.1182/blood-2002-11-3387. pmid:12515714
[35]
Ramachandrareddy H, Bouska A, Shen Y, Ji M, Rizzino A, Chan WC, et al. BCL6 promoter interacts with far upstream sequences with greatly enhanced activating histone modifications in germinal center B cells. Proc Natl Acad Sci U S A. 2010;107(26):11930–5. doi: 10.1073/pnas.1004962107. pmid:20547840
[36]
Batlle-López A, Cortiguera MG, Rosa-Garrido M, Blanco R, Del Cerro E, Torrano V, et al. Novel CTCF binding at a site in exon1A of BCL6 is associated with active histone marks and a transcriptionally active locus. Oncogene. 2013;(April):1–11. doi: 10.1038/onc.2013.535
[37]
Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T, et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nature immunology. 2006;7(7):773–782. doi: 10.1038/ni1357. pmid:16767092
[38]
Demongeot J, Goles E, Morvan M, Noual M, Sené S. Attraction basins as gauges of robustness against boundary conditions in biological complex systems. PLoS One. 2010 Jan;5(8):e11793. doi: 10.1371/journal.pone.0011793. pmid:20700525
[39]
Huang S. The molecular and mathematical basis of Waddington’s epigenetic landscape: A framework for post-Darwinian biology? BioEssays. 2012 Feb;34(2):149–157. doi: 10.1002/bies.201100031. pmid:22102361
[40]
Kjeldsen MK, Perez-Andres M, Schmitz A, Johansen P, Boegsted M, Nyegaard M, et al. Multiparametric flow cytometry for identification and fluorescence activated cell sorting of five distinct B-cell subpopulations in normal tonsil tissue. American Journal of Clinical Pathology. 2011;136(6):960–969. doi: 10.1309/AJCPDQNP2U5DZHVV. pmid:22095383
[41]
Perez-Andres M, Paiva B, Nieto WG, Caraux a, Schmitz a, Almeida J, et al. Human peripheral blood B-Cell compartments: A crossroad in B-cell traffic. Cytometry Part B—Clinical Cytometry. 2010;78(SUPPL. 1):47–60. doi: 10.1002/cyto.b.20547.
[42]
Sánchez-Corrales YE, Alvarez-Buylla ER, Mendoza L. The Arabidopsis thaliana flower organ specification gene regulatory network determines a robust differentiation process. J Theor Biol. 2010;264(3):971–83. doi: 10.1016/j.jtbi.2010.03.006. pmid:20303988
[43]
Cattoretti G, Shaknovich R, Smith PM, J？ck Hm, Murty VV, Alobeid B. Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance. Journal of immunology (Baltimore, Md: 1950). 2006 Nov;177(10):6930–9. doi: 10.4049/jimmunol.177.10.6930.
[44]
Ochiai K, Maienschein-Cline M, Simonetti G, Chen J, Rosenthal R, Brink R, et al. Transcriptional Regulation of Germinal Center B and Plasma Cell Fates by Dynamical Control of IRF4. Immunity. 2013 May;38(5):918–929. doi: 10.1016/j.immuni.2013.04.009. pmid:23684984
[45]
Holder MJ, Liu YJ, Defrance T, Flores-Romo L, MacLennan IC, Gordon J. Growth factor requirements for the stimulation of germinal center B cells: evidence for an IL-2-dependent pathway of development. Int Immunol. 1991;3(12):1243–51. doi: 10.1093/intimm/3.12.1243. pmid:1723294
[46]
Scheeren Fa, Naspetti M, Diehl S, Schotte R, Nagasawa M, Wijnands E, et al. STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression. Nat Immunol. 2005;6(3):303–13. doi: 10.1038/ni1172. pmid:15711548
[47]
Nojima T, Haniuda K, Moutai T, Matsudaira M, Mizokawa S, Shiratori I, et al. In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo. Nat Commun. 2011;2:465. doi: 10.1038/ncomms1475. pmid:21897376
[48]
Arpin C, Déchanet J, Van Kooten C, Merville P, Grouard G, Brière F, et al. Generation of memory B cells and plasma cells in vitro. Science. 1995;268(5211):720–2. doi: 10.1126/science.7537388. pmid:7537388
[49]
Niu H, Ye BH, Dalla-Favera R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription？? factor. Genes Dev. 1998;12(13):1953–1961. doi: 10.1101/gad.12.13.1953. pmid:9649500
[50]
Kwon H, Thierry-Mieg D, Thierry-Mieg J, Kim HP, Oh J, Tunyaplin C, et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity. 2009;31(6):941–52. doi: 10.1016/j.immuni.2009.10.008. pmid:20064451
[51]
Yasuda T, Hayakawa F, Kurahashi S, Sugimoto K, Minami Y, Tomita A, et al. B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation. J Immunol. 2012;188(12):6127–34. doi: 10.4049/jimmunol.1103039. pmid:22593617
[52]
Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol. 2005;175(12):7867–79. doi: 10.4049/jimmunol.175.12.7867. pmid:16339522
[53]
Berglund LJ, Avery DT, Ma CS, Moens L, Deenick EK, Bustamante J, et al. IL-21 signalling via STAT3 primes human na？ve B cells to respond to IL-2 to enhance their differentiation into plasmablasts. Blood. 2013;122(24):3940–3950. doi: 10.1182/blood-2013-06-506865. pmid:24159173
[54]
Shapiro-Shelef M, Lin KI, McHeyzer-Williams LJ, Liao J, McHeyzer-Williams MG, Calame K. Blimp-1 Is Required for the Formation of Immunoglobulin Secreting Plasma Cells and Pre-Plasma Memory B Cells. Immunity. 2003;19(4):607–620. doi: 10.1016/S1074-7613(03)00267-X. pmid:14563324
[55]
Shapiro-Shelef M, Lin KI, Savitsky D, Liao J, Calame K. Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J Exp Med. 2005;202(11):1471–6. doi: 10.1084/jem.20051611. pmid:16314438
[56]
Kallies A, Nutt SL. Terminal differentiation of lymphocytes depends on Blimp-1. Current opinion in immunology. 2007;19(2):156–62. doi: 10.1016/j.coi.2007.01.003. pmid:17291741
[57]
Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet. 1997 Jun;16(2):161–70. doi: 10.1038/ng0697-161. pmid:9171827
[58]
Huang C, Hatzi K, Melnick A. Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms. Nat Immunol. 2013 Mar;14(4). doi: 10.1038/ni.2543.
[59]
Shapiro-Shelef M, Lin KI, Savitsky D, Liao J, Calame K. Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J Exp Med. 2005 Dec;202(11):1471–6. doi: 10.1084/jem.20051611. pmid:16314438
[60]
Mittrucker HW. Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function. Science. 1997;275(5299):540–543. doi: 10.1126/science.275.5299.540. pmid:8999800
Urbánek P, Wang ZQ, Fetka I, Wagner EF, Busslinger M. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell. 1994 Dec;79(5):901–12. doi: 10.1016/0092-8674(94)90079-5. pmid:8001127
[63]
Nera KP, Kohonen P, Narvi E, Peippo A, Mustonen L, Terho P, et al. Loss of Pax5 promotes plasma cell differentiation. Immunity. 2006 Mar;24(3):283–93. doi: 10.1016/j.immuni.2006.02.003. pmid:16546097
[64]
Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity. 2004;21(1):81–93. doi: 10.1016/j.immuni.2004.06.010. pmid:15345222
[65]
Todd DJ, McHeyzer-Williams LJ, Kowal C, Lee AH, Volpe BT, Diamond B, et al. XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development. The Journal of experimental medicine. 2009;206(10):2151–9. doi: 10.1084/jem.20090738. pmid:19752183
[66]
Baron BW, Anastasi J, Montag A, Huo D, Baron RM, Karrison T, et al. The human BCL6 transgene promotes the development of lymphomas in the mouse. Proc Natl Acad Sci U S A. 2004;101(39):14198–203. doi: 10.1073/pnas.0406138101. pmid:15375218
[67]
Usui T, Wakatsuki Y, Matsunaga Y, Kaneko S, Koseki H, Kita T, et al. Overexpression of B cell-specific activator protein (BSAP/Pax-5) in a late B cell is sufficient to suppress differentiation to an Ig high producer cell with plasma cell phenotype. J Immunol. 1997;158(7):3197–204. pmid:9120274
[68]
Kurosaki T, Kometani K, Ise W. Memory B cells. Nature Reviews Immunology. 2015;15(3):149–159. doi: 10.1038/nri3802. pmid:25677494
[69]
Cattoretti G, Angelin-Duclos C, Shaknovich R, Zhou H, Wang D, Alobeid B. PRDM1/Blimp-1 is expressed in human B-lymphocytes committed to the plasma cell lineage. J Pathol. 2005;206(1):76–86. doi: 10.1002/path.1752. pmid:15772984
[70]
Teng Y, Takahashi Y, Yamada M, Kurosu T, Koyama T, Miura O, et al. IRF4 negatively regulates proliferation of germinal center B cell-derived Burkitt’s lymphoma cell lines and induces differentiation toward plasma cells. Eur J Cell Biol. 2007 Oct;86(10):581–9. doi: 10.1016/j.ejcb.2007.05.006. pmid:17651861
[71]
Reljic R, Wagner SD, Peakman LJ, Fearon DT. Suppression of Signal Transducer and Activator of Transcription 3-Dependent B Lymphocyte Terminal Differentiation by Bcl-6. J Exp Med. 2000;192(12):1841–1848. doi: 10.1084/jem.192.12.1841. pmid:11120780
[72]
Horikawa K, Takatsu K. Interleukin-5 regulates genes involved in B-cell terminal maturation. Immunology. 2006 Aug;118(4):497–508. doi: 10.1111/j.1365-2567.2006.02382.x. pmid:16895557
[73]
Turner CA, Mack DH, Davis MM. Pillars article: Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. 1994. J Immunol. 2010 Jul;185(1):5–14. doi: 10.4049/jimmunol.1090043. pmid:20562267
[74]
Lin Y. Repression of c-myc Transcription by Blimp-1, an Inducer of Terminal B Cell Differentiation. Science. 1997 Apr;276(5312):596–599. doi: 10.1126/science.276.5312.596. pmid:9110979
[75]
Piskurich JF, Lin KI, Lin Y, Wang Y, Ting JP, Calame K. BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nat Immunol. 2000 Dec;1(6):526–32. doi: 10.1038/82788. pmid:11101876
[76]
Yasuda T, Kometani K, Takahashi N, Imai Y, Aiba Y, Kurosaki T. ERKs induce expression of the transcriptional repressor Blimp-1 and subsequent plasma cell differentiation. Sci Signal. 2011 Jan;4(169):ra25. doi: 10.1126/scisignal.2001592. pmid:21505187
[77]
Morrison aM, Nutt SL, Thévenin C, Rolink a, Busslinger M. Loss- and gain-of-function mutations reveal an important role of BSAP (Pax-5) at the start and end of B cell differentiation. Semin Immunol. 1998 Apr;10(2):133–42. doi: 10.1006/smim.1998.0115. pmid:9618759
[78]
Lin KI, Angelin-Duclos C, Kuo TC, Calame K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Biol. 2002;22(13):4771–80. doi: 10.1128/MCB.22.13.4771-4780.2002. pmid:12052884
[79]
Falini B, Fizzotti M, Pucciarini A, Bigerna B, Marafioti T, Gambacorta M, et al. A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. Blood. 2000;95(6):2084–92. pmid:10706878 doi: 10.1182/blood-2013-08-522011
[80]
Cattoretti G, Pasqualucci L, Ballon G, Tam W, Nandula SV, Shen Q, et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer cell. 2005 May;7(5):445–55. doi: 10.1016/j.ccr.2005.03.037. pmid:15894265
[81]
Martínez-Sosa P, Mendoza L. The regulatory network that controls the differentiation of T lymphocytes. Biosystems. 2013;113(2):96–103. doi: 10.1016/j.biosystems.2013.05.007. pmid:23743337
[82]
Mendoza L, Pardo F. A robust model to describe the differentiation of T-helper cells. Theory Biosci. 2010;p. 283–293.
[83]
Shaffer aL, Rosenwald A, Staudt LM. Decision making in the immune system: Lymphoid Malignancies: the dark side of B-cell differentiation. Nat Rev Immunol. 2002 dec;2(12):920–933. doi: 10.1038/nri953. pmid:12461565
[84]
Shaffer AL, Young RM, Staudt LM. Pathogenesis of Human B Cell Lymphomas. Annu Rev Immunol. 2012 apr;30(1):565–610. doi: 10.1146/annurev-immunol-020711-075027. pmid:22224767
[85]
Tunyaplin C, Shaffer aL, Angelin-Duclos CD, Yu X, Staudt LM, Calame KL. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol. 2004;173(2):1158–65. doi: 10.4049/jimmunol.173.2.1158. pmid:15240705
[86]
Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM. BCL-6 Represses Genes that Function in Lymphocyte Differentiation, Inflammation, and Cell Cycle Control. Immunity. 2000;13(2):199–212. doi: 10.1016/S1074-7613(00)00020-0. pmid:10981963
[87]
Gupta S, Jiang M, Anthony A, Pernis AB. Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4. The Journal of experimental medicine. 1999;190(12):1837–1848. doi: 10.1084/jem.190.12.1837. pmid:10601358
[88]
Alinikula J, Nera KP, Junttila S, Lassila O. Alternate pathways for Bcl6-mediated regulation of B cell to plasma cell differentiation. European journal of immunology. 2011;41(8):2404–13. doi: 10.1002/eji.201141553. pmid:21674482
[89]
Decker T, Pasca di Magliano M, McManus S, Sun Q, Bonifer C, Tagoh H, et al. Stepwise Activation of Enhancer and Promoter Regions of the B Cell Commitment Gene Pax5 in Early Lymphopoiesis. Immunity. 2009 Apr;30(4):508–520. doi: 10.1016/j.immuni.2009.01.012. pmid:19345119
[90]
Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102(5):553–63. doi: 10.1016/S0092-8674(00)00078-7. pmid:11007474
[91]
Dedeoglu F. Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NF B. International Immunology. 2004;16(3):395–404. doi: 10.1093/intimm/dxh042. pmid:14978013
[92]
Gonda H, Sugai M, Nambu Y, Katakai T, Agata Y, Mori KJ, et al. The balance between Pax5 and Id2 activities is the key to AID gene expression. The Journal of experimental medicine. 2003;198(9):1427–37. doi: 10.1084/jem.20030802. pmid:14581609
[93]
Tran TH, Nakata M, Suzuki K, Begum NA, Shinkura R, Fagarasan S, et al. B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. Nature immunology. 2010;11(2):148–54. doi: 10.1038/ni.1829. pmid:19966806
[94]
Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, et al. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. The Journal of experimental medicine. 2004;200(8):967–77. doi: 10.1084/jem.20040973. pmid:15492122
[95]
Sciammas R, Davis MM. Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation. The Journal of Immunology. 2004;172(9):5427–40. doi: 10.4049/jimmunol.172.9.5427. pmid:15100284
[96]
Kauffman SA. Metabolic stability and epigenesis in randomly constructed genetic nets. J Theor Biol. 1969 Mar;22(3):437–467. doi: 10.1016/0022-5193(69)90015-0. pmid:5803332
[97]
Wang RS, Saadatpour A, Albert R. Boolean modeling in systems biology: an overview of methodology and applications; 2012.
[98]
Helikar T, Kowal B, McClenathan S, Bruckner M, Rowley T, Madrahimov A, et al. The Cell Collective: Toward an open and collaborative approach to systems biology. BMC systems biology. 2012;6(1):96. doi: 10.1186/1752-0509-6-96. pmid:22871178
[99]
Müssel C, Hopfensitz M, Kestler Ha. BoolNet—an R package for generation, reconstruction, and analysis of Boolean networks. Bioinformatics. 2010;26(10):1378–1380. doi: 10.1093/bioinformatics/btq124. pmid:20378558
[100]
Schmidt C, Kim D, Ippolito GC, Naqvi HR, Probst L, Mathur S, et al. Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright. EMBO J. 2009 Mar;28(6):711–24. doi: 10.1038/emboj.2009.20. pmid:19214191
[101]
Zotos D, Coquet JM, Zhang Y, Light A, D’Costa K, Kallies A, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010 Feb;207(2):365–78. doi: 10.1084/jem.20091777. pmid:20142430
[102]
Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med. 2010 Feb;207(2):353–63. doi: 10.1084/jem.20091738. pmid:20142429
[103]
Rankin AL, MacLeod H, Keegan S, Andreyeva T, Lowe L, Bloom L, et al. IL-21 Receptor Is Critical for the Development of Memory B Cell Responses. J Immunol. 2011 Jan;186(2):667–74. doi: 10.4049/jimmunol.0903207. pmid:21169545
[104]
Mendoza L, Xenarios I. A method for the generation of standardized qualitative dynamical systems of regulatory networks. Theor Biol Med Model. 2006;3:13. doi: 10.1186/1742-4682-3-13. pmid:16542429
[105]
Weinstein N, Mendoza L. Building Qualitative Models of Plant Regulatory Networks with SQUAD. Front Plant Sci. 2012;3(April):72. doi: 10.3389/fpls.2012.00072. pmid:22639661
[106]
Soetaert K, Petzoldt T, Setzer R. Solving Differential Equations in R. R J. 2010;2(December):5–15. doi: 10.18637/jss.v033.i09
