Abstract
To determine the number of B cells seeding germinal centres, different authors have used immunohistology of germinal centre sections in conjunction with assuming a binomial distribution of the fractions of two phenotypically distinct B cell populations participating in a given immune response. This approach further assumed that germinal centres are closed to continuous B cell entry. Using such a model, it has been concluded that germinal centres contain two to eight clones, a figure that is usually taken and cited as being essentially correct. The present re-evaluation of those and related experiments lead to an extended mathematical model. This model includes an estimation of errors created by data sampling, two new parameters that take into account possible mistakes in classification of single population GC sections, and the likely variability in the number of seeding B cells. Fitting this new model to experimental data resulted in an estimated mean number of ⟨n⟩ = 23–37 seeder B cells.
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References
Janeway C (2005) Immunobiology: the immune system in health and disease, 6th edn. Garland Science, New York
Flajnik MF (2002) Comparative analyses of immunoglobulin genes: surprises and portents. Nat Rev Immunol 2:688–698
Manser T (2004) Textbook germinal centers? J Immunol 172:3369–3375
Flemming W (1885) Studien ueber regeneration der gewebe. Arch Mikrosk Anat 24:50–97
Nieuwenhuis P, Opstelten D (1984) Functional anatomy of germinal centers. Am J Anat 170:421–435
Conway E (1937) Cyclic changes in lymphatic nodules. Anat Rec 69:487–513
Ehrich WE, Harris TN (1945) The site of antibody formation. Science 101:28–31
Hellman T, White G (1930) Das verhalten lymphatischen gewebes wihrend eines immunisierungsprozesses. Virchows Arch Path Anat 278:221–257
Ringertz N, Adamson CA (1950) The lymph-node response to various antigens; an experimental-morphological study. Acta Pathologica Et Microbiologica Scandinavica. Supplementum 86:1–69
Congdon CC, Makinodan T (1961) Splenic white pulp alteration after antigen injection: relation to time of serum antibody production. Am J Pathol 39:697–709
Congdon CC (1964) The early histologic effects of antigenic stimulation. Arch Pathol 78:83–96
Hanna MG (1964) An autoradiographic study of the germinal center in spleen white pulp during early intervals of the immune response. Lab Invest 13:95–104
Thorbecke GJ, Asofsky RM, Hochwald GM, Siskind GW (1962) Gamma globulin and antibody formation in vitro. III. induction of secondary response at different intervals after the primary; the role of secondary nodules in the preparation for the secondary response. J Exp Med 116:295–310
Hanna M, Netteshe P (1966) Studies of lymphatic tissue germinal centers during an immune reaction – localization of 125I-labeled heterologous and isologous proteins. J Reticuloendothel Soc 3:363
Hanna MG, Szakal AK (1968) Localization of 125I-labeled antigen in germinal centers of mouse spleen: histologic and ultrastructural autoradiographic studies of the secondary immune reaction. J Immunol 101:949–962
Humphrey JH, Askonas BA, Auzins I, Schechter I, Sela M (1967) The localization of antigen in lymph nodes and its relation to specific antibody-producing cells. II. comparison of iodine-125 and tritium labels. Immunology 13:71–86
Nossal GJ, Ada GL, Austin CM (1964) Antigens in immunity. IV. cellular localization of 125-I- and 131-I-labelled flagella in lymph nodes. Aust J Exp Biol Med Sci 42:311–330
Nossal GJ, Abbot A, Mitchell J, Lummus Z (1968) Antigens in immunity. XV. ultrastructural features of antigen capture in primary and secondary lymphoid follicles. J Exp Med 127: 277–290
White R (1963) Functional recognition of immunologically competent cells by means of the fluorescent antibody technique. In: Wolstenholme GEW, Knight J (eds) The immunologically competent cell. Churchill (Ciba Foundation Study Group, No. 16), London, pp 6–19
Tew JG, Mandel TE (1979) Prolonged antigen half-life in the lymphoid follicles of specifically immunized mice. Immunology 37:69–76
Tew JG, Phipps RP, Mandel TE (1980) The maintenance and regulation of the humoral immune response: persisting antigen and the role of follicular antigen-binding dendritic cells as accessory cells. Immunol Rev 53:175–201
Coico RF, Bhogal BS, Thorbecke GJ (1983) Relationship of germinal centers in lymphoid tissue to immunologic memory. VI. transfer of B cell memory with lymph node cells fractionated according to their receptors for peanut agglutinin. J Immunol 131:2254–2257
MacLennan IC, Gray D (1986) Antigen-driven selection of virgin and memory B cells. Immunol Rev 91:61–85
Rouse RV, Reichert RA, Gallatin WM, Weissman IL, Butcher EC (1984) Localization of lymphocyte subpopulations in peripheral lymphoid organs: directed lymphocyte migration and segregation into specific microenvironments. Am J Anat 170:391–405
Weigert MG, Cesari IM, Yonkovich SJ, Cohn M (1970) Variability in the lambda light chain sequences of mouse antibody. Nature 228:1045–1047
Eisen HN, Siskind GW (1964) Variations in affinities of antibodies during the immune response. Biochemistry 3:996–1008
Berek C, Berger A, Apel M (1991) Maturation of the immune response in germinal centers. Cell 67:1121–1129
Jacob J, Kelsoe G, Rajewsky K, Weiss U (1991) Intraclonal generation of antibody mutants in germinal centres. Nature 354:389–392
Jacob J, Przylepa J, Miller C, Kelsoe G (1993) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. the kinetics of V region mutation and selection in germinal center B cells. J Exp Med 178:1293–1307
McHeyzer-Williams MG, McLean MJ, Lalor PA, Nossal GJ (1993) Antigen-driven B cell differentiation in vivo. J Exp Med 178:295–307
Ziegner M, Berek C (1994) Analysis of germinal centres in the immune response to oxazolone. Adv Exp Med Biol 355:201–205
MacLennan IC, Johnson GD, Liu YJ, Gordon J (1991) The heterogeneity of follicular reactions. Res Immunol 142:253–257
Kepler TB, Perelson AS (1993) Somatic hypermutation in B cells: an optimal control treatment. J Theor Biol 164:37–64
Or-Guil M, Wittenbrink N, Weiser AA, Schuchhardt J (2007) Recirculation of germinal center B cells: a multilevel selection strategy for antibody maturation. Immunol Rev 216:130–141
Radmacher MD, Kelsoe G, Kepler TB (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
Liu YJ, Zhang J, Lane PJ, Chan EY, MacLennan IC (1991) 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
Jacob J, Kassir R, Kelsoe G (1991) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. i. the architecture and dynamics of responding cell populations. J Exp Med 173:1165–1175
Paus D, Phan TG, Chan TD, 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
Phan TG, Paus D, Chan TD, Turner ML, Nutt SL, 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
Kroese FG, Wubbena AS, Seijen HG, Nieuwenhuis P (1987) Germinal centers develop oligoclonally. Eur J Immunol 17:1069–1072
Kroese FG, Wubbena AS, Seijen HG, Nieuwenhuis P (1988) The de novo generation of germinal centers is an oligoclonal process. Adv Exp Med Biol 237:245–250
Hermans MH, Wubbena A, Kroese FG, Hunt SV, Cowan R, Opstelten D (1992) The extent of clonal structure in different lymphoid organs. J Exp Med 175:1255–1269
Jacob J, Kelsoe G (1992) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. a common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J Exp Med 176:679–687
Lee SM, Chao A (1994) Estimating population size via sample coverage for closed capture-recapture models. Biometrics 50:88–97
Simon H (1955) On a class of skew distribution functions. Biometrika 42:425–440
Yule G (1925) A mathematical theory of evolution, based on the conclusions of Dr. J.C. Willis, FRS. Philos Trans R Soc Lond B 213:21–87
Hsieh C, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY (2004) Recognition of the peripheral self by naturally arising CD25 + CD4 + T cell receptors. Immunity 21:267–277
Leanderson T, Kllberg E, Gray D (1992) Expansion, selection and mutation of antigen-specific B cells in germinal centers. Immunol Rev 126:47–61
Longo NS, Lipsky PE (2006) Why do B cells mutate their immunoglobulin receptors? Trends Immunol 27:374–380
Moreira JS, Faro J (2006) Re-evaluating the recycling hypothesis in the germinal centre. Immunol Cell Biol 84:404–410
Foote J, Milstein C (1991) Kinetic maturation of an immune response. Nature 352:530–532
Foote J, Eisen HN (1995) Kinetic and affinity limits on antibodies produced during immune responses. Proc Natl Acad Sci USA 92:1254–1256
Ziegner M, Steinhauser G, Berek C (1994) Development of antibody diversity in single germinal centers: selective expansion of high-affinity variants. Eur J Immunol 24:2393–2400
Hanna MG, Congdon CC, Wust CJ (1966) Effect of antigen dose on lymphatic tissue germinal center changes. Proc Soc Exp Biol Med (New York, N.Y.) 121:286–290
Szakal AK, Taylor JK, Smith JP, Kosco MH, Burton GF, Tew JJ (1990) Kinetics of germinal center development in lymph nodes of young and aging immune mice. Anat Rec 227:475–485
Tew JG, DiLosa RM, Burton GF, Kosco MH, Kupp LI, Masuda A, Szakal AK (1992) Germinal centers and antibody production in bone marrow. Immunol Rev 126:99–112
Kosco MH, Burton GF, Kapasi ZF, Szakal AK, Tew JG (1989) Antibody-forming cell induction during an early phase of germinal centre development and its delay with ageing. Immunology 68:312–318
de Vinuesa CG, Cook MC, Ball J, Drew M, Sunners Y, Cascalho M, Wabl M, Klaus GG, MacLennan IC (2000) Germinal centers without T cells. J Exp Med 191:485–494
Gaspal FMC, McConnell FM, Kim M, Gray D, Kosco-Vilbois MH, Raykundalia CR, Botto M, Lane PJL (2006) The generation of thymus-independent germinal centers depends on CD40 but not on CD154, the T cell-derived CD40-ligand. Eur J Immunol 36:1665–1673
Lentz VM, Manser T (2001) Cutting edge: germinal centers can be induced in the absence of T cells. J Immunol 167:15–20
Han S, Hathcock K, Zheng B, Kepler TB, Hodes R, Kelsoe G (1995) Cellular interaction in germinal centers. roles of CD40 ligand and B7-2 in established germinal centers. J Immunol 155:556–567
Han S, Zheng B, Porto JD, Kelsoe G (1995) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. IV. affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance. J Exp Med 182:1635–1644
Porto JMD, Haberman AM, Shlomchik MJ, Kelsoe G (1998) Antigen drives very low affinity B cells to become plasmacytes and enter germinal centers. J Immunol 161:5373–5381
Porto JMD, Haberman AM, Kelsoe G, Shlomchik MJ (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
Arakawa H, Kuma K, Yasuda M, Furusawa S, Ekino S, Yamagishi H (1998) Oligoclonal development of B cells bearing discrete Ig chains in chicken single germinal centers. J Immunol 160:4232–4241
Shlomchik MJ, Watts P, Weigert MG, Litwin S (1998) Clone: a Monte-Carlo computer simulation of B cell clonal expansion, somatic mutation, and antigen-driven selection. Curr Top Microbiol Immunol 229:173–197
Schwickert TA, Lindquist RL, Shakhar G, Livshits G, Skokos D, Kosco-Vilbois MH, Dustin ML, Nussenzweig MC (2007) In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446:83–87
Hauser AE, Shlomchik MJ, Haberman AM (2007) In vivo imaging studies shed light on germinal-centre development. Nat Rev Immunol 7:499–504
Bende RJ, van Maldegem F, Triesscheijn M, Wormhoudt TAM, Guijt R, van Noesel CJM (2007) Germinal centers in human lymph nodes contain reactivated memory B cells. J Exp Med 204:2655–2665
Acknowledgments
This work was supported by grants SAF2007-63152 (MICINN, Spain) and PIRSES-GA-2008-230665 (7th FP, EC) to JF and by the BMBF (grant 0315005B) and the VolkswagenStiftung to MOG. The authors wish to thank R. Ribeiro and V. Ganusov for critical reading of the manuscript.
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Faro, J., Or-Guil, M. (2011). Reassessing Germinal Centre Reaction Concepts. In: Molina-París, C., Lythe, G. (eds) Mathematical Models and Immune Cell Biology. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7725-0_12
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