A theory of germinal center B cell selection, division, and exit.

High-affinity antibodies are generated in germinal centers in a process involving mutation and selection of B cells. Information processing in germinal center reactions has been investigated in a number of recent experiments. These have revealed cell migration patterns, asymmetric cell divisions, and cell-cell interaction characteristics, used here to develop a theory of germinal center B cell selection, division, and exit (the LEDA model). According to this model, B cells selected by T follicular helper cells on the basis of successful antigen processing always return to the dark zone for asymmetric division, and acquired antigen is inherited by one daughter cell only. Antigen-retaining B cells differentiate to plasma cells and leave the germinal center through the dark zone. This theory has implications for the functioning of germinal centers because compared to previous models, high-affinity antibodies appear one day earlier and the amount of derived plasma cells is considerably larger.

[1]  C. Berek,et al.  Maturation of the immune response in germinal centers , 1991, Cell.

[2]  Michael Meyer-Hermann,et al.  University of Birmingham Deriving a germinal center lymphocyte migration model from two-photon data , 2008 .

[3]  Dagmar Iber,et al.  An analysis of B cell selection mechanisms in germinal centers. , 2006, Mathematical medicine and biology : a journal of the IMA.

[4]  K. Toellner,et al.  T Helper 1 (th1) and Th2 Characteristics Start to Develop during T Cell Priming and Are Associated with an Immediate Ability to Induce Immunoglobulin Class Switching , 1998 .

[5]  Jason G. Cyster,et al.  Imaging of Germinal Center Selection Events During Affinity Maturation , 2007, Science.

[6]  Clemens Utzny,et al.  Immunological synapses are versatile structures enabling selective T cell polarization. , 2005, Immunity.

[7]  M. Nussenzweig,et al.  A dynamic T cell–limited checkpoint regulates affinity-dependent B cell entry into the germinal center , 2011, The Journal of experimental medicine.

[8]  I. Maclennan,et al.  Quantitative analysis of molecules which distinguish functional compartments within germinal centers , 1993, European journal of immunology.

[9]  H. Jäck,et al.  Stages of Germinal Center Transit Are Defined by B Cell Transcription Factor Coexpression and Relative Abundance , 2006, The Journal of Immunology.

[10]  Joost B. Beltman,et al.  B cells within germinal centers migrate preferentially from dark to light zone , 2011, Proceedings of the National Academy of Sciences.

[11]  J. Banchereau,et al.  The differences in survival and phenotype between centroblasts and centrocytes. , 1994, Advances in experimental medicine and biology.

[12]  K. Toellner,et al.  Low-level Hypermutation in T Cell–independent Germinal Centers Compared with High Mutation Rates Associated with T Cell–dependent Germinal Centers , 2002, The Journal of experimental medicine.

[13]  M. Beksac,et al.  T-helper-1 (Th1) and Th2 cytokines after allogeneic hematopoietic stem cell transplantation (allo-HSCT). , 2008, Turkish journal of haematology : official journal of Turkish Society of Haematology.

[14]  I. Maclennan,et al.  Germinal centres in T-cell-dependent antibody responses. , 1992, Immunology today.

[15]  Michael Meyer-Hermann,et al.  Antigen Feast or Famine , 2012, Science.

[16]  K. G. Smith,et al.  Dissecting affinity maturation: a model explaining selection of antibody-forming cells and memory B cells in the germinal centre. , 2000, Immunology today.

[17]  Dagmar Iber,et al.  A mathematical model for germinal centre kinetics and affinity maturation. , 2002, Journal of theoretical biology.

[18]  J. Goldman,et al.  B Cell Ligand Discrimination Through a Spreading and Contraction Response , 2006, Science.

[19]  R. D. de Boer,et al.  A mathematical model on germinal center kinetics and termination. , 1999, Journal of immunology.

[20]  J. Macartney,et al.  Cell kinetics of the germinal center reaction ‐ a stathmokinetic study , 1992, European journal of immunology.

[21]  Michael P. Cancro,et al.  Asymmetric B Cell Division in the Germinal Center Reaction , 2012, Science.

[22]  G. Oster,et al.  Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self-non-self discrimination. , 1979, Journal of theoretical biology.

[23]  Mark J. Miller,et al.  Two-Photon Imaging of Lymphocyte Motility and Antigen Response in Intact Lymph Node , 2002, Science.

[24]  K. Calame,et al.  Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. , 2006, Immunity.

[25]  Garnett Kelsoe,et al.  Predicted and inferred waiting times for key mutations in the germinal centre reaction: Evidence for stochasticity in selection , 1998, Immunology and cell biology.

[26]  Jun Zhang,et al.  Sites of specific B cell activation in primary and secondary responses to T cell‐dependent and T cell‐independent antigens , 1991, European journal of immunology.

[27]  Ramit Mehr,et al.  The Dynamics of Germinal Centre Selection as Measured by Graph-Theoretical Analysis of Mutational Lineage Trees , 2002, Developmental immunology.

[28]  M. Hanna.  AN AUTORADIOGRAPHIC STUDY OF THE GERMINAL CENTER IN SPLEEN WHITE PULP DURING EARLY INTERVALS OF THE IMMUNE RESPONSE. , 1964, Laboratory investigation; a journal of technical methods and pathology.

[29]  G. Nossal,et al.  The molecular and cellular basis of affinity maturation in the antibody response , 1992, Cell.

[30]  A S Perelson,et al.  Cyclic re-entry of germinal center B cells and the efficiency of affinity maturation. , 1993, Immunology today.

[31]  M. Waisberg,et al.  Endocytosed BCRs sequentially regulate MAPK and Akt signaling pathways from intracellular compartments , 2011, Nature Immunology.

[32]  Hanna Mg.  AN AUTORADIOGRAPHIC STUDY OF THE GERMINAL CENTER IN SPLEEN WHITE PULP DURING EARLY INTERVALS OF THE IMMUNE RESPONSE. , 1964 .

[33]  M. Diamond,et al.  Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants , 2011, The Journal of experimental medicine.

[34]  Philip K Maini,et al.  Cutting Edge: Back to “One-Way” Germinal Centers1 , 2005, The Journal of Immunology.

[35]  I. Maclennan,et al.  Is rapid proliferation in B centroblasts linked to somatic mutation in memory B cell clones? , 1988, Immunology letters.

[36]  A. Deutsch,et al.  Recycling probability and dynamical properties of germinal center reactions. , 2001, Journal of theoretical biology.

[37]  Facundo D. Batista,et al.  Asymmetric Segregation of Polarized Antigen on B Cell Division Shapes Presentation Capacity , 2012, Science.

[38]  C. Milstein,et al.  Mutation Drift and Repertoire Shift in the Maturation of the Immune Response , 1987, Immunological reviews.

[39]  Michael L. Dustin,et al.  In vivo imaging of germinal centres reveals a dynamic open structure , 2007, Nature.

[40]  Klaus Rajewsky,et al.  Intraclonal generation of antibody mutants in germinal centres , 1991, Nature.

[41]  J. Baldridge,et al.  Monophosphoryl lipid A (MPL) formulations for the next generation of vaccines. , 1999, Methods.

[42]  M. Meyer-Hermann,et al.  The type of seeder cells determines the efficiency of germinal center reactions , 2002, Bulletin of mathematical biology.

[43]  Michael Meyer-Hermann,et al.  Germinal centres seen through the mathematical eye: B-cell models on the catwalk. , 2009, Trends in immunology.

[44]  M. Kosco-Vilbois.  Are follicular dendritic cells really good for nothing? , 2003, Nature Reviews Immunology.

[45]  Michael Meyer-Hermann,et al.  Germinal Center Dynamics Revealed by Multiphoton Microscopy with a Photoactivatable Fluorescent Reporter , 2010, Cell.

[46]  Anja E Hauser,et al.  Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. , 2007, Immunity.

[47]  N. Fazilleau,et al.  Plasma cells negatively regulate the follicular helper T cell program , 2010, Nature Immunology.

[48]  Michael Meyer-Hermann,et al.  A concerted Action of B Cell Selection Mechanisms , 2007, Adv. Complex Syst..

[49]  Jhagvaral Hasbold,et al.  Activation-Induced B Cell Fates Are Selected by Intracellular Stochastic Competition , 2012, Science.

[50]  I. Maclennan,et al.  Mechanism of antigen-driven selection in germinal centres , 1989, Nature.

[51]  Philip D. Hodgkin,et al.  Quantitative Regulation of B Cell Division Destiny by Signal Strength , 2008, The Journal of Immunology.

[52]  Kenneth G. C. Smith,et al.  The extent of affinity maturation differs between the memory and antibody‐forming cell compartments in the primary immune response , 1997, The EMBO journal.

[53]  C. Berek,et al.  The dynamic structure of the germinal center. , 1998, Immunology today.