Immune system learning and memory quantified by graphical analysis of B-lymphocyte phylogenetic trees.

The immune system learns from its encounters with pathogens and memorizes its experiences. One of the mechanisms it uses for this purpose is the intra-individual evolution of antigen receptors on B lymphocytes, achieved via hypermutation and selection of antigen receptor variable region genes during an immune response. We have developed a novel method for analyzing the graphical properties of phylogenetic trees of receptor genes which have been mutated and selected during an immune response. In the study presented here, we address the artifacts introduced by experimental methods of cell collection for DNA analysis, the meaning of each parameter measured on the tree graphs, and the differences between the dynamics of the humoral immune response in different lymphoid tissues.

[1]  Thomas B. Kepler,et al.  Enhanced Evolvability in Immunoglobulin V Genes Under Somatic Hypermutation , 1999, Journal of Molecular Evolution.

[2]  T. Kepler.  Codon bias and plasticity in immunoglobulins. , 1997, Molecular biology and evolution.

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

[4]  S. Litwin,et al.  Models for antigen receptor gene rearrangement. II. Multiple rearrangement in the TCR: allelic exclusion or inclusion? , 1999, Journal of immunology.

[5]  K. Rajewsky,et al.  Natural occurrence and origin of somatically mutated memory B cells in mice , 1992, The Journal of experimental medicine.

[6]  U. Storb,et al.  Effects on Somatic Hypermutation: Intact Primary Mechanism Accompanied by Secondary Modifications , 1999 .

[7]  M. Wabl,et al.  Hypermutation in antibody affinity maturation. , 1999, Current opinion in immunology.

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

[9]  T. Manser,et al.  Evolution of antibody structure during the immune response. The differentiative potential of a single B lymphocyte , 1989, The Journal of experimental medicine.

[10]  R. Mage,et al.  Generation of heterogeneous rabbit anti‐DNP antibodies by gene conversion and hypermutation of rearranged VL and VH genes during clonal expansion of B cells in splenic germinal centers , 2000, European journal of immunology.

[11]  C. Kocks,et al.  Stepwise intraclonal maturation of antibody affinity through somatic hypermutation. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Shlomchik,et al.  Clone: a Monte-Carlo computer simulation of B cell clonal expansion, somatic mutation, and antigen-driven selection. , 1998, Current topics in microbiology and immunology.

[13]  T B Kepler,et al.  Statistical inference of sequence-dependent mutation rates. , 2001, Current opinion in genetics & development.

[14]  A S Perelson,et al.  Somatic mutation leads to efficient affinity maturation when centrocytes recycle back to centroblasts. , 1997, Journal of immunology.

[15]  S. Litwin,et al.  Models for antigen receptor gene rearrangement. I. Biased receptor editing in B cells: implications for allelic exclusion. , 1999, Journal of immunology.

[16]  K. Rajewsky,et al.  Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. , 1993, The EMBO journal.

[17]  T. Kepler,et al.  Genetic plasticity of V genes under somatic hypermutation: statistical analyses using a new resampling-based methodology. , 1999, Genome research.

[18]  R. Mage,et al.  Analyses of single B cells by polymerase chain reaction reveal rearranged VH with germline sequences in spleens of immunized adult rabbits: implications for B cell repertoire maintenance and renewal. , 1998, Journal of immunology.

[19]  D. Winter,et al.  Dual enigma of somatic hypermutation of immunoglobulin variable genes: targeting and mechanism , 1998, Immunological reviews.

[20]  Ramit Mehr,et al.  Age‐ and tissue‐specific differences in human germinal center B cell selection revealed by analysis of IgVH gene hypermutation and lineage trees , 2002, European journal of immunology.

[21]  J L van Hemmen,et al.  Memory in idiotypic networks due to competition between proliferation and differentiation. , 1993, Bulletin of mathematical biology.

[22]  C. Milstein,et al.  Memory in the B-cell compartment: antibody affinity maturation. , 2000, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[23]  D. Nicolae,et al.  Effects of sequence and structure on the hypermutability of immunoglobulin genes. , 2002, Immunity.

[24]  P J Ciclitira,et al.  Immunoglobulin genes from human duodenal and colonic plasma cells are mutated. , 1997, Biochemical Society transactions.

[25]  R Mehr,et al.  Modeling the meta-dynamics of lymphocyte repertoires. , 2001, Archivum immunologiae et therapiae experimentalis.

[26]  Franco Celada,et al.  Affinity maturation and hypermutation in a simulation of the humoral immune response , 1996, European journal of immunology.

[27]  Michael Meyer-Hermann,et al.  A mathematical model for the germinal center morphology and affinity maturation. , 2002, Journal of theoretical biology.

[28]  G. Kelsoe.  Life and death in germinal centers (redux). , 1996, Immunity.

[29]  R Mehr,et al.  Reconciling repertoire shift with affinity maturation: the role of deleterious mutations. , 1999, Journal of immunology.

[30]  P. Isaacson,et al.  Sequence analysis of human IgVH genes indicates that ileal lamina propria plasma cells are derived from Peyer's patches , 1997, European journal of immunology.

[31]  M. Shlomchik,et al.  Antigen drives very low affinity B cells to become plasmacytes and enter germinal centers. , 1998, Journal of immunology.

[32]  Paolo Casali,et al.  Somatic immunoglobulin hypermutation. , 2002, Current opinion in immunology.

[33]  Tilo Beyer,et al.  A possible role of chemotaxis in germinal center formation. , 2002, International immunology.

[34]  G. Kelsoe,et al.  Facultative role of germinal centers and T cells in the somatic diversification of IgVH genes , 1995, The Journal of experimental medicine.

[35]  Thomas B. Kepler,et al.  The Nucleotide-Replacement Spectrum Under Somatic Hypermutation Exhibits Microsequence Dependence That Is Strand-Symmetric and Distinct from That Under Germline Mutation1 , 2000, The Journal of Immunology.

[36]  P. Lipsky,et al.  Analysis of the targeting of the hypermutational machinery and the impact of subsequent selection on the distribution of nucleotide changes in human V rearrangements , 1998, Immunological reviews.

[37]  R. Mage,et al.  Gene conversion and hypermutation during diversification of VH sequences in developing splenic germinal centers of immunized rabbits. , 1999, Journal of immunology.

[38]  P. Lipsky,et al.  Somatic hypermutation of VκJκ rearrangements: targeting of RGYW motifs on both DNA strands and preferential selection of mutated codons within RGYW motifs , 1999 .

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

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

[41]  Ramit Mehr,et al.  Analysis of Mutational Lineage Trees from Sites of Primary and Secondary Ig Gene Diversification in Rabbits and Chickens1 , 2004, The Journal of Immunology.

[42]  S H Kleinstein,et al.  Toward quantitative simulation of germinal center dynamics: biological and modeling insights from experimental validation. , 2001, Journal of theoretical biology.

[43]  T. Kepler,et al.  Plasticity under somatic mutation in antigen receptors. , 1998, Current topics in microbiology and immunology.

[44]  J. Spencer,et al.  Characteristics of sequences around individual nucleotide substitutions in IgVH genes suggest different GC and AT mutators. , 1999, Journal of immunology.

[45]  G. Kelsoe,et al.  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 , 1993, The Journal of experimental medicine.

[46]  C. Berek,et al.  Development of antibody diversity in single germinal centers: selective expansion of high‐affinity variants , 1994, European journal of immunology.

[47]  R. Mehr,et al.  Models for Antigen Receptor Gene Rearrangement. III. Heavy and Light Chain Allelic Exclusion1 , 2003, The Journal of Immunology.

[48]  César Milstein,et al.  Monitoring and interpreting the intrinsic features of somatic hypermutation , 1998, Immunological reviews.

[49]  T. Manser,et al.  Contrasting the in situ behavior of a memory B cell clone during primary and secondary immune responses. , 1999, Journal of immunology.

[50]  T. Honjo,et al.  Molecular mechanism of class switch recombination: linkage with somatic hypermutation. , 2002, Annual review of immunology.

[51]  L. Boursier,et al.  Base-specific sequences that bias somatic hypermutation deduced by analysis of out-of-frame human IgVH genes. , 1998, Journal of immunology.

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

[53]  P. Lipsky,et al.  Targeting and selection of mutations in human Vλ rearrangements , 2000 .

[54]  R. Mage,et al.  Distinct Clonal Ig Diversification Patterns in Young Appendix Compared to Antigen-Specific Splenic Clones , 2002, The Journal of Immunology.