TY - JOUR
T1 - Antigen-driven selection in germinal centers as reflected by the shape characteristics of immunoglobulin gene lineage trees
T2 - A large-scale simulation study
AU - Shahaf, Gitit
AU - Barak, Michal
AU - Zuckerman, Neta S.
AU - Swerdlin, Naamah
AU - Gorfine, Malka
AU - Mehr, Ramit
N1 - Funding Information:
The authors are grateful to Pini Akiva, Daniel Dotan and Barak Yaish for help with earlier versions of the simulation, to Drs. Deborah Dunn-Walters and Steven Kleinstein for critical reading of the manuscript, and to Ms. Hanna Edelman for help in manuscript preparation. The work was part of Gitit Shahaf and Michal Barak's studies towards the Ph.D. degree in Bar-Ilan University, and was supported in parts by the following grants (to RM): Israel Science Foundation Grants nos. 759/01-1 and 546, an Israel Cancer Research Fund project grant, a Systems Biology prize grant from Teva Pharmaceuticals, Human Frontiers Science Program—a Young Investigator Grant and a Research Grant, and a Swedish Foundation for Strategic Research Grant funding the Strategic Research Center for studies on Integrative Recognition in the Immune System (IRIS), Karolinska Institute, Stockholm, Sweden. The ministry of Science and Technology Ph.D. scholarship for advancing women in science, The Yeshaya Horowitz Association through the Center for Complexity Science Ph.D. scholarship, Bar Ilan University President's Ph.D. scholarship, and a Dean's excellence Ph.D. scholarship of The Mina and Everard Goodman Faculty of Life Sciences (to NSZ).
PY - 2008/11/21
Y1 - 2008/11/21
N2 - During the immune response, the generation of memory B lymphocytes in germinal centers involves affinity maturation of the cells' antigen receptors, based on somatic hypermutation of receptor genes and antigen-driven selection of the resulting mutants. Affinity maturation is vital for immune protection, and is the basis of humoral immune learning and memory. Lineage trees of somatically hypermutated immunoglobulin genes often serve to qualitatively illustrate claims concerning the dynamics of affinity maturation in germinal centers. Here, we derive the quantitative relationships between parameters characterizing affinity maturation dynamics (proliferation, differentiation and mutation rates, initial affinity of the Ig to the antigen, and selection thresholds) and the mathematical properties of lineage trees, using a computer simulation which combines mathematical models for all mature B cell populations, stochastic models of hypermutation and selection, lineage tree generation and measurement of graphical tree characteristics. We identified seven key lineage tree properties, and found correlations of these with initial clone affinity and with the selection threshold. These two parameters were found to be the main factors affecting lineage tree shapes in both primary and secondary response trees. The results also confirm that recycling from centrocytes back to centroblasts is highly likely.
AB - During the immune response, the generation of memory B lymphocytes in germinal centers involves affinity maturation of the cells' antigen receptors, based on somatic hypermutation of receptor genes and antigen-driven selection of the resulting mutants. Affinity maturation is vital for immune protection, and is the basis of humoral immune learning and memory. Lineage trees of somatically hypermutated immunoglobulin genes often serve to qualitatively illustrate claims concerning the dynamics of affinity maturation in germinal centers. Here, we derive the quantitative relationships between parameters characterizing affinity maturation dynamics (proliferation, differentiation and mutation rates, initial affinity of the Ig to the antigen, and selection thresholds) and the mathematical properties of lineage trees, using a computer simulation which combines mathematical models for all mature B cell populations, stochastic models of hypermutation and selection, lineage tree generation and measurement of graphical tree characteristics. We identified seven key lineage tree properties, and found correlations of these with initial clone affinity and with the selection threshold. These two parameters were found to be the main factors affecting lineage tree shapes in both primary and secondary response trees. The results also confirm that recycling from centrocytes back to centroblasts is highly likely.
KW - B lymphocyte
KW - Germinal center (GC)
KW - Immunoglobulin (Ig) gene lineage trees
KW - Mathematical model
KW - Somatic hypermutation (SHM)
UR - http://www.scopus.com/inward/record.url?scp=54249165359&partnerID=8YFLogxK
U2 - 10.1016/j.jtbi.2008.08.005
DO - 10.1016/j.jtbi.2008.08.005
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C2 - 18786548
AN - SCOPUS:54249165359
SN - 0022-5193
VL - 255
SP - 210
EP - 222
JO - Journal of Theoretical Biology
JF - Journal of Theoretical Biology
IS - 2
ER -