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Front Immunol. 2018 Sep 25;9:2020. doi: 10.3389/fimmu.2018.02020. eCollection 2018.

Computer Simulation of Multi-Color Brainbow Staining and Clonal Evolution of B Cells in Germinal Centers.

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Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany.
Centre for Individualised Infection Medicine, Hanover, Germany.
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, United States.


Clonal evolution of B cells in germinal centers (GCs) is central to affinity maturation of antibodies in response to pathogens. Permanent or tamoxifen-induced multi-color recombination of B cells based on the brainbow allele allows monitoring the degree of color dominance in the course of the GC reaction. Here, we use computer simulations of GC reactions in order to replicate the evolution of color dominance in silico and to define rules for the interpretation of these data in terms of clonal dominance. We find that a large diversity of clonal dominance is generated in simulated GCs in agreement with experimental results. In the extremes, a GC can be dominated by a single clone or can harbor many co-existing clones. These properties can be directly derived from the measurement of color dominance when all B cells are stained before the GC onset. Upon tamoxifen-induced staining, the correlation between clonal structure and color dominance depends on the timing and duration of the staining procedure as well as on the total number of stained B cells. B cells can be stained with 4 colors if a single brainbow allele is used, using both alleles leads to 10 different colors. The advantage of staining with 10 instead of 4 colors becomes relevant only when the 10 colors are attributed with rather similar probability. Otherwise, 4 colors exhibit a comparable predictive power. These results can serve as a guideline for future experiments based on multi-color staining of evolving systems.


brainbow; clonal selection; computer simulation; germinal center; mathematical modeling; multiphoton imaging; sequencing

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