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Open AccessArticle

Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts

1
IBM Research Zurich, 8803 Rüschlikon, Switzerland
2
Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland
3
École Normale Supérieure, 75005 Paris, France
4
Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds LS9 7TF, UK
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(6), 1448; https://doi.org/10.3390/cells9061448
Received: 15 April 2020 / Revised: 29 May 2020 / Accepted: 8 June 2020 / Published: 10 June 2020
(This article belongs to the Special Issue Quantitative Models of Autoimmunity)
Germinal centers (GCs) are specialized compartments within the secondary lymphoid organs where B cells proliferate, differentiate, and mutate their antibody genes in response to the presence of foreign antigens. Through the GC lifespan, interclonal competition between B cells leads to increased affinity of the B cell receptors for antigens accompanied by a loss of clonal diversity, although the mechanisms underlying clonal dynamics are not completely understood. We present here a multi-scale quantitative model of the GC reaction that integrates an intracellular component, accounting for the genetic events that shape B cell differentiation, and an extracellular stochastic component, which accounts for the random cellular interactions within the GC. In addition, B cell receptors are represented as sequences of nucleotides that mature and diversify through somatic hypermutations. We exploit extensive experimental characterizations of the GC dynamics to parameterize our model, and visualize affinity maturation by means of evolutionary phylogenetic trees. Our explicit modeling of B cell maturation enables us to characterise the evolutionary processes and competition at the heart of the GC dynamics, and explains the emergence of clonal dominance as a result of initially small stochastic advantages in the affinity to antigen. Interestingly, a subset of the GC undergoes massive expansion of higher-affinity B cell variants (clonal bursts), leading to a loss of clonal diversity at a significantly faster rate than in GCs that do not exhibit clonal dominance. Our work contributes towards an in silico vaccine design, and has implications for the better understanding of the mechanisms underlying autoimmune disease and GC-derived lymphomas. View Full-Text
Keywords: GC; B cell receptor; somatic hypermutation; nucleotide sequence; antibody affinity; affinity maturation; immunoglobulin; clonal competition; clonal burst; clonal dominance; stochastic models; affinity models GC; B cell receptor; somatic hypermutation; nucleotide sequence; antibody affinity; affinity maturation; immunoglobulin; clonal competition; clonal burst; clonal dominance; stochastic models; affinity models
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MDPI and ACS Style

Pélissier, A.; Akrout, Y.; Jahn , K.; Kuipers , J.; Klein , U.; Beerenwinkel, N.; Rodríguez Martínez , M. Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts. Cells 2020, 9, 1448. https://doi.org/10.3390/cells9061448

AMA Style

Pélissier A, Akrout Y, Jahn  K, Kuipers  J, Klein  U, Beerenwinkel N, Rodríguez Martínez  M. Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts. Cells. 2020; 9(6):1448. https://doi.org/10.3390/cells9061448

Chicago/Turabian Style

Pélissier, Aurélien; Akrout, Youcef; Jahn , Katharina; Kuipers , Jack; Klein , Ulf; Beerenwinkel, Niko; Rodríguez Martínez , María. 2020. "Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts" Cells 9, no. 6: 1448. https://doi.org/10.3390/cells9061448

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