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dc.contributor.author
Pélissier, Aurélien
dc.contributor.author
Akrout, Youcef
dc.contributor.author
Jahn, Katharina
dc.contributor.author
Kuipers, Jack
dc.contributor.author
Klein, Ulf
dc.contributor.author
Beerenwinkel, Niko
dc.contributor.author
Rodríguez Martínez, María
dc.date.accessioned
2020-06-25T06:04:51Z
dc.date.available
2020-06-24T22:17:03Z
dc.date.available
2020-06-25T06:04:51Z
dc.date.issued
2020-06
dc.identifier.issn
2073-4409
dc.identifier.other
10.3390/cells9061448
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/422277
dc.identifier.doi
10.3929/ethz-b-000422277
dc.description.abstract
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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
MDPI
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
GC
en_US
dc.subject
B cell receptor
en_US
dc.subject
somatic hypermutation
en_US
dc.subject
nucleotide sequence
en_US
dc.subject
antibody affinity
en_US
dc.subject
affinity maturation
en_US
dc.subject
immunoglobulin
en_US
dc.subject
clonal competition
en_US
dc.subject
clonal burst
en_US
dc.subject
clonal dominance
en_US
dc.subject
stochastic models
en_US
dc.subject
affinity models
en_US
dc.title
Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2020-06-10
ethz.journal.title
Cells
ethz.journal.volume
9
en_US
ethz.journal.issue
6
en_US
ethz.pages.start
1448
en_US
ethz.size
25 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Basel
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03790 - Beerenwinkel, Niko / Beerenwinkel, Niko
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03790 - Beerenwinkel, Niko / Beerenwinkel, Niko
ethz.date.deposited
2020-06-24T22:17:11Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2020-06-25T06:05:03Z
ethz.rosetta.lastUpdated
2022-03-29T02:29:17Z
ethz.rosetta.versionExported
true
ethz.COinS
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