Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts
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 affi...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-06-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/9/6/1448 |
| _version_ | 1797565600011124736 |
|---|---|
| author | Aurélien Pélissier Youcef Akrout Katharina Jahn Jack Kuipers Ulf Klein Niko Beerenwinkel María Rodríguez Martínez |
| author_facet | Aurélien Pélissier Youcef Akrout Katharina Jahn Jack Kuipers Ulf Klein Niko Beerenwinkel María Rodríguez Martínez |
| author_sort | Aurélien Pélissier |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T19:15:26Z |
| format | Article |
| id | doaj.art-d9c27d7c0aad4fdba72f238dbf81270e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:15:26Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-d9c27d7c0aad4fdba72f238dbf81270e2023-11-20T03:28:52ZengMDPI AGCells2073-44092020-06-0196144810.3390/cells9061448Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal BurstsAurélien Pélissier0Youcef Akrout1Katharina Jahn 2Jack Kuipers 3Ulf Klein 4Niko Beerenwinkel5María Rodríguez Martínez 6IBM Research Zurich, 8803 Rüschlikon, SwitzerlandÉcole Normale Supérieure, 75005 Paris, FranceDepartment of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, SwitzerlandDepartment of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, SwitzerlandLeeds Institute of Medical Research at St. James’s, University of Leeds, Leeds LS9 7TF, UKDepartment of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, SwitzerlandIBM Research Zurich, 8803 Rüschlikon, SwitzerlandGerminal 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.https://www.mdpi.com/2073-4409/9/6/1448GCB cell receptorsomatic hypermutationnucleotide sequenceantibody affinityaffinity maturation |
| spellingShingle | Aurélien Pélissier Youcef Akrout Katharina Jahn Jack Kuipers Ulf Klein Niko Beerenwinkel María Rodríguez Martínez Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts Cells GC B cell receptor somatic hypermutation nucleotide sequence antibody affinity affinity maturation |
| title | Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts |
| title_full | Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts |
| title_fullStr | Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts |
| title_full_unstemmed | Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts |
| title_short | Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts |
| title_sort | computational model reveals a stochastic mechanism behind germinal center clonal bursts |
| topic | GC B cell receptor somatic hypermutation nucleotide sequence antibody affinity affinity maturation |
| url | https://www.mdpi.com/2073-4409/9/6/1448 |
| work_keys_str_mv | AT aurelienpelissier computationalmodelrevealsastochasticmechanismbehindgerminalcenterclonalbursts AT youcefakrout computationalmodelrevealsastochasticmechanismbehindgerminalcenterclonalbursts AT katharinajahn computationalmodelrevealsastochasticmechanismbehindgerminalcenterclonalbursts AT jackkuipers computationalmodelrevealsastochasticmechanismbehindgerminalcenterclonalbursts AT ulfklein computationalmodelrevealsastochasticmechanismbehindgerminalcenterclonalbursts AT nikobeerenwinkel computationalmodelrevealsastochasticmechanismbehindgerminalcenterclonalbursts AT mariarodriguezmartinez computationalmodelrevealsastochasticmechanismbehindgerminalcenterclonalbursts |