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Computational exploration of B memory cell differentiation

Author(s):

M. Thomas
Conference/Journal:

Master Thesis, SS17
Abstract:

The causes and mechanisms involved in the differentiation of B memory cells are still poorly understood, partly due to a lack of reliable experimental protocols to identify and study them. The last five years have seen an increasing development of such exper-imental methods and a plethora of experimental results [47, 31, 14, 39] on B memory cell differentiation. They were accompanied by several competing theories on the fate selection mechanisms of germinal center B cells [39, 14, 2, 41]. In this project, I built an extracellular model of the germinal center dynamics and an intracellular model of B cells to investigate three of those theories. In doing so, I created an extension to the Gillespie algorithm [17] that allows efficient simulation of individual properties un-der specific circumstances and I suggested an improved model of the shape of antibodies.

Newer evidence showed that the B cell fate is heavily dependent on the age of the germinal center [47]. This already dismisses two out of the three theories, since they are based on mechanisms that are time-invariant over the lifetime of a germinal center. The remaining theory suggests that B cell fate is dependent on the affinity of the B cell’s B cell receptor (BCR) [39]. I combined the findings of Mar´ıa Rodr´ıguez Mart´ınez’s previous paper [26] with new evidence [36, 32], which results in a model predicting ex-actly that dependence of fate selection on affinity suggested by the remaining theory. Moreover, it is the first model capable of explaining the evidence that fate selection is dependent on germinal center age [47]. Subsequently, I optimized parameters for the model and contrasted their stable regions with parameters derived from the literature. From that, I was able to identify agreements and differences between model and litera-ture that may suggest future research opportunities.

Finally, I returned to the B cell fate selection theory about asymmetric cell division [2, 41]. While asymmetric cell division cannot explain how the fate selection changes over time, it may still influence its dynamics. However, I found that asymmetric cell division did not influence the performance of affinity maturation positively or negatively, and may therefore coexist with the given model. This is consistent with previous speculation that asymmetric cell division may not explain B cell fate selection and may have a yet undiscovered, different purpose [15].

Supervisors: John Lygeros, Maria Rodriguez Martinez

Year:

2017
Type of Publication:

(12)Diploma/Master Thesis
Supervisor:



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% Autogenerated BibTeX entry
@PhdThesis { Xxx:2017:IFA_5706
}
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