Mathematical modelling of a germinal center
"Mathematical modelling of a germinal center shows that B-cell abundancy and affinity within expanded clonal families do not correlate: implications for repertoire sequencing."
Immunoglobulin repertoire sequencing strategies are successfully applied to identify expanded antigen-activated B-cell clones that play a role in the pathogenesis of immune disorders. These clones comprise lineages of subclones comprising variants within a VJ family produced by somatic hypermutation. B-cell receptor binding affinities for the antigen of these subclones are higher than affinities of the naïve B cells in the background population, which is a direct consequence of the higher initial affinity of the activated B-cell(s) and the subsequent affinity maturation process in the germinal centre (GC). However, repertoire sequencing only provides information about subclone abundancies and not about their affinities. Consequently, although repertoire sequencing successfully identifies clones involved in disease, the selection of the most abundant (i.e., expanded) subclone(s) within of a clonal family may not correspond to the highest affinity subclone. Unfortunately, the determination of affinities of many subclones within a clonal family is virtually impossible with current experimental technologies and, consequently, the relation between abundancy and affinity remains to be established. However, knowledge about affinities within clonal families would likely improve the selection of relevant subclones for further characterization and antigen screening. Therefore, to gain insight in the affinity distribution among (un)expanded subclones we developed a computational model that simulates affinity maturation in a single GC while tracking individual subclones in terms of abundancy and affinity. We show that the model correctly captures the overall GC dynamics, and that the amount of expansion is qualitatively comparable to expansion observed from B cells isolated from a human lymph node from a healthy individual. Analysis of the fraction of high- and low-affinity subclones among of the unexpanded and expanded subclones reveals that both compartments contain a mixture of high- and low-affinity B cells. Thus, our model suggests that highly abundant subclones identified by repertoire sequencing are not necessarily the highest affinity B cells within their lineage. We conclude that although selection of highly abundant subclones from B cell repertoires provides us with B cells involved in (auto)immune disorders, the utility of repertoire sequencing might be even further improved by following selection strategies that do not merely consider subclone abundance.
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