B-cell clonality and DNA Repair in the germinal center

This thesis explores B-cell responses in germinal centers (GCs), transient structures in lymphoid organs crucial for antibody diversification. We analyzed B-cell receptor repertoires in individual GCs within a human lymph node, revealing marked heterogeneity and shared B-cell clones across GCs. This indicates migration and re-engagement of antigen-experienced B cells, suggesting convergent evolution of individual GCs, aligning with mouse studies.
Currently, there is little consensus on how to exactly define a B-cell clone. We explored different definitions of B-cell clones and and assessed their impact on B-cell diversity metrics. We propose that intermediate stringency in clonal grouping resulted in the most biologically plausible results.
Additionally, we developed a multiscale computational model to simulate B-cell (clonal) dynamics in the GC. The simulations of the model are in good agreement with experimental data from individual GCs and can potentially bridge the gap between experimental data and computational immunology.
Furthermore, we investigated the E3 ubiquitin ligase Huwe1's role in B-cell function. Our results demonstrate Huwe1's essential role in B-cell proliferation, class switch recombination, and somatic hypermutation by regulating the C-MYC transcription factor's output.
This thesis enhances our understanding of B-cell biology, offering new insights into immune responses and adaptive immunity regulation. Our methodological approaches and findings could potentially be applied for future diagnostic and therapeutic benefits in immunology.