INVESTIGATING IMMUNE SYSTEM REGULATION THROUGH CROSS-DISEASE GENETIC ANALYSIS AND B CELL FATE DECISIONS

Autoimmune diseases cluster into families, suggesting a shared genetic mechanism. Common genetic causes might indicate shared pathogenic mechanisms that cross-disease therapies could target. In this thesis, I investigated the genetic relationship among nine immune-mediated diseases. I identified three different sets of immune-mediated diseases that shared genetic susceptibilities. Using genomic structural equation modelling, I showed that three groups represented three latent shared genetic structures: gastrointestinal tract diseases, rheumatic and systemic diseases, and allergic diseases. Surprisingly, only 5% of the susceptibility genomic regions were shared among the groups, suggesting that the three latent structures were driven by different genetic components. I then sought to link the associated genomic regions to functional pathways for each group, and I found that they converged in altering the same immune-mediated pathways in T cells. I found evidence that showed the causal role of 46 genes in predisposing to the three disease groups; eight of these genes are already targeted by treatments in autoimmunity and could be exploited for drug repurposing. Supporting preclinical data with genetic evidence can significantly increase the chance of developing a successful drug. The prioritised causal genes and cell-states will be a resource for downstream validation studies. The IL-21 and IL-2 locus was the only one shared between the three groups of autoimmune diseases. IL-21 is a key cytokine in the crosstalk between B and T cells. Therefore, characterising the genetic and molecular mechanisms governing B cell activation is necessary to understand immune-mediated diseases and immune system biology. To study the role of B cell activation and diversification in autoimmunity, I established an in vitro model of B cell activation. I mapped the gene regulatory networks (GRNs) controlling naïve and memory B cell differentiation. I found that similar GRNs govern naïve and memory B cell activation during the early stages of activation. At later stages, naïve B cells could acquire two divergent GRNs, promoting differentiation into either plasma cells or GC cells. However, memory B cells engaged almost exclusively the plasma cell GRNs. By perturbing the GRNs with CRISPR knock-outs, I showed that IRF4 was necessary for acquiring both GC and plasma cell fates. Further, knock-out of the GRNs governing the plasma cell fate rewired the memory B cell transcriptome and induced the emergence of GC cells. Finally, I studied the clonal control of gene expression and found heritable transcriptional programs among sister cells. These results illustrate the heterogeneity of differentiation outcomes of human naïve and memory B cells, furthering our understanding of GRNs driving B cell fate choices.