Grant: Project Grant

Antibodies protect us from pathogens and are a primary weapon used by our immune system. In order from antibodies to be maximally effective, they must be optimally evolved towards their target. This process of evolution takes place in defined structures called germinal centres (GCs). While this process is incredibly rapid and efficient, it comes at a cost; the cells in which antibodies originate (B cells) need to turn on an enzyme that mutates their DNA, which greatly increases the chances of cancer-causing mutations. Moreover, if these antibodies inadvertently recognize the host, it can result in an autoimmune condition. Therefore, tight control of GCs is essential for human health. We have been studying a protein receptor on B cells involved in regulating the GC, which is called Siglec-G (Siglec-10 in humans). Loss of Siglec-G leads to an out-of-control GC, which includes autoantibodies and lymphoma. This project aims to establish: (i) the precise outcomes of a GC when the function of Siglec-G is blocked; (ii) how Siglec-G regulates the GC through interactions with a key partner cell called T follicular helper cells; (iii) whether function of Siglec-G is conserved with Siglec-10 in humans. Overall, new insights from this project can enable new innovative approaches to modulate immune responses in autoimmunity and cancer, while providing fundamental information about how to design more effective vaccines.