Grant: Project Grant

Antibodies mediate much of the protective effect of most vaccines, are a major line of defence against pathogens, and toxins, and provide immunological memory to prevent reinfections. To be effective, antibodies need to bind to their target pathogenic organism or toxin very tightly, to neutralize them and bring them to other immune cells that can eliminate them. Antibodies are produced by specialized cells named B lymphocytes. The antibodies against any given pathogen originate from relatively few B lymphocytes. This initial response is useful but not optimal for protection. As B lymphocytes multiply, their antibodies evolve to acquire high affinity and the ability to interact with other cells in a relatively short time after the infection or immunization. The mechanisms underlying this improvement in antibody quality operate by making mutations and DNA damage to modify the antibody genes. This is initiated by a mutagenic enzyme named AID that is only expressed in B lymphocytes. Unfortunately, as a side effect, AID can change other genes and predispose the B cells to become lymphoma. We study the mechanisms that regulate AID activity, enabling an efficient antibody response while minimizing the collateral damage. For this project, we did a large-scale survey of the proteins that could regulate the activity of AID. We have identified several candidates that regulate the ability of AID to make mutations at the antibody genes but also elsewhere in the genome. Using B lymphocytes and mouse models of immunization, combined with biochemical and molecular biology techniques, we will understand how these proteins regulate AID and their importance for antibody responses. Harnessing these new mechanisms could help design better immunization strategies, or defects in the proteins involved could explain immunodeficiencies.