Grant: Project Grant

Antibodies are a major component of the human immune system. A large repertoire of specialized cells named B-lymphocytes, each producing a different antibody, are constantly renewed to be able to detect any of innumerable and constantly evolving pathogens. The initial recognition of a pathogen, by the antibody on the surface of a B-lymphocyte, signals the onset of changes in the genes encoding the antibody, which will allow improving its affinity and effectivity to eliminate the infection. Most vaccination strategies rely on stimulating the B-lymphocytes that produce antibodies against known pathogens so that they expand and undergo the AID-mediated antibody improvements before any exposure to the actual pathogen. The genetic mechanisms that shape the antibodies and mediate immunity are initiated by an enzyme named AID. As a side effect of changing the antibody genes, AID can also cause collateral genetic damage. This can predispose to cancer or negatively affect the B-lymphocyte's ability to multiply, which is critical for the process of generating a protective response. We study the mechanisms that balance these beneficial and detrimental effects of AID. We investigate how AID reaches the genome and how much it works once there, which have a direct impact on the antibody response. On one side, these mechanisms need to allow sufficient AID activity to produce useful antibodies. On the other hand, they need to protect the genome from excessive damage. Our results would allow explaining the cause of immunodeficiency when the mechanisms we study do not work and enable manipulations for therapeutic applications. Salient examples would be to treat autoimmune diseases mediated by antibodies, boosting the efficacy of immunization in aged people, or enhancing vaccination to increase the chances of generating infrequent antibodies, such as those that neutralize rapidly evolving viruses.