Diversification des anticorps par désamination de l'ADN dans le centre germinatif

 

Javier Marcelo Di Noia

Institut de recherches cliniques de Montréal [IRCM]

 

Domaine : maladies infectieuses et immunitaires

Programme Chercheurs-boursiers de mérite

Concours 2019-2020

To be able to defend us against most pathogens, the human immune system needs to produce specific antibodies of high affinity and with functions tailored to each individual threat. This extraordinary capacity is mediated by mechanisms that change (mutate) the antibody genes to permit the selection of the best antibody variants. Importantly, the same mechanisms that improve the antibodies can sometimes fail and cause immunodeficiency, or malfunction and predispose to lymphoma or leukemia. This is an inevitable trade-off of the way our sophisticated and highly effective immune system evolved, but it has a real impact on human health in our days.

To pinpoint the causes and develop remedies for these diseases, we must understand the normal functioning of the mechanisms that change and select antibodies. The major area of our research program studies the function and regulation of the enzyme that mutates the antibody genes (named AID), to understand how it works and what limits its potentially pathological side effects. We also study how the mechanisms that change the antibody genes influence the biology of the cells that produce antibodies in response to immunization or infection.

Our research in this area has implication for understanding human diseases and improving vaccination strategies. The second area of our research program studies a recently discovered enzyme that is related to but distinct from AID. This enzyme has an activity never before described in vertebrates and may participate in producing the building blocks of DNA. Because of this, it can also metabolize and limit the efficacy of a certain type of anti-cancer drugs that resemble the DNA building blocks. We study the normal function of this enzyme and how it contributes to rendering cancer cells resistant to treatment.