IRCM Researchers

We study the mechanisms that improve the quality of antibodies elicited during an immune response. At any point in time, each person has many “naïve” B lymphocyte cells that have never seen antigen, each expressing a unique antibody with a random antigenic specificity. Upon infection or immunization, a few of these naïve B cells can recognize those specific antigens via antibody molecules expressed on their cell surface. After engaging with antigen, B cells start proliferating, express the enzyme Activation induced deaminase (AID) and form microanatomical structures termed germinal centers. 

AID can directly introduce mutations in the genome and induces DNA damage with several consequences. In germinal center B cells, AID activity is preferentially targeted to antibody genes. There, AID initiates class switch recombination, which allows antibodies to switch from the default IgM isotype to other isotypes better suited to eliminate specific antigens or pathogens, i.e. IgG, IgA, or IgE. AID also introduces point mutations that change the antigen-binding region of the antibody, thereby affecting antibody affinity.  This process is known as somatic hypermutation. Among the random pool of mutants created by AID, the organization of the germinal center allows for the selection of B cells with mutations that encode antibodies of high affinity. This occurs largely through the interaction of B cells with T lymphocytes. The B cells that are selected can either undergo further cycles of mutation and selection or differentiate and exit the germinal center. Differentiation generates plasma cells, which secrete antibodies for up to a lifetime, and memory B cells that can be quickly activated upon exposure to the same antigen. Unfortunately, AID can also outside the antibody genes and produce potentially deleterious or oncogenic DNA damage elsewhere in the genome. The combination of AID activity and proliferation increases the chances of oncogenic events in B cells. Indeed, most B cell lymphomas originate from germinal center B cells. AID can contribute to lymphoma evolution.

We investigate the mechanisms that allow optimal AID activity at the antibody genes, thereby preventing immunodeficiency, while minimizing AID-induced oncogenic or deleterious DNA damage. We elucidate these mechanisms at the molecular level, but we also study how they shape the germinal center reaction, by affecting the fitness and differentiation of the B cells. We use mouse models to study B cells in vivo and antibody responses, as well as B cell lymphoma cells to understand their pathological implications