Research Unit in Mechanisms of Genetic Diversity
Producing efficient antibodies during the immune response
In a nutshell
The antibodies protect us from infections and toxins. Producing efficient antibodies requires that the B lymphocytes undergo programmed mutagenesis of the antibody genes within the specialized anatomical structure of germinal centers in lymphoid tissues. Any defect in this process leads to immunodeficiency. At the same time, the mutagenic process of the antibody genes and the unique environment in the germinal center can predispose to cancer (B cell lymphomas).
We study the mechanisms that mutate the antibody genes and biology of the germinal center B lymphocytes. Our objectives are to understand how protective immunity is achieved while minimizing the risk of cancer, and to identify mechanisms that can be manipulated to target cancerous B cells or improve antibody responses.
B lymphocytes that enter the germinal center use the mechanism of somatic hypermutation (SHM) to change the sequence of the VARIABLE region of the antibody, which changes the affinity for its cognate antigen.
SHM is coupled to Darwinian selection of the B cell based on the affinity of the antibody, which requires interactions of the B cell with antigen presenting cells and T lymphocytes.
Cycles of mutation and selection within the germinal center permit the improvement of the antibody response within a few days of antigen exposure, and the generation of immunological memory.
Another mutagenic mechanism - class switch recombination (CSR) - exchanges the default "CONSTANT" region of the antibody heavy chain, IgM, for another one defining the IgG, IgE or IgA classes. Each antibody class specializes in eliminating different antigens by mediating specific interactions with immune cells and factors.
SHM and CSR are initiated by the deamination of cytosine bases in DNA to uracil by the enzyme Activation Induced Deaminase (AID), a unique enzyme that mutates the self-genome to fulfill its biological role.
The mechanisms regulating AID, and those that ensure the survival and dynamics of germinal center B cells, are not only critical for optimal immunity but also to protect from unintended oncogenic consequences during the process.
Why does it matter ?
AID and the germinal center reaction are essential for immune responses against a majority of pathogens, as well as for the success of vaccination. Defects in any of these mechanisms cause immunodeficiency.
The mutagenic activity of AID causes collateral DNA damage that predisposes to cancer like B cell lymphoma and leukemia.
Understanding the functioning of AID in the context of the germinal center is central to understanding how to improve immunization strategies (vaccination), as well as to diagnose or treat immune related diseases.
Ongoing research projects :
- The regulation of AID to prevent oncogenic side effects during SHM and CSR.
- The mechanisms regulating germinal center dynamics for optimal antibody responses.
- Characterization of enzymes regulating the incorporation of uracil into the DNA.
If you are a motivated student that likes research and you are seeking to pursue MSc or PhD, please send us a letter of motivation, CV and university transcripts demonstrating excellent academic records. Graduate students can register at either Université de Montréal or McGill University.
Post-docs candidates should submit a letter of motivation, ideally with a brief project proposal, and full CV (academic records, list of publications, technical skills and names of references).
Please email javier.di.noia(at)ircm.qc.ca
We are @ the IRCM (Institut de Recherches Cliniques de Montréal) in downtown Montreal. (Click find us)
110 Av des Pins Ouest H2W 1R7, Montréal, Québec, Canada
Contact Dr Javier M Di Noia