Research Unit in Mechanisms of Genetic Diversity
Producing efficient antibodies during the immune response
In a nutshell
We study the molecular mechanisms producing efficacious antibodies during the immune response. We also study how the malfunction of these mechanisms can cause immune pathologies or cancer.
Antibodies produced by B lymphocytes are the proteins that protect vertebrate animals from infections and toxins. During an immune response, the antibody genes of B lymphocytes are modified by programmed mutagenesis. This happens within specialized anatomical structures named germinal centers in lymphoid tissues.
These mechanisms are necessary for an efficient immune response and their dysfunction can lead to either immunodeficiency or autoimmunity. In addition, because of the mutagenic nature, these mechanisms can predispose to B cell lymphoma.
Our field of research
Vertebrates produce antibodies as protection against invading microorganisms and toxins. During the course of an infection, the quality of the antibodies improves (i.e. they increase their affinity for the antigen) and change their class to acquire new biological properties. Each antibody class specializes in neutralizing different pathogens. This improvements to the antibody response requires genetic changes that are actively introduced at the immunoglobulin genes of B lymphocytes, as well as a specialized microenvironment where the mutations can be selected: the germinal center.
B lymphocytes within 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 the antigen. SHM is initiated by the enzyme Activation Induced Deaminase (AID), a unique enzyme that mutates the self-genome by changing cytosine bases in DNA to uracils (a base normally found in RNA). AID also triggers the mechanism of class switch recombination (CSR), which remodels the antibody heavy chain locus to change eliminate the exons coding for the default IgM isotype and brings other exons, encoding for IgG, IgE or IgA , next to the variable region.
SHM is coupled to a selection process in the germinal center, by which those B cells expressing antibodies of higher affinity have better chances of receiving survival and proliferation signals from T helper lymphocytes. Repeated cycles of mutation and selection within the germinal center result in an enhanced antibody response within a few days of antigen exposure, and the generation of immunological memory.
Why does it matter ?
The mechanisms regulating AID and germinal center B cell dynamics are critical for the immune response. It is important to identify and understand these mechanisms because their malfunction often underlies immune pathologies like immunodeficiency and autoimmunity, as well as cancers derived from germinal center B cells.
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
Ongoing research projects :
- Identifying mechanisms regulating AID.
- Characterizing mechanisms regulating germinal center dynamics.
- Characterizing enzymes regulating the incorporation of uracil into the DNA.
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