Research Unit in Mechanisms of Genetic Diversity
Understanding the mechanisms that make antibodies efficient during the immune response.
Antibodies are produced by B lymphocytes. During an infection or after vaccination, antigen-specific B lymphocytes form specialized structures known as germinal centers, where they turn on mutagenic mechanisms to remodel the immunoglobulin genes encoding for the antibody light and heavy chain.
Two mechanisms - somatic hypermutation (SHM) and immunoglobulin gene conversion (IgGC) - can change the sequence of the VARIABLE region of the antibody, which recognizes the antigen.
The diversification of the Variable region by programmed mutation is linked to a process of darwinian selection of the antibody variants with the highest affinity for the antigen. This cycle of mutation and selection happens within the unique anatomical structure of the germinal centers, and explains the improvement of antibody response a few days after the first exposure to the antigen, as well as the generation of memory B cells.
A third mechanism - class switch recombination (CSR) - exchanges the default "CONSTANT" region of the antibody heavy chain that defines the IgM isotype for another one, to produce IgG, IgE or IgA. Each antibody class specializes in eliminating different antigens by mediating specific interactions with immune cells and soluble factors.
SHM, IgGC and CSR are initiated by the deamination of cytosine bases in DNA by the enzyme Activation Induced Deaminase (AID). Defects in any of these mechanisms can cause immunodeficiency.
AID is unique in that it directly mutates the genome to fulfill its biological role. Unfortunately, AID causes collateral damage in the form of genomic mutations and chromosomal translocations that predispose to cancer such as B cell lymphoma and leukemia.
We investigate :
- The mechanisms that regulate the mutagenic enzyme AID and their relevance to prevent immunodeficiency and cancer.
- The interplay between AID and DNA repair to protect B cells in the germinal center, which must proliferate in the presence of DNA damage.
We use structure-function, biochemistry, cell
biology and genetics to study the regulation of AID and its interplay with DNA
repair pathways. We also use mouse models with deficiencies in key components of the pathways involved in SHM and CSR.
We have discovered several mechanisms regulating
AID protein stability and localization, as well as a link between AID and DNA
repair during class switch recombination. We have also exhaustively analyzed
the role of the DNA repair enzyme uracil-DNA glycosylase UNG during the germinal center response,
in the mechanisms of antibody diversification and in modulating the oncogenic
effects of AID.
Dr Javier M Di Noia
H2W 1R7, Montréal, Québec, Canada