Mice and men – along with many other organisms – encounter an array of pathogens during their life, and have evolved a complex immune system to protect against infections. A cornerstone of this protection is the process of V(D)J recombination that randomly combines V, D and J segments to generate a large pool of receptors (T cell receptors and antibodies) that can detect any pathogen that invades the host. However, out of necessity, these receptors are generated prior to the actual infection. As a result, in a developing B cell, once an antibody reaches the cell surface, it is primarily selected for its inability to bind components of the host itself. But later in life when antibodies encounter a pathogen, the body now can use this pathogen as a template to generate much better antibodies. This is achieved by somatic hypermutation (SHM) – a process wherein high levels of mutations are introduced into the antibody genes eventually leading to higher affinity antibodies. SHM not only for prevents recurrent infections by a single pathogen, but also forms the basis of protection conferred by many vaccines.
There are several curious features of SHM –
1. It starts with conversion of cytosines to uracils by a protein called activation induced deaminase (AID).
2. It is specific to activated B cells and, within these, to antibody genes.
3. Uracils are one of the most common lesions naturally encountered by normal cells and, therefore, not surprisingly, cells have very robust repair pathways to correct these.
4. But SHM utilizes many of the factors involved in normal repair and perverts them to generate a lot of mutations in the variable region of the antibody genes.
5. AID also produces uracils in the switch regions a few kilobases downstream of the variable region and, again, recruits many of the same repair factors. But here it leads to double strand breaks and class switch recombination (CSR). This allows the cell to generate antibodies of different isotypes and therefore switch effector functions.
6. Most interestingly, despite sharing AID and many repair factors, SHM and CSR can and do occur independent of each other.
Using cell line and transgenic mouse models, we are interested in understanding how SHM and CSR unfold differentially at the molecular level. And why they lead to high levels of mutations and breaks in the immunoglobulin genes while sparing the rest of the genome. This is especially important since mistargeting of these processes can lead to B cell lymphomas and possibly other types of cancers.