Somatic Hypermutation Group
Mutations in Immunoglobulin Genes
Marilyn Diaz, Ph.D.
Mutations tend to be viewed as the deleterious products of DNA replication errors or DNA damage caused by cellular metabolism or environmental mutagens. However, B cells of the vertebrate adaptive immune system undergo a programmed process of immunoglobulin somatic hypermutation (SHM) that is activated during the course of an immune response. After exposure to a pathogen, SHM targets mutations to the variable regions of immunoglobulin genes, the regions that encode the amino acids in the immunoglobulin receptor which directly interact with foreign antigens. This process occurs in transient lymphoid structures known as germinal centers that form in the spleen, lymph nodes and ileal Peyer’s patches. As the mutations accumulate, a cellular mechanism selects B cells that display immunoglobulin receptor variants enhanced in their ability to recognize and bind the foreign antigen. The selected B cells then differentiate into memory B cells that contribute strongly to the enhanced immune response seen upon re-exposure to the antigen and that contribute to the effectiveness of vaccines.
The molecular mechanism of SHM is unknown. Recent data suggest the involvement of error-prone DNA polymerases, DNA mismatch-repair enzymes and a novel activation-induced cytosine deaminase (AID). The Somatic Hypermutation Group uses both transgenic/knockout mouse models and hypermutating human B-cell lines to investigate a number of specific questions. Do multiple polymerases contribute to SHM? What are the signal transduction pathways that activate SHM? What mechanism ensures the exquisite targeting of AID to the variable regions of immunoglobulin genes while sparing the nearby constant regions? The group is also interested in the mechanistic links between the immunoglobulin mutator and generalized DNA transactions. Is SHM akin to general mutagenesis, but in real time? If so, this deliberate process of hypermutation may reveal itself to be a model for the study of mutagenesis. The group is also studying the contribution of somatically-mutated memory B cells to autoimmune disease.
Major areas of research:
- The mechanism of action of the immunoglobulin mutator
- The biology of memory B cells
- The role in autoimmunity of somatically mutated memory B cells
- Investigation of the biomolecular mechanisms underlying somatic hypermutation
- Somatic hypermutation as a possible model for mutagenesis
- Exploration of the contribution of somatically mutated memory B cells to autoimmune disease
Marilyn Diaz, Ph.D., heads the Somatic Hypermutation Group within the Laboratory of Molecular Genetics. She received her Ph.D. in evolution from the University of South Carolina. She received the Presidential Early Career Award for Scientists and Engineers in 2002.