The primary goal of the somatic hypermutation group is to understand the mechanism that introduces mutations into immunoglobulin genes of B lymphocytes and how improper regulation of this mechanism can lead to autoimmunity. B cells of the immune system contribute to primary and secondary immune responses by producing antibodies that mark pathogens for destruction by other components of the immune system. The B cell response has, among its devices, three mechanisms of somatic genetic alteration that enhance diversity as well as specificity of the immunoglobulin receptor: 1) V(D)J recombination (which T cells undergo as well), 2) immunoglobulin somatic hypermutation (SHM), and 3) class-switch recombination (CSR). V(D)J recombination generates the pre-immune highly diverse B cell repertoire and is independent of antigen (pre-immune repertoire). CSR is the mechanism responsible for the generation of downstream isotypes from IgM such as IgG, IgA and IgE, and can also take place in foci of antibody-forming cells. SHM is a mechanism that introduces mutations, into the DNA encoding the variable regions of immunoglobulin receptors, via deamination of cytosines by activation-induced deaminase (AID), and is the focus of our lab. Because the variable portion of the immunoglobulin receptor directly interacts with the foreign antigen, mutations that alter amino acids in this region impact recognition and binding of the antibody molecule to the antigen. Through this process, high affinity memory B cells are formed, but when not regularly properly, it can lead to disease. We are concerned with understanding the SHM mechanism, its regulation, and its impact to autoimmunity. Specifically, we are interested in the following questions about SHM that remain unanswered: 1) How is AID regulated to prevent deamination of non-immunoglobulin genes? Deregulation of AID has been linked to development of certain B cell lymphomas, 2) The role of a novel protein we discovered, SLIP-GC, in protecting B cell genomes from AID-mediated deamination. 3) The role of error-prone DNA polymerases in immunoglobulin mutation and 4) The contribution of AID to autoimmune disease.
Marilyn Diaz, Ph.D., heads the Somatic Hypermutation Group within the Laboratory of Molecular Genetics. She received her Ph.D. in evolutionary biology from the University of South Carolina. She then trained in immunology with Dr. Martin Flajnik at University of Maryland and Dr. Norman Klinman at Scripps Research Institute while a Burroughs Wellcome Fellow of the Life Science Research Foundation. She received the Presidential Early Career Award for Scientists and Engineers in 2002.