In mammals, the innate and adaptive immune systems are functionally coordinated to protect them from pathogenic microbial infections. Cells of the innate immune system, such as macrophages and natural killer cells, recognize foreign molecules non-specifically and respond quickly to eliminate the microbe. In contrast, T and B cells of the adaptive immune system respond more slowly but recognize a unique molecule (or antigen) on the microbe. Antigen recognition activates and expands a T or B cell clone. The development of antigen specific T and B cells is genetically programmed through a somatic DNA recombination process called V(D)J recombination, which allows T cells to express antigen specific receptors and B cells to produce plasma membrane-bound immunoglobulins, which are more commonly known as antibodies. Antigen-activated B cells can further alter the immunoglobulin (Ig) coding genes through class switch recombination (CSR) and somatic hypermutation (SHM). CSR alters the isotype of the expressed Ig from the default IgM to IgG, IgE, or IgA through a DNA break and ligation reaction. SHM introduces untemplated mutations within the Ig variable coding regions to permit the selection of high affinity Ig. Both CSR and SHM require the activity of activation- induced cytidine deaminase (AID), an enzyme that removes the amino group on deoxycytidine bases in DNA. AID-deficiency leads to a primary immunodeficiency (Hyper-IgM syndrome) in humans and a complete block in CSR and SHM. Dysregulated AID activity generates mutations and translocations in proto-oncogenes that lead to mature B cell lymphomas. More recently, AID has been shown to regulate autoantibody production in models of lupus. Our research has shown that AID is phosphorylated directly by PKA (cAMP-dependent Protein Kinase A) and this phosphorylation promotes the interaction of AID with base excision repair proteins. In addition, our published work showed that the PKA-mediated phosphorylation of AID is dependent on the DNA break response kinase ATM (ataxia telangiectasia mutated). However, the molecular pathway that controls ATM-dependent PKA phosphorylation of AID and the subsequent formation of DNA breaks within the Ig genes that are required for CSR is unknown. This proposal seeks to identify how ATM-dependent and PKA-directed AID phosphorylation allows B cells to generate DNA breaks only in the Ig genes to generate antibody-mediated immunity. The results from this research will allow us to develop more effective vaccines and antibody-based therapies to treat diseases, such as viral infections and cancer.
This proposal seeks to understand how different types of antibodies are produced by the immune system. The studies will allow us to design more effective vaccines and antibody-based therapies to treat diseases such as viral infections and cancer.
