AID biology

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B lymphocytes are the immune system cells that recognize and dispose pathogens such as viruses and bacteria though special receptors on their cell surface known as antibodies. How the immune system recognizes and eliminates pathogens via antibody molecules depends to a great extent on two genetic processes targeting B cell antibody genes: somatic hypermutation and class switch recombination. The first mechanism introduces random point mutations at the N terminal portion of the antibody gene. Mutations coupled to cell selection during the immune response increase the binding affinity of the antibody for the pathogen. The second mechanism changes (via gene recombination) the C terminal portion of the antibody gene, which in turns dictates the strategy used by the immune system to eliminate the pathogen in question. Both somatic hypermutation and switch recombination are carried out by a newly discovered enzyme: AID. The importance of AID in the immune response is highlighted in AID deficient humans and animals, which are highly susceptible to infection and exhibit gut flora-dependent hyperplasia of intestinal villi. Conversely, complex diseases such as autoimmunity have long been associated with AID-dependent hypermutation. Moreover, untimely, ectopic, or elevated AID expression results in translocations and malignant transformation of B cells and T cells. These considerations emphasize the need to understand the molecular pathways that regulate AID expression and activity. To explore AID regulation in an animal model we generated AID reporter mice. By fusing to the AID gene green and yellow fluorescent molecules (isolated from the jellyfish Aequorea victoria), we were able to visualize AID expressing B cells during a variety of immunological settings. The study, which was recently published in the Journal of Experimental Medicine, showed that AID expression is restricted to a B lymphocyte population that interacts with follicular dendritic cells and activated CD4 T cells in a specialized microenvironment known as the germinal center. The other major findings reported in the manuscript include: i) AID is readily shut down as cells exit the germinal center microenviroment. ii) During T cell independent immune responses, a large number of pre-plasma cells (which secrete antibody molecules during the immune response) express AID prior to terminal differentiation. iii) Activated B cells in the gut lamina propria can also express AID. iv) AID is not present in immature bone marrow B cells but its expression can be induced upon retroviral infection. Currently, we are combining our AID reporter system to a mouse model of autoimmunity. The mice, known as MRL/lpr, show systemic autoimmunity, lymphadenopathy associated with T cell proliferation, and immune complex glomerulonephritis, all of which are characteristic of systemic lupus erythematosus and arthritis in humans. Thus a primary goal for our studies is to better delineate the role of AID in the development of autoimmune diseases with clinical relevance.