Evolution of antibody affinity modification in fishes

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Two desired outcomes of vaccination are: 1) immunologic memory, whereby there is a large increase in the number of long-lived immune memory cells that will be able to recognize the disease that you were vaccinated against. 2) improved recognition of disease organism by tweaking the genes of the molecules used to recognize the pathogen. This latter process termed antibody affinity maturation involves the intentional mutation of a select part of our genome in the hopes of improving the design of the antibodies that it encodes, so they can better bind to a pathogen that the organism has been exposed to. Mutation of the genome is a delicate business that must be tightly regulated so that unintended mutation doesn't lead to cancers or autoimmune diseases. Our research studies the conditions in which the mutation process takes place. Specifically we study how this system operates in the most primitive of organisms that are able to make antibodies - the fishes. Sharks and fishes seem to have a very simplified method of altering their antibody genes. By studying the simpler system (compared to mammals) we hope to understand the most basic cellular and molecular necessities for how the system works, and what can cause it to go wrong as it does in many autoimmune diseases. In autoimmune diseases the antibody genes are altered so they mistake our own tissues for that of a pathogen. The conditions under which this happens in mammals look similar to how fish drive the mutation process. It is possible that what occurs normally in fish parallels what happens in some mammalian diseases, and studying fish may open windows to understanding the development of auto-immunity in humans. Specifically we are studying a mutational system that tweaks existing antibodies and makes them a better fit for the pathogen that they recognize. Our first goal is to verify that fish have the same sort of mutational system as mammals (i.e. that fish are a model system to study mammalian mutational systems). This involves studying the mutations that accumulate in the antibody genes from tissues in which we believe the process is happening. Our second goal is to study how cells that have undergone mutations are checked to make sure they are not making antibodies to self i.e. autoimmune antibodies. At this point they have been sentenced to death and if they can't still recognize the pathogen then they will die. Some of the cells involved in the 'checking' appear to be different in fish and we are verifying that point. Lastly we are developing transgenic cells and fish that can be used to study other components of the antibody affinity maturation. The cells and fish are genetically engineered to 'light-up' all cells in which AID is active thereby allowing us to observe the cells involved in the mutational system as they exist in translucent zebrafish.