Maturation of the Anitbody Response to a Protein Antigen

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9630412 Jemmerson Following exposure of the immune system of experimental animals such as mice to small chemical compounds, the antibodies that are produced initially by the white cells bind the compounds weakly, then after about one week, the antibodies that are made begin to bind the compounds more strongly until a maximum binding ability is achieved. This increased strength in binding, also known as affinity, results from changes, or mutations, in the genes that code for the antibodies. Although not yet definitively shown, it is believed that this model also applies to the immune response to more complex molecules including proteins which are present on microorganisms that the immune system normally eliminates. In this study, this model will be extended to the immune response to a protein that has been well-characterized both structurally and chemically, cytochrome c. In preliminary work it has been determined that several mutations in the genes encoding antibodies specific for cytochrome c do occur after immunizing mice with the protein and that together these mutants result in higher affinity antibody binding. Now, the effect of each of the mutations in the antibody genes on the affinity will be tested by altering the genes at each of the several sites independently. In addition, the structure of a complex of an antibody bound to the protein will be determined using the technique of X-ray crystallography to find out whether the mutations cause changes in the antibodies that directly contact the target molecule (antigen) or whether the effects are indirect. The cytochrome c to be employed in this study is a protein expressed in mice. Previously it was found that the antibody genes used in the immune response to this self antigen are also used in response to a related protein and that during the response the antibodies acquire higher affinity for this protein than for the self antigen. In this study, the mutations in the antibody genes that allo w for this conversion will be determined. It has been suggested for a long time that this may be a general mechanism for immunological recognition of foreign antigens but an experimental system to study it has been available. In summary, this study will extend our understanding of affinity maturation in the antibody response from what was previously known in studies of model compounds to a more complex, protein antigen. It will also provide further insight into how immune recognition of foreign antigens may initiate with the response of antibody-producing white blood cells that possibly evolved to recognize self antigens. ***