The main overall objective of this work is to define the molecular, biological, biochemical and genetic events that control the expression of immunoglobulins. We are working on the control of the expression of antibodies comprising the dominant cross-reactive idiotype associated with the response of A/J mice to the hapten-Rho-azophenylarsonate (Ars). This idiotype is expressed as a family of related antibodies generated by somatic mutation of a few germ-line genes. This proposal deals in depth with the analysis of the timing of somatic mutation induction, i.e. when is it turned on, when, if ever, is it turned off and is mutation alone responsible for the accumulation of high affinity antibodies. We will also study the consequences to the animal of the induction of a large number of mutations altering, at random, induced antibodies. In particular, we will test the idea that mutations can lead to anti-self reactivities. The basic methodology employed is to produce hybridomas from immune animals and then determine their sequence (number of somatic mutations), affinity for antigen and cross-reactivities with DNA and other """"""""self"""""""" antigens. We will also test the idea that many """"""""self"""""""" antibodies are encoded in the germ-line of the mouse and are modified away from self by somatic mutation. We are also studying the induction of mutation and immunoglobulin secretion in an antigen-specific B cell hybridoma line that is representative of a resting B cell. These studies will provide us with new insights into a fundamental mechanism responsible for the specificity of the humoral immune response. We also expect to learn a great deal about the origins and control of expression of anti-self antibodies in autoimmune disease.
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