This grant is concerned with the ontogenesis of B cells and mutations that affect it. The experiments are designed to test a new hypothesis, based on several novel experiments which explain the origin and phenotype of CD5+ B cells on the one hand and memory B cells on the other. The proposal is that CD5 is induced by slg cross-linking (thymus independent type 2 [TI-2]) antigens, but not thymus dependent (TD), antigens. In contrast, cognate T helper-B cell interactions in response to T dependent antigens induce the generation of memory B cells which remain CD5 and decrease surface j11d. This model will be extensively tested during this grant period. This is important to do because validation of the hypothesis promises to give insight into several outstanding immunological problems, such as the origins of the CD5+ cells which are responsible for the production of a prominent form of autoantibody (so-called """"""""natural"""""""" or low-affinity antibody), and the pathogenesis of chronic lymphatic leukemia which is characterized by an expansion of CD5+ cells. Further, the definition of the conditions for the induction of memory B cells would provide a system for studying the regulation of the mutation process. The proposed experiments are designed to test the basic features of the model. In addition, the basis for the regulated expression of CD5 will be determined. A direct test of a system for inducing somatic mutation in immunoglobulin in vitro is proposed. Finally, the basis for a heightened sensitivity of CD5 cells to deletion by programmed cell death will be examined.
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