.o. The murine antibody repertoire experiences a series of expansions and contractions that coincide with specific stages of B-cell development arid differentiation. The initial repertoire of antibody specificities generated by V(D)J recombination is reduced during B-cell maturation by the effects of immunological tolerance mechanism acting on immature and transitional B cells. The purging of autoreactivity from developmentally immature B cell compartments it is thought to be accomplished by at least three mechanisms: cional deletion by apoptosis, inactivation by energy, and receptor editing, the induction of secondary V(D)J gene rearrangements to replace self- reactive receptors. Receptor editing is believed to be the premiere mechanism for B-cell tolerance. Questions remain, however, regarding how the process of receptor editing acts and whether experimental evidence for receptor editing reflects the induction of genetic changes in autoimmune B cells or selection for variants that spontaneously undergo secondary rearrangements. We shall investigate the tolerizing contractions of the B-cell repertoire with particular reference to: 1) the signals and developmental stages of B cells that initiatelsupport receptor editing;2) the role of self-antigens in the induction of regulated RAG 1/2 expression and rearrangement, and;3) the selection criteria that might determine clonal tolerance/selection during B-cell maturation in viva. Qom cap mop axiom 0-c 0opccc woo'- t00 0co -td
Antibody responses to diverse antigens, including the antigens expressed by pathogenic microbes, are possible by virtue of a series of genomic rearrangements that generate millions of distinct antibody molecules specific for only a single antigen. This remarkable genetic process is determined during early B-cell development and generates substantial numbers of cells that react with normal tissues. The studies proposed in this application will reveal how this remarkable genetic diversity is controlled and becomes focused on the recognition of foreign- and not self-antigens.
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