SEARCH FOR NOVEL B CELL HYPERACTIVITY GENES

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Our long-term goal is to identify the genes and their products that determine hyperactivity of B cells, particularly B-1 (DC5-lineage) B cells. New Zealand Black (NZB) mice, that have a life-long hyperactivity ob B-1 cells, will be studied. NZB mice not only develop autoimmune disease but also a high incidence of malignant lymphomas of B-1 B cells that are very similar to human CLL and the B cell lymphomas developing the AIDS patients. In addition B-1 B cells are hyperactive in the inflamed joints of rheumatoid arthritis (RA) patients where they play a major role in antigen presentation and activation of inflammatory cells. We have preliminary evidence showing that the hyperactive B cells of NZB mice differentially express several genes that are not expressed in normal B cells. In this development and feasibility study, we would like to confirm the identity of these B cell hyperactivity genes. Eventually we aim to clone the full length cDNA for these differentially expressed genes, sequence them, study their genomic organization and define their function. This search for B cell hyperactivity genes may reveal novel genes or new function for known genes. Besides its relevance to RA and malignant B cell lymphomas as stated above, this project could enhance our understanding of the basic mechanisms of B cell differentiation, signal transduction, tolerance and apoptosis.