Our proposal is designed to test the hypothesis that there are normal restraints preventing the producers of natural autoantibody - CD5+ B cells - from progressing via somatic mutation and isotype switching to the production of pathogenic autoantibody. The likely restraints include: a specific prohibition against cognate interaction with T helper cells; prohibition of somatic mutation or switching, and a resistance to the induction of tolerance. We go on to suggest that in autoimmune prone individuals (strains), cognate interaction does take place, resulting in switching, mutation, and clonal expansion of cells producing high-affinity autoantibodies, and, ultimately, significant pathology. We will test the proposition that natural autoantibody producing B cells from autoimmune prone mouse strains (individuals) can respond to cognate interactions with helper T cells, generating isotype switching and somatic mutation. We will test the idea that stimuli which ordinarily induce programmed cell death or anergy have no such affect on B cells from the autoimmune prone. These experiments are based on our recent work showing that the B cell CD5 phenotype arises from thymus independent type 2 (sIg cross-linking) activation, while cognate interaction with T cells generates CD5 j11dlow cells. We have also found that once generated normal CD5+ B cells die in response to sIg cross-linking. the basic hypothesis to be tested is that CD5+ cells from disease prone individuals are resistant to these restraints. If validated, this would explain the many hitherto puzzling observations which link polysystem autoimmune disease, natural autoantibodies, CD5+ B cells and chronic lymphatic leukemia.
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