In humans and mice, many B-cells of fetal or neonatal origin produce autoantibodies. Typically these cells are CD5+ and their antibodies are IgM and lack somatic mutations. Several lines of evidence implicate CD5+ B-cells in some forms of autoimmunity, both human and murine. Further, there is strong evidence indicating that some pathogenic, somatically mutated, IgG autoantibodies are derived from the fetal/neonatal repertoire. The problem arises as to the events in autoimmune prone individuals that induce somatic mutation and isotype switching in autoantibody producing B-cells. While both environmental and genetic events might be responsible, the investigators are interested in those events intrinsic to B-cells. Their proposal is designed to test the hypothesis that there are normal restraints intrinsic to the producers of natural autoantibody (CD5+ B-cells) that prevent them from progressing via somatic mutation and isotype switching to the production of pathogenic autoantibody. Possible internal restraints on CD5 B-cells include: an inability to participate in cognate interactions with T helper cells; a failure to express the machinery needed for somatic mutation, sensitivity to tolerance induction. The experiments proposed are based on their recent work showing that the B-cell CD5+ CD23low (B-1a) phenotype can be induced by thymus independent type 2 (slg cross-linking) activation, while cognate interactions leading to activation via CD40-ligand on activated T helper cells generates CD5-CD23hi B-cells. These findings indicate that naive B-cells can respond to alternative activation signals by expressing different surface phenotypes. The investigators will test the proposition that natural autoantibody producing (B-1) cells from normal mouse strains are poor responders (compared to B-2 cells) to slg cross-linking, CD40 ligation or cognate interactions with helper T-cells. They will also compare the ability of B-1 and B-2 cells to generate somatic mutations in response to in vivo or in vitro stimulation with cognate T helper cells. They further suggest, and will test, the proposition that the B-1 cells of autoimmune prone strains, in contrast to B-1 cells of wild type origin, can participate in cognate interactions with T helper cells, resulting in mutation and clonal expansion of cells producing high-affinity autoantibodies, and, ultimately, significant pathology. If validated, this would help to explain the many hitherto puzzling observations which link polysystem autoimmune disease with natural autoantibodies and CD5+ B-cells.
