Autoimmunity, Immune Deficiency and Cancer: Multiple Roles of the Protein Tyrosine Phosphate SHP-1

One of a large number of mutant mice used in immunological research, the motheaten mouse was the first model of a specific protein tyrosine phosphatase deficiency. Mice carrying one of two allelic mutations at the motheaten locus have severe systemic autoimmunity and immune dysfunction as a result of mutations in the hematopoietic-cell phosphatase (Hcph) gene, which encodes the protein tyrosine phosphatase SHP-1. Studies using motheaten (me/me) and viable motheaten (mev/mev) mice have increased the understanding of numerous signaling pathways in immune and hematopoietic cells. A number of studies on SHP-1 function in normal and pathologic states are described here. Homozygous mev/mev mice have an increased percentage of autoantibody associated B-1 B-cells that express the cell surface glycoprotein CD5. To investigate the hypothesis that absence of CD5 in mev/mev mice will result in decreased systemic autoimmunity, we created a stock of CD5nullmev/mev mice. These mice have a longer lifespan than mev/mev mice, associated with reduced pulmonary inflammatory disease, splenic macrophage numbers, and serum IgM levels. However, autoantibodies against dsDNA and histone proteins were not significantly reduced. These studies suggest that CD5 expression is not required for autoantibody production, but otherwise indicate a role for CD5 in the development of immunopathologic lesions in mev/mev mice. Dysregulated macrophage populations in mev/mev mice presumably have secondary effects on other cell types. To examine these effects, as well as the primary results of SHP-1 deficiency in macrophages, we developed a stock of mice transgenic for a dominant-negative form of SHP-1, under control of a macrophage specific promoter. The catalytically inactive dominant-negative protein should occupy SH2 binding sites, blocking the recruitment of functional wild-type SHP-1. SHP-1 plays a putative role in oncogenesis. To substantiate this role, we have monitored tumor development in aged +/me and +/mev mice. Preliminary studies do not support the hypothesis that a spontaneous chondroblastic osteosarcoma that occurred in an aging +/mev mouse was caused by loss of SHP-1 expression. Nonetheless, we describe the transplantable cell-line derived from this tumor, which mimics the process of endochondral ossification in vivo and is a potentially valuable model for studies of osteosarcoma and bone biology