Mechanisms of autoimmunity in mice lacking the mer membrane tyrosine kinase

There has been increased recent interest in the role of macrophages (Mp) and dendritic cells in systemic lupus erythematosus pathogenesis. The mer receptor tyrosine kinase, expressed on Mp and dendritic cells, mediates the binding of the former but not the latter to apoptotic cells. mer also is important in determining the cytokine profile that ensues after phagocytosis. Mice lacking mer develop antinuclear antibodies and rheumatoid factor. These autoantibodies appear to arise mostly from the splenic marginal zone. Stimulated spleen cells and peritoneal Mp from mer-deficient mice have increased expression of tumor necrosis factor alpha and IκBα, along with increased spontaneous expression of CD30L. The proinflammatory cytokine profile of mer-deficient mice may contribute to the immunogenicity of apoptotic debris. In vitro ligation of mer from normal Mp leads to diminished tumor necrosis factor alpha expression and increased IL-10 and IL-4. mer, which controls both phagocytosis and cytokine synthesis after exposure to apoptotic cells, may be an attractive target for therapeutic intervention in inflammatory and autoimmune disorders.