Mice with Blood Cells Deficient in GPI-linked Proteins - The Generation of a Murine Model to Investigate the Pathogenesis and Pathophysiology of Paroxysmal Nocturnal Hemoglobinuria (PNH)

摘要

Clinical characteristics of PNH include anemia due to intravascular hemolysis and hemoglobinuria, complications caused by bone marrow failure, and recurrent thrombosis. Despite the cloning of the Piga gene and the recent insights into the molecular lesion that causes the loss of glycosyl phosphatidylinositol-(GPI) linked proteins, much of the pathophysiology of this disease remains unexplained. A murine model that mimics the human disease would thus be a very valuable tool to study the pathogenesis and pathophysiology of PNH. Mice with blood cells deficient in GPI-linked proteins have been generated by several different approaches. Targeted recombination of the murine homologue Piga in embryonic stem cells (ES cells) is complicated by a high embryonic lethality and the lack of germline transmission of the disrupted Piga gene. To target Piga gene inactivation specifically to hematopoietic cells we and other investigators have therefore used conditional Piga gene inactivation employing the Cre/loxP system. Inthis review we will discuss Cre/loxP mediated Piga gene inactivation, summarize and compare the approaches that have been chosen to produce mice with PIGA(-) blood cells, and discuss the insights gained so far by analyzing mice with PIGA(-) blood cells. Further investigation of hematopoiesis and immune response in these mice might help to explain the pathogenesis and pathophysiology of PNH, provide new insights into the functional role of GPI-linked proteins on blood cells, and possibly provide the experimental system for studying PNH therapy.