Molecular pathogenesis of bone marrow failure as a major cause of death in paroxysmal nocturnal hemoglobinuria

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The prevalence of aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH) that manifest fatal marrow failure are relatively high in Japan. The marrow failure shows good response to immunosuppressive therapy, indicating that marrow failure is immune-mediated. However, the pathogenesis including molecular targets on hematopoietic cells recognized by lymphocytes is unknown yet.In the present study, we show both that stress-inducible membrane proteins (or NKG2D ligands) such as ULBP and MICA/B were pathologically expressed on granulocytes and bone marrow CD34+ cells of patients with PNH and aplastic anemia, and that the granulocytes were injured by autologous lymphocytes dependently on the ligand expression in vitro (Hanaoka, et. al., Blood 2006). We then propose that the ligands are the molecular targets for lymphocytes in immune-mediated impairment of hemotopoiesis in the marrow failure syndromes such as PNH and aplastic anemia. lb support the hypothesis, we prospectively analyzed the clinical courses for one up to five years of 3 patients with aplastic anemia-PNH syndromes and 2 patients with aplastic anemia. We then found that one or more of the sress-inducible NKG2D ligands were expressed on their granulocytes. The expression closely associated not only with pancytbpenia reflecting marrow failure, but also with a favorable response of marrow failure to immunosuppressive therapy.We thus conclude that at least a part of patients with idiopathic bone marrow failure syndromes including PNH and aplastic anemia are exposed to a certain stress to induce the NKG2D ligands on their blood cells and that the ligand expression triggers off or promotes the NKG2D-mediated blood cell injury by autologous lymphocytes, leading to marrow failure (Kawaguchi & Nakakuma, Int J Hematol 2007). Currently, we are confirming the NKG2D-mediated marrow cells injury by in vitro colony formation inhibition assays with antibodies to NKG2D and its ligands.