Molecular mechanism of immune-mediated marrow failure in paroxysmal nocturnal hemoglobinuria

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Paroxysmal nocturnal hemoglobinuria (PNH) and idiopathic aplastic anemia (AA) share immune-mediated bone marrow (BM) injury. However, the precise mechanism of the BM injury remains unknown. Recently, we showed that leukemic K562 cells were less sensitive to natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIG-A mutations (Nagakura et al., Blood 2002 ; 100 : 1031-37). In the present study, we found that the decreased NK sensitivity of the leukemic cells was conferred by a deficiency of stress-inducible GPI-linked membrane UL16 binding proteins (ULBP) that activate NK and T cells, indicating that ULBP appeared on blood cells can intensify NK cell-mediated cytotoxicity in vitro. Of clinical interest, we found some PNH patients harboring ULBP-expressing (ULBP^+) blood cells. Thus, we expected that ULBP^+ cells could be injured by autologous cytotoxic effector cells (NK and CD8^+ T cells) expressing NKG2D, a receptor for ULBP. Actually, granulocytes of PNH patients carrying ULBP^+ granulocytes were shown to be susceptible to killing by autologous peripheral blood mononuclear cells including the effector cells. In contrast, the ULBP-associated killing was not observed in healthy donors nor PNH patients who had no ULBP^+ granulocytes. These results suggest that PNH patients undergo ULBP-associated marrow injury if they sustain pathogenic pressure to induce the stress proteins. We therefore conclude that the ULBP-NKG2D engagement is implicated in the pathogenesis of BM failure in a proportion of patients with BM failure syndromes and that the membrane expression of ULBP could be a useful clinical marker of immune-mediated marrow injury.