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

阵发性夜间血红蛋白尿（PNH）和特发性再生障碍性贫血（AA）共享免疫介导的骨髓（BM）损伤。然而，颅脑损伤的确切机制尚不清楚。最近，我们发现白血病K562细胞在体外获得猪- a突变后，对自然杀伤（NK）细胞介导的细胞毒性不太敏感（Nagakura等人，Blood 2002; 100: 1031-37）。在本研究中，我们发现白血病细胞的NK敏感性降低是由于缺乏激活NK和T细胞的应激诱导的gpi连接膜UL16结合蛋白（ULBP），这表明ULBP出现在血细胞上可以增强NK细胞介导的体外细胞毒性。在临床研究中，我们发现一些PNH患者体内含有表达ULBP的血细胞。因此，我们预计ULBP^+细胞可能会受到表达ULBP受体NKG2D的自体细胞毒效应细胞（NK和CD8^+ T细胞）的损伤。事实上，携带ULBP +粒细胞的PNH患者的粒细胞易被包括效应细胞在内的自体外周血单个核细胞杀死。相比之下，在健康供者和没有ULBP +粒细胞的PNH患者中未观察到ULBP相关的杀伤。这些结果表明，如果PNH患者维持致病压力以诱导应激蛋白，则会发生ulbp相关的骨髓损伤。因此，我们得出结论，ULBP- nkg2d参与了部分骨髓衰竭综合征患者骨髓衰竭的发病机制，ULBP的膜表达可能是免疫介导的骨髓损伤的一个有用的临床标志物。

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.