Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Blood. 2012 Nov 8;120(19):4058-67. doi: 10.1182/blood-2012-02-408864. Epub 2012 Sep 18.
Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.
噬血细胞性淋巴组织细胞增生症（HLH）的特征是骨髓巨噬细胞吞噬造血干细胞（HSCs）的调节失控，这可能是由全身炎症性细胞因子血症引起的。在本研究中，我们表明 HLH 的发病机制涉及到由表面 CD47 和信号调节蛋白α（SIRPA）之间的相互作用所操作的抗吞噬系统的损伤。在 HLH 患者中，SIRPA 的表达水平变化和 HLH 特异性多态性并未发现。相比之下，表面 CD47 的表达在 HLH 加重时特异性地下调，但在健康受试者中没有下调。HLH 患者的骨髓 HSCs 数量减少到健康对照组的约 20%，并且来自正常供体的巨噬细胞从 HLH 患者中体外吞噬 HSCs，但不吞噬来自健康对照组的 HSCs。此外，在炎症细胞因子的作用下，正常 HSCs 而不是祖细胞或成熟血细胞，充分下调 CD47 以被巨噬细胞吞噬。在 HLH 患者和健康对照者中，即使存在炎症细胞因子，HSC 阶段的吞噬前钙网蛋白的表达也被抑制。这些数据表明，CD47-SIRPA 抗吞噬系统在维持 HSCs 中起着关键作用，而其通过 HSC 特异性 CD47 下调的破坏可能对 HLH 的发展至关重要。
