Human Papillomavirus Immunology Laboratory, Science Applications International Corporation (SAIC)-Frederick, Incorporated, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Br J Haematol. 2013 Oct;163(1):81-92. doi: 10.1111/bjh.12475. Epub 2013 Jul 25.
Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia (DBA), and Shwachman-Diamond syndrome (SDS) are characterized by the progressive development of bone marrow failure. Overproduction of tumour necrosis factor-α (TNF-α) from activated bone marrow T-cells has been proposed as a mechanism of FA-related aplasia. Whether such overproduction occurs in the other syndromes is unknown. We conducted a comparative study on bone marrow mononuclear cells to examine the cellular subset composition and cytokine production. We found lower proportions of haematopoietic stem cells in FA, DC, and SDS, and a lower proportion of monocytes in FA, DC, and DBA compared with controls. The T- and B-lymphocyte proportions were similar to controls, except for low B-cells in DC. We did not observe overproduction of TNF-α or IFN-γ by T-cells in any patients. Induction levels of TNF-α, interleukin (IL)-6, IL-1β, IL-10, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in monocytes stimulated with high-dose lipopolysaccharide (LPS) were similar at 4 h but lower at 24 h when compared to controls. Unexpectedly, patient samples showed a trend toward higher cytokine level in response to low-dose (0·001 μg/ml) LPS. Increased sensitivity to LPS may have clinical implications and could contribute to the development of pancytopenia by creating a chronic subclinical inflammatory micro-environment in the bone marrow.
范可尼贫血（FA）、先天性角化不良（DC）、 Diamond-Blackfan 贫血（DBA）和 Shwachman-Diamond 综合征（SDS）的特征是骨髓衰竭的进行性发展。来自激活的骨髓 T 细胞的肿瘤坏死因子-α（TNF-α）的过度产生被认为是 FA 相关再生障碍的一种机制。其他综合征中是否存在这种过度产生尚不清楚。我们对骨髓单核细胞进行了一项比较研究，以检查细胞亚群组成和细胞因子产生。我们发现 FA、DC 和 SDS 中的造血干细胞比例较低，FA、DC 和 DBA 中的单核细胞比例较低。T 和 B 淋巴细胞比例与对照组相似，除了 DC 中的 B 细胞较低。我们没有观察到 T 细胞在任何患者中过度产生 TNF-α或 IFN-γ。与对照组相比，高剂量脂多糖（LPS）刺激的单核细胞中 TNF-α、白细胞介素（IL）-6、IL-1β、IL-10、粒细胞集落刺激因子和粒细胞-巨噬细胞集落刺激因子的诱导水平在 4 小时相似，但在 24 小时时较低。出乎意料的是，与对照组相比，患者样本在低剂量（0·001 μg/ml）LPS 刺激下表现出更高细胞因子水平的趋势。对 LPS 的敏感性增加可能具有临床意义，并可能通过在骨髓中产生慢性亚临床炎症微环境导致全血细胞减少症的发展。
