Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany.
Histopathology. 2012 Aug;61(2):200-11. doi: 10.1111/j.1365-2559.2012.04209.x. Epub 2012 Jun 13.
There is increasing evidence that autoimmunity is involved in the pathogenesis of myelodysplastic syndromes (MDS). We examined the number of apoptotic cells, and analysed the T cells and the T cell receptor gene rearrangements in bone marrow trephines of patients with low-grade MDS [refractory anaemia (RA), refractory anaemia with ringed sideroblasts (RAS) and refractory cytopenia with multilineage dysplasia (RCMD)] to investigate the correlation between T cells and apoptosis.
Bone marrow trephines from 30 patients with RA, seven patients with RCMD, four patients with RAS and 11 normal bone marrow donors were stained for CD3 and for apoptotic cells using immunohistochemistry and terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate (dUTP) nick end labelling (TUNEL) technique, respectively. The positive cells were quantified by computer-assisted image analysis. In addition, CD 8 and T cell-restricted intracellular antigen-1 (TIA-1)-positive cells were analysed by single staining and evaluated semiquantitatively by light microscopy. Junctional diversity of the T cell receptor (TCR) α-, β- and γ-chains were analysed in 24 cases of RA and RCMD by reverse transcription-polymerase chain reaction (RT-PCR). In all cases of RA, RCMD and RAS an increase of apoptotic cells was accompanied by an increase of T cells, when compared to normal donors (P < 0.001). Expression of TIA-1 was found in 33 of 41 patients with low-grade MDS. In contrast, normal controls showed either no or only very weak expression. Furthermore, 14 of 24 cases with low-grade MDS showed clonal TCR gene rearrangement.
These findings provide evidence that increased apoptosis in low-grade MDS correlates with increased numbers of cytotoxic T cells. A considerable proportion of the MDS cases showed clonal TCR rearrangement suggesting an antigen-driven selection of the T cells. We therefore speculate that cases of MDS can be accompanied by a presumably autoreactive T cell-mediated apoptosis induction in bone marrow cells.
越来越多的证据表明自身免疫与骨髓增生异常综合征（MDS）的发病机制有关。我们检查了低级别 MDS [难治性贫血（RA）、难治性贫血伴环形铁幼粒细胞（RAS）和难治性血细胞减少伴多系发育异常（RCMD）]患者骨髓活检中的凋亡细胞数量，并分析了 T 细胞和 T 细胞受体基因重排，以研究 T 细胞与凋亡之间的相关性。
使用免疫组织化学和末端脱氧核苷酸转移酶 2'-脱氧尿苷，5'-三磷酸（dUTP）缺口末端标记（TUNEL）技术分别对 30 例 RA、7 例 RCMD、4 例 RAS 和 11 例正常骨髓供体的骨髓活检进行 CD3 和凋亡细胞染色。通过计算机辅助图像分析对阳性细胞进行定量。此外，通过单染色分析 CD8 和 T 细胞限制性细胞内抗原-1（TIA-1）阳性细胞，并通过光学显微镜进行半定量评估。通过逆转录-聚合酶链反应（RT-PCR）分析 24 例 RA 和 RCMD 的 TCRα、β和γ链的连接多样性。与正常供体相比，所有 RA、RCMD 和 RAS 病例的凋亡细胞增加伴随着 T 细胞增加（P < 0.001）。在 41 例低级别 MDS 患者中发现 33 例表达 TIA-1。相比之下，正常对照组要么没有表达，要么只有非常弱的表达。此外，24 例低级别 MDS 中有 14 例显示克隆 TCR 基因重排。
这些发现提供了证据表明，低级别 MDS 中凋亡增加与细胞毒性 T 细胞数量增加相关。相当一部分 MDS 病例显示克隆 TCR 重排，提示 T 细胞受到抗原驱动的选择。因此，我们推测 MDS 病例可能伴有骨髓细胞中可能自身反应性 T 细胞介导的凋亡诱导。
