Hematology Branch, School of Medicine, University of Salerno, Italy.
Mini Rev Med Chem. 2011 Jun;11(6):544-52. doi: 10.2174/138955711795843356.
To explore whether predisposition to bone marrow failure syndromes (BMF), such aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH) and myelosysplastic syndromes (MDS), is found in killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) ligand (KIR-L) gene variations or cytokine polymorphisms.
We studied a cohort of 77 patients with AA, 129 with MDS and 285 healthy controls for the frequencies of KIR-L and KIR genotypes and 22 selected single nucleotide polymorphisms (SNPs) located within 10 cytokine (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL12, IFN- γ, TNF- α, TGF- β) and 3 cytokine receptor (IL-1R, IL-1RA, IL-4Rα) genes.
In AA we found a decreased frequency of inhibitory KIR-2DL3 genes. In MDS, no difference in the frequency of KIR genotype was identified; however, a decreased frequency of 2DL3 was found in hypocellular MDS. Analysis of the KIR genotype in correlation with the corresponding KIR-L profile, revealed a decreased frequency of stimulatory 2DS1/C2 mismatch both in AA and MDS. In AA and MDS cohorts, compared to controls, we found a higher frequency of TT codon 10 variant and of GG codon 25 variant of TGF- β gene, consistent with a high secretory phenotype. This relationship was even more pronounced in PNH and hypocellular MDS. We confirm that the hypersecretory genotype T/T at position -874 of INF-γ gene was overrepresented only in AA and correlates with presence of a PNH clone. Instead in MDS patients, the frequency of G/A polymorphism at position -308 on the TNF- α gene promoter, which correlates with higher TNF- α production, was found significantly higher. Moreover, hypocellular MDS was characterized by a higher prevalence of IL-10 GCC/GCC haplotype, which is functionally associated with a low secretor phenotype.
Our findings suggest that alterations in KIR/KIR-L matching, such as increased 3DL2 and decreased 2DS1 mismatch, and in the polymorphisms of TGFβ1, IFN-γ, TNF- α and IL-10 may account for the propensity to immunemediated killing of hematopoietic stem cells and/or ineffective hematopoiesis characteristic of AA and MDS. Further studies are needed to elucidate whether these immunogenetic traits may be involved in increased risk of developing immune-mediated BMF.
探讨杀伤细胞免疫球蛋白样受体（KIR）和人类白细胞抗原（HLA）配体（KIR-L）基因变异或细胞因子多态性是否存在于骨髓衰竭综合征（BMF）易感性中，如再生障碍性贫血（AA）、阵发性夜间血红蛋白尿（PNH）和骨髓增生异常综合征（MDS）。
我们研究了 77 例 AA 患者、129 例 MDS 患者和 285 例健康对照者的 KIR-L 和 KIR 基因型频率以及位于 10 个细胞因子（IL-1α、IL-1β、IL-2、IL-4、IL-6、IL-10、IL12、IFN-γ、TNF-α、TGF-β）和 3 个细胞因子受体（IL-1R、IL-1RA、IL-4Rα）基因内的 22 个选定的单核苷酸多态性（SNP）。
在 AA 中，我们发现抑制性 KIR-2DL3 基因的频率降低。在 MDS 中，未发现 KIR 基因型频率的差异；然而，低细胞性 MDS 中发现 2DL3 频率降低。KIR 基因型与相应 KIR-L 谱的分析显示，AA 和 MDS 中均存在刺激 2DS1/C2 错配的频率降低。与对照组相比，在 AA 和 MDS 队列中，我们发现 TGF-β 基因的 TT 密码子 10 变体和 GG 密码子 25 变体的频率更高，这与高分泌表型一致。这种关系在 PNH 和低细胞性 MDS 中更为明显。我们证实，INF-γ 基因位置-874 的高分泌基因型 T/T 仅在 AA 中过度表达，并且与 PNH 克隆的存在相关。相反，在 MDS 患者中，TNF-α 基因启动子位置-308 的 G/A 多态性，其与更高的 TNF-α 产生相关，其频率显著升高。此外，低细胞性 MDS 具有更高的 IL-10 GCC/GCC 单倍型的患病率，其功能与低分泌表型相关。
我们的研究结果表明，KIR/KIR-L 匹配的改变，如 3DL2 的增加和 2DS1 错配的减少，以及 TGFβ1、IFN-γ、TNF-α 和 IL-10 的多态性可能导致针对造血干细胞的免疫介导杀伤和/或 AA 和 MDS 特征性的无效造血。需要进一步研究阐明这些免疫遗传特征是否与发生免疫介导的 BMF 的风险增加有关。
