De Re Valli, Caggiari Laura, De Zorzi Mariangela, Repetto Ombretta, Zignego Anna Linda, Izzo Francesco, Tornesello Maria Lina, Buonaguro Franco Maria, Mangia Alessandra, Sansonno Domenico, Racanelli Vito, De Vita Salvatore, Pioltelli Pietro, Vaccher Emanuela, Berretta Massimiliano, Mazzaro Cesare, Libra Massimo, Gini Andrea, Zucchetto Antonella, Cannizzaro Renato, De Paoli Paolo
Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy.
Experimental and Clinical Medicine, University of Florence, Florence, Italy.
PLoS One. 2015 Feb 20;10(2):e0117420. doi: 10.1371/journal.pone.0117420. eCollection 2015.
The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression.
We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher's exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC.
Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases.
宿主对丙型肝炎病毒（HCV）感染的先天性免疫反应存在变异性，这就需要排除宿主杀伤细胞免疫球蛋白样受体（KIR）和人类白细胞抗原（HLA）基因型在HCV相关疾病中可能发挥的作用：因此，我们探讨了KIR/HLA基因型与慢性HCV感染（CHC）之间的关系，以及它们与HCV相关肝癌（HCC）或淋巴增殖性疾病进展风险的关系。
我们分析了396例HCV阳性患者的数据，其中包括CHC患者（n = 125）、HCC患者（118例）和淋巴增殖性疾病患者（153例），以及501例HCV阴性患者。所有患者均为HIV和HBV阴性。采用KIR-SSO法确定KIR分型。采用PCR和基因扫描分析检测KIR2DL5和KIR2DS4变异体。采用基于PCR序列的分型方法进行HLA/Ⅰ类基因分型。研究了KIR基因与配体HLA分子之间的相互作用。使用Fisher精确检验和Cochran-Armitage趋势检验估计频率差异。使用连锁不平衡检验估计KIR等位基因的非随机关联。我们发现KIR2DS2/KIR2DL2基因与HCV相关的淋巴增殖性疾病有关。此外，具有HLA-Bw6 KIR3DL1+基因组合的个体发生淋巴瘤的风险高于冷球蛋白血症。发现KIR2DS3基因是与慢性HCV感染相关的主要基因，而HLA-Bw4 + KIR3DS1+的减少与发生HCC的风险增加有关。
我们的数据突出了先天性免疫系统在HCV相关疾病发生发展中的作用，特别是KIR2DS3和KIR2D基因显示出能够指导HCV疾病进展，主要是朝着淋巴增殖性疾病发展。此外，KIR3D/HLA基因组合的测定可指导HCV向淋巴瘤而非肝病发展。在这种情况下，IFN-α疗法作为HCV感染和淋巴增殖性疾病的标准疗法，已知能够短暂增强NK细胞的细胞毒性，支持NK细胞对抗HCV相关和淋巴增殖性疾病的作用。
