已显示IFNL4和PDCD1基因的遗传变体影响丙型肝炎病毒(HCV)感染的自发清除。我们调查了734例HCV阳性患者的IFNL4rs12979860和PDCD1多态性,包括461例不同严重程度的肝病和273例淋巴增生性疾病患者,以确定这些基因与患者预后的关联。
通过定量PCR研究了单倍型编码的PDCD1mRNA在肝细胞癌(HCC)组织和外周血单核细胞中的表达水平。流式细胞术检测PD-1及其配体PD-L1。
HCV相关疾病患者IFNL4rs12979860C/T或T/T基因型频率明显高于献血者(P<0.0001)。与HCC相比,表达IFNλ4变体的患者在HCV相关疾病中的频率增加,与HCC组织中的PDCD1mRNA水平相比,在携带PD-1.3A或PD-1.7G等位基因(P=.0025和P=.0167)。仅在混合型冷球蛋白血症(MC)患者中发现PD-1.3和IFNL4之间的连锁不平衡(LD)(HCC中LD=0;MC中LD=72)。MC患者的PBMC在CD19IgMB细胞中表达低水平的PD-L1,在CD4T细胞中表达低水平的PD-1,表明调节性B细胞-T细胞相互作用参与MC的发病机理。
集体,我们的数据表明IFNλ4表达对HCV相关HCC的发展有重要贡献,并且在MC中IFNL4和PDCD1也有重要贡献。
对IFNL4和PDCD1基因的研究有助于更好地理解宿主遗传因素和免疫抗原对HCV相关疾病结局的影响。我们的数据支持IFNλ4的表达与研究的所有不同的HCV相关疾病之间的关联,这阻止了IFNλ3的表达。除此之外,有证据表明,较高的IFNλ4表达与年轻时的肝细胞相关。HCV阳性冷球蛋白血症患者的B细胞上低PD-L1和CD4T细胞上高PD-1的表达模式表明PD-1/PD-L1信号在调节B细胞-T细胞相互作用中的关键作用在这种淋巴增殖性疾病中。
Genetic variants of IFNL4 and PDCD1 genes have been shown to influence the spontaneous clearance of hepatitis C virus (HCV) infection. We investigated the IFNL4 rs12979860 and the PDCD1 polymorphisms in 734 HCV-positive patients, including 461 cases with liver disease of varying severity and 273 patients with lymphoproliferative disorders to determine the association of these genes with patient\'s outcome.
Expression levels of PDCD1 mRNA encoded by haplotypes were investigated by quantitative PCR in hepatocellular carcinoma (HCC) tissue and peripheral blood mononuclear cells. Flow cytometry was used to detect PD-1 and its ligand PD-L1.
The frequency of IFNL4 rs12979860 C/T or T/T genotypes was significantly higher in patients with HCV-related diseases than blood donors (P < .0001). Patients expressing the IFNλ4 variant with one amino acid change that reduces IFNλ4 secretion was found increased in frequency in HCV-related diseases compared to HCC PDCD1 mRNA levels in HCC tissue were significantly higher in cases carrying the PD-1.3 A or the PD-1.7 G allele (P = .0025 and P = .0167). Linkage disequilibrium (LD) between PD-1.3 and IFNL4 was found in patients with mixed
cryoglobulinaemia (MC) only (LD = 0 in HCC; LD = 72 in MC). PBMCs of MC patients expressed low levels of PD-L1 in CD19+IgM+B cells and of PD-1 in CD4+T cells suggesting the involvement of regulatory B cell-T cell interaction to the pathogenesis of MC.
Collectively, our data indicate an important contribution of IFNλ4 expression to the development of HCV-related HCC and an epistatic contribution of IFNL4 and PDCD1 in MC.
Studies of IFNL4 and PDCD1 genes are helpful to better understand the role of host genetic factors and immune antigens influencing the outcome of HCV-related diseases. Our data support an association between the expression of IFNλ4, which prevents the expression of IFNλ3, with all the different HCV-related diseases studied, and besides, evidence that a higher IFNλ4 expression is associated with hepatocellular at a younger age. The expression pattern of low PD-L1 on B cells and high PD-1 on CD4+T-cells in patients with HCV-positive
cryoglobulinaemia suggests a critical role of the PD-1/PD-L1 signaling in modulating B cell-T cell interaction in this lymphoproliferative disease.