慢性HBV感染不同临床表型的免疫因子表达模式及免疫遗传特征研究
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摘要
慢性HBV（hepatitis B virus，乙型肝炎病毒）感染多种临床表型的形成机制一直为研究者广为关注。一般认为，宿主遗传因素决定的个体免疫差异在慢性HBV感染的临床转归中起决定作用。慢性HBV感染时机体免疫系统的两大核心改变是树突状细胞激活初始型T细胞能力降低和Th分化失衡。在众多的细胞因子中，尚不清楚何种免疫因素在慢性HBV感染临床表型多样性中起主导作用。全基因组关联研究发现HLA-DQ、HLA-DP基因多态性与持续HBV感染存在关联，但尚无机制上的进一步解释。对HBeAg阴性慢性乙型肝炎的免疫发病机制和宿主遗传发病机制尚无深入研究。慢性HBV感染个体化治疗也迫切需要对其进行免疫状态的评估和宿主遗传特征筛选。
本研究通过包括30个细胞因子/趋化因子的蛋白质芯片来评估慢性HBV感染者不同临床表型的免疫因子表达模式；通过蛋白质相互作用分析评估免疫因子的效应差异；在此基础上筛选出与慢性HBV感染临床转归密切相关的免疫分子；通过病例-对照的遗传关联研究观察这些因子的基因多态性与慢性HBV感染临床表型之间的关联。研究将丰富慢性HBV感染临床表型多样性形成的机制，并为预测慢性HBV感染的临床转归及早期干预治疗提供策略。
主要研究结果如下：
1.对持续ALT（alanine aminotransferase，丙氨酸氨基转移酶）正常的慢性HBV感染者而言，JAK-STAT信号通路的细胞因子表达普遍上调是其重要的免疫特征；较高的表达水平提示较佳的预后；γ链细胞因子、IL-12p70、IL-23p19和IL-29升高引起的免疫效应改变可能对促进自发性HBeAg血清转换和HBV清除发挥重要作用。
2.对慢性乙型肝炎患者而言，炎性趋化因子CXCL9、CXCL10、CXCL11和CCL20适合作为活动性肝炎的免疫评估指标；ALT>5×ULN（upper limit of normal，正常上限值）的HBeAg阳性慢性乙型肝炎与非活动性HBV携带有较多相似的免疫基础可能是这部分人群可以获得较高血清免疫学应答的基础；与HBeAg阳性慢性乙型肝炎相比，IL-29、IL-17、IFN-γ、IL-6、CCL5等上调表达缺陷和IL-21的表达上调所引起免疫效应改变可能与HBeAg阴性慢性乙型肝炎形成机制有关；IL-29和IFN-γ等因子表达上调可作为评价HBeAg阴性慢性乙型肝炎血清免疫学应答的标志。
3.通过HBV清除者与持续HBV感染者的对照遗传关联研究，发现天然免疫、炎症应答和炎性趋化因子等免疫环节的基因多态性与持续HBV感染的易感性密切关联；HLA-DQ、HLA-DP基因多态性与持续HBV感染密切关联最显著；HLA-DQ rs7453920、IL10rs1800872和MX1rs467960呈显著协同遗传，GTC基因型为持续HBV感染的高危基因型；TLR9rs352140与持续HBV感染单独关联。
4.通过HBeAg阳性慢性乙型肝炎与HBeAg阴性慢性乙型肝炎的对照遗传关联研究，发现IL1B、IRAK1、IL4基因多态性与HBeAg阴性慢性乙型肝炎存在关联；男性IL12A基因多态性、女性IL6R基因多态性可能与不同性别HBeAg阴性慢性乙型肝炎的易感性存在关联。
5.通过活动性HBV感染与非活动性HBV携带的对照遗传关联研究，发现IFNG、IL12B、IL15、IL17A、IL1B、IL28B、IL6ST、IL9、TNFRSF18基因多态性与非活动性HBV携带存在关联；IFNG rs2069705独立与非活动性HBV携带关联；IL15rs10833、IL28B rs8099917、IL6ST rs2112979和TNFRSF18rs3819001协同一致遗传，女性CTGC型和TTAC基因型更倾向于发生非活动性HBV携带；女性SLC10A1rs12882299与非活动性HBV携带存在关联。
总之，本研究通过蛋白质芯片技术较为全面的对慢性HBV感染不同临床表型的免疫因子表达模式进行了评估，获得了一些有利于HBV清除的免疫特征，明确了细胞因子与炎症活动程度的关联；并通过病例-对照遗传关联研究筛选出了与持续HBV感染、HBeAg阴性慢性乙型肝炎、非活动性HBV携带等存在关联的基因多态性位点；研究丰富了慢性HBV感染临床表型多样性形成的机制，所筛选出来的免疫特征和基因多态性位点可用于慢性HBV感染的预后评估。
The mechanism of various clinical states of chronic hepatitis B virus (HBV) infectionhas been widely concerned. In generally, the individual differences of the host immunitydetermined by genetic play a crucial role in the clinical outcome of chronic HBV infection.The immune response initiated by the T-cell response to viral antigens is thought to befundamental for viral clearance and disease pathogenesis in HBV infection. However, there isnot clear about the role of numerous cytokines in the mechanism of clinical phenotypediversity of chronic HBV infection.Although the association between HLA-DQ and HLA-DPgene polymorphisms and persistently chronic HBV infection was found by genome-wideassociation studies, there is no further explanation of the mechanism. There are few studyfocused on the immune pathogenesis and host genetic pathogenesis of HBeAg-negativechronic hepatitis B. It is necessary to assess the immune state and screen host genetic featuresfor the individual treatment of chronic HBV infection.
We aimed to evaluate the immune status by detecting the cytokine/chemokine levels ofdifferent clinical phenotypes of chronic HBV infection based on a design protein array, whichincluded30cytokines and chemokines associated with anti-HBV immune, to evaluateimmune effect of cytokines by protein-protein interactions analysis, which completed throughSTRING (Search Tool for the Retrieval of Interacting Genes/Proteins), a database of knownand predicted protein interactions, to screen the cytokines related to the outcomes of chronicHBV infection on the basis of the protein array results, and to observe the association betweengene polymorphisms and clinical phenotype of chronic HBV infection by case-control geneticassociation studies. The study will enrich the mechanism of clinical phenotype diversity ofchronic HBV infection and provide the strategies for predicting the clinical outcome ofchronic HBV infection and intervention treatment.
The results were listed as follow.
1. For HBV infection patients with persistently normal alanine aminotransferase (ALT) levels, the up-regulation of cytokines in JAK-STAT pathway was an important factor. Thehigher level expression was associated with the better prognosis of HBV infection. Theelevation of γ chain cytokines, IL-12p70, IL-23p19, and IL-29in inactive HBV carrier andresolved hepatitis B suggested that the change of lymphocyte function caused by thesecytokines may be key factors to promote spontaneous HBeAg seroconversion and HBVclearance.
2. For patients with chronic hepatitis B, CXCL9CXCL10CXCL11and CCL20wereavailable markers to assess the immune state for active hepatitis. The immune foundation ofHBeAg-positive chronic hepatitis B patients with ALT over5times upper limit of normal wassimilar to inactive HBV carriers. This may be associated with the high rate of HBeAgseroconversion in this part of patients after antivirus treatment. Compared with HBeAg-positive chronic hepatitis B, the up-regulation expression defection of IL-29, IL-17, IFN-gamma, IL-6, and CCL5and compensatory increase of IL-21may be associated with theforming mechanism of HBeAg-negative chronic hepatitis B. Up-regulation of IL-29andIFN-gamma levels may be used as markers to evaluate serum immunological response forHBeAg-negative chronic hepatitis Bpatients.
3. Through genetic association studies between chronic HBV infection and resolvedhepatitis B, we demonstrated that gene polymorphisms of natural immunity, inflammationresponse, and inflammatory chemokines were associated with susceptibility to chronic HBVinfection. Among these genes, the most significant was HLA-DQ and HLA-DP genepolymorphisms. HLA-DQ rs7453920, IL10rs1800872and MX1rs467960were highlylinkage, and GTC haplotype with high-risk of chronic HBV infection. TLR9rs352140wasassociated with chronic HBV infection independent of other polymorphisms.
4. Through genetic association studies between HBeAg-positive chronic hepatitis B andHBeAg-negative chronic hepatitis B, we found that gene polymorphisms of IL1B, IRAK1,and IL4were associated with susceptibility to HBeAg-negative chronic hepatitis B. IL12Agene polymorphism for male and IL6R gene polymorphism for female may be associatedwith susceptibility to HBeAg-negative chronic hepatitis B of male and female, respectively.
5. Through genetic association studies between active HBV infection and inactive HBVcarriers, we found that gene polymorphisms of IFNG, IL12B, IL15, IL17A, IL1B, IL28B,IL6ST, IL9, and TNFRSF18were associated with susceptibility to inactive HBV carriers. IFNG rs2069705was independently associated with inactive HBV carriers and “A” allele wasprone to inactive HBV carriers. IL15rs10833, IL28B rs8099917, IL6ST rs2112979andTNFRSF18rs3819001were highly linkage. CTGC haplotype and TTAC haplotype for femalewere prone to inactive HBV carries. SLC10A1rs12882299for female was associated withinactive HBV carriers.
Conclusion: This study comprehensively demonstrated the differences of immuneamong various states of chronic HBV infection by a protein array and obtained some featuresassociated with HBV clearance or HBeAg seroconversion. The association betweeninflammatory activities and cytokines levels was further clarified. Through genetic associationstudies among different states of HBV infection, the gene polymorphisms loci associated withchronic HBV infection, HBeAg-negative chronic hepatitis B, and inactive HBV carriers werescreened. This study has enriched the mechanism of various clinical states of chronic HBVinfection. Features of immune state and gene polymorphism loci can be used for prognosticassessment of chronic HBV infection.
本研究通过包括30个细胞因子/趋化因子的蛋白质芯片来评估慢性HBV感染者不同临床表型的免疫因子表达模式；通过蛋白质相互作用分析评估免疫因子的效应差异；在此基础上筛选出与慢性HBV感染临床转归密切相关的免疫分子；通过病例-对照的遗传关联研究观察这些因子的基因多态性与慢性HBV感染临床表型之间的关联。研究将丰富慢性HBV感染临床表型多样性形成的机制，并为预测慢性HBV感染的临床转归及早期干预治疗提供策略。
主要研究结果如下：
1.对持续ALT（alanine aminotransferase，丙氨酸氨基转移酶）正常的慢性HBV感染者而言，JAK-STAT信号通路的细胞因子表达普遍上调是其重要的免疫特征；较高的表达水平提示较佳的预后；γ链细胞因子、IL-12p70、IL-23p19和IL-29升高引起的免疫效应改变可能对促进自发性HBeAg血清转换和HBV清除发挥重要作用。
2.对慢性乙型肝炎患者而言，炎性趋化因子CXCL9、CXCL10、CXCL11和CCL20适合作为活动性肝炎的免疫评估指标；ALT>5×ULN（upper limit of normal，正常上限值）的HBeAg阳性慢性乙型肝炎与非活动性HBV携带有较多相似的免疫基础可能是这部分人群可以获得较高血清免疫学应答的基础；与HBeAg阳性慢性乙型肝炎相比，IL-29、IL-17、IFN-γ、IL-6、CCL5等上调表达缺陷和IL-21的表达上调所引起免疫效应改变可能与HBeAg阴性慢性乙型肝炎形成机制有关；IL-29和IFN-γ等因子表达上调可作为评价HBeAg阴性慢性乙型肝炎血清免疫学应答的标志。
3.通过HBV清除者与持续HBV感染者的对照遗传关联研究，发现天然免疫、炎症应答和炎性趋化因子等免疫环节的基因多态性与持续HBV感染的易感性密切关联；HLA-DQ、HLA-DP基因多态性与持续HBV感染密切关联最显著；HLA-DQ rs7453920、IL10rs1800872和MX1rs467960呈显著协同遗传，GTC基因型为持续HBV感染的高危基因型；TLR9rs352140与持续HBV感染单独关联。
4.通过HBeAg阳性慢性乙型肝炎与HBeAg阴性慢性乙型肝炎的对照遗传关联研究，发现IL1B、IRAK1、IL4基因多态性与HBeAg阴性慢性乙型肝炎存在关联；男性IL12A基因多态性、女性IL6R基因多态性可能与不同性别HBeAg阴性慢性乙型肝炎的易感性存在关联。
5.通过活动性HBV感染与非活动性HBV携带的对照遗传关联研究，发现IFNG、IL12B、IL15、IL17A、IL1B、IL28B、IL6ST、IL9、TNFRSF18基因多态性与非活动性HBV携带存在关联；IFNG rs2069705独立与非活动性HBV携带关联；IL15rs10833、IL28B rs8099917、IL6ST rs2112979和TNFRSF18rs3819001协同一致遗传，女性CTGC型和TTAC基因型更倾向于发生非活动性HBV携带；女性SLC10A1rs12882299与非活动性HBV携带存在关联。
总之，本研究通过蛋白质芯片技术较为全面的对慢性HBV感染不同临床表型的免疫因子表达模式进行了评估，获得了一些有利于HBV清除的免疫特征，明确了细胞因子与炎症活动程度的关联；并通过病例-对照遗传关联研究筛选出了与持续HBV感染、HBeAg阴性慢性乙型肝炎、非活动性HBV携带等存在关联的基因多态性位点；研究丰富了慢性HBV感染临床表型多样性形成的机制，所筛选出来的免疫特征和基因多态性位点可用于慢性HBV感染的预后评估。
The mechanism of various clinical states of chronic hepatitis B virus (HBV) infectionhas been widely concerned. In generally, the individual differences of the host immunitydetermined by genetic play a crucial role in the clinical outcome of chronic HBV infection.The immune response initiated by the T-cell response to viral antigens is thought to befundamental for viral clearance and disease pathogenesis in HBV infection. However, there isnot clear about the role of numerous cytokines in the mechanism of clinical phenotypediversity of chronic HBV infection.Although the association between HLA-DQ and HLA-DPgene polymorphisms and persistently chronic HBV infection was found by genome-wideassociation studies, there is no further explanation of the mechanism. There are few studyfocused on the immune pathogenesis and host genetic pathogenesis of HBeAg-negativechronic hepatitis B. It is necessary to assess the immune state and screen host genetic featuresfor the individual treatment of chronic HBV infection.
We aimed to evaluate the immune status by detecting the cytokine/chemokine levels ofdifferent clinical phenotypes of chronic HBV infection based on a design protein array, whichincluded30cytokines and chemokines associated with anti-HBV immune, to evaluateimmune effect of cytokines by protein-protein interactions analysis, which completed throughSTRING (Search Tool for the Retrieval of Interacting Genes/Proteins), a database of knownand predicted protein interactions, to screen the cytokines related to the outcomes of chronicHBV infection on the basis of the protein array results, and to observe the association betweengene polymorphisms and clinical phenotype of chronic HBV infection by case-control geneticassociation studies. The study will enrich the mechanism of clinical phenotype diversity ofchronic HBV infection and provide the strategies for predicting the clinical outcome ofchronic HBV infection and intervention treatment.
The results were listed as follow.
1. For HBV infection patients with persistently normal alanine aminotransferase (ALT) levels, the up-regulation of cytokines in JAK-STAT pathway was an important factor. Thehigher level expression was associated with the better prognosis of HBV infection. Theelevation of γ chain cytokines, IL-12p70, IL-23p19, and IL-29in inactive HBV carrier andresolved hepatitis B suggested that the change of lymphocyte function caused by thesecytokines may be key factors to promote spontaneous HBeAg seroconversion and HBVclearance.
2. For patients with chronic hepatitis B, CXCL9CXCL10CXCL11and CCL20wereavailable markers to assess the immune state for active hepatitis. The immune foundation ofHBeAg-positive chronic hepatitis B patients with ALT over5times upper limit of normal wassimilar to inactive HBV carriers. This may be associated with the high rate of HBeAgseroconversion in this part of patients after antivirus treatment. Compared with HBeAg-positive chronic hepatitis B, the up-regulation expression defection of IL-29, IL-17, IFN-gamma, IL-6, and CCL5and compensatory increase of IL-21may be associated with theforming mechanism of HBeAg-negative chronic hepatitis B. Up-regulation of IL-29andIFN-gamma levels may be used as markers to evaluate serum immunological response forHBeAg-negative chronic hepatitis Bpatients.
3. Through genetic association studies between chronic HBV infection and resolvedhepatitis B, we demonstrated that gene polymorphisms of natural immunity, inflammationresponse, and inflammatory chemokines were associated with susceptibility to chronic HBVinfection. Among these genes, the most significant was HLA-DQ and HLA-DP genepolymorphisms. HLA-DQ rs7453920, IL10rs1800872and MX1rs467960were highlylinkage, and GTC haplotype with high-risk of chronic HBV infection. TLR9rs352140wasassociated with chronic HBV infection independent of other polymorphisms.
4. Through genetic association studies between HBeAg-positive chronic hepatitis B andHBeAg-negative chronic hepatitis B, we found that gene polymorphisms of IL1B, IRAK1,and IL4were associated with susceptibility to HBeAg-negative chronic hepatitis B. IL12Agene polymorphism for male and IL6R gene polymorphism for female may be associatedwith susceptibility to HBeAg-negative chronic hepatitis B of male and female, respectively.
5. Through genetic association studies between active HBV infection and inactive HBVcarriers, we found that gene polymorphisms of IFNG, IL12B, IL15, IL17A, IL1B, IL28B,IL6ST, IL9, and TNFRSF18were associated with susceptibility to inactive HBV carriers. IFNG rs2069705was independently associated with inactive HBV carriers and “A” allele wasprone to inactive HBV carriers. IL15rs10833, IL28B rs8099917, IL6ST rs2112979andTNFRSF18rs3819001were highly linkage. CTGC haplotype and TTAC haplotype for femalewere prone to inactive HBV carries. SLC10A1rs12882299for female was associated withinactive HBV carriers.
Conclusion: This study comprehensively demonstrated the differences of immuneamong various states of chronic HBV infection by a protein array and obtained some featuresassociated with HBV clearance or HBeAg seroconversion. The association betweeninflammatory activities and cytokines levels was further clarified. Through genetic associationstudies among different states of HBV infection, the gene polymorphisms loci associated withchronic HBV infection, HBeAg-negative chronic hepatitis B, and inactive HBV carriers werescreened. This study has enriched the mechanism of various clinical states of chronic HBVinfection. Features of immune state and gene polymorphism loci can be used for prognosticassessment of chronic HBV infection.
引文
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