Cytokine Expression Pattern And Immunogenetic Features Of Different Of Chronic Hepatitis B Virus Infection Patients

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.