The Changing Expression Levels On T Cell Subsets、PD-1and B Cells Of Chronic Hepatitis C Patients During Interferon Therapy

At present, about200million people have been infected with HCV around theworld, and the chronicity of hepatitis C was up to60-70%.5-20%of them mightdevelop to liver fibrosis, therefore, chronic hepatitis C(chronic hepatitis C, CHC) hasbecome a major public health problem that seriously threats human health. Studieshave been found that the major reasons for the chronicity of hepatitis C, including theimmune evasion evolved by virus rapid mutations and less effective virus removalresulting from dysfunctional lymphocytes.The dysfunctional lymphocytes may berelated to T cell apoptosis、peripheral tissue tolerance、T cell exhaustion and othermechanisms, may also be related to the B cell dysfunction. About this, some scholarsabroad have reported that B lymphocyte increased after HCV infection, consisderingthat long-term HCV antigen stimulation could cause a cloned proliferation of Blymphocytes continuously, but the changes of B lymphocyte has not been reported inchina.Many foreign scholars believe that dysfunction of T cells (including the effectsof HCV-specific CD8+T cells and CD4+T helper cells) may be related to theup-regulated expression of PD-1and its ligand. PD-1, named as the programmed celldeath-1, can be induced expression on the surface of CD4+T cells,CD8+Tcells,natural killer cells T (NKT), B cells, monocytes and other cells. Function analysis showed that, its cytoplasmic domain contained two tyrosine signaltransmission motifs, which can be combined with enzyme tyrosine phosphorylationSHP-2after the phosphorylation, and further make the downstream effects moleculessuch as tyrosine kinase (Syk) and phosphatidyl inositol kinase (PI3K)dephosphorylation to regulate cell function. After combined with its ligands PD-L, thePD-1produced an immune suppressing signal, which can restrain the immuneregulation function of CD4+T cells and the Virus removal function of CD8+T cells, andconsequently lead to less effective virus HCV removal and the chronicity of hepatitisC.The treatment of CHC is mainly antiviral therapy, and its recognized internationalstandard treatment is Pegylated interferon(PEG-IFN) plus ribavirin（RBV），whichwould regulate the immune system, increase the body antiviral immunological functionand directly inhibit viruses replication mechanism and consequently make thesustained virological response (SVR) rate increase to about70%, compared with just40%SVR of ordinary interferon. However, under the existing treatment condition,there are still a considerable number of patients with no response or relapse aftertreatment. Research on the effectiveness of interferon therapy is always hot issue inrecent years, and most of them think that virus and host factors altogether affect thetreatment outcome of interferon therapy, and different virological response typesduring treatment can provide valuable information in the prediction for the treatmenteffect. About the different expression levels on T cell subsets、PD-1and B cells ofchronic hepatitis C（CHC）patients with different response types, at present there arefew reports in China. In this study,20cases of rapid virological response（RVR）and20cases of null response（NR）selected from141chronic hepatitis c patients with thePEG-interferon alpha-2a plus ribavirin treatment were retrospectively analyzed.Observe the expression levels on T cell subsets(CD4T+、CD8T+)、PD-1、B cells ofchronic hepatitis C（CHC）patients duing interfern therapy, and discuss the body’simmune status and the relationship between PD-1and different response types (RVR orNR）in the CHC patients during interferon therapy. ObjectivesObserve the changing expression levels on T cell subsets(CD4T+、CD8T+)、PD-1、B cells of chronic hepatitis C（CHC）patients during interferon therapy and discuss itsclinical significance.MethodsAll subjects were selected from141cases CHC patients by PEG-IFN α-2atherapy, of which20cases achieved rapid virological response（RVR）,20casesachieved null response （NR）. And20healthy controls were comprised of controlgroup in this study. The expression levels of T cell subsets, PD-1and B cells inperipheral blood of all subjects before and12weeks after PEG-IFN therapy weredetected by flow cytometry. The alanine aminotransferase and total bilirubin in theserum were measured by automatic biochemical analyzer,；the HCV viral load weredetected by the COBAS AmpliPrep/COBASTaqMan48automatic carrier instruments.Results1. Compared with those of normal controls, the expression levels of CD4+T,CD4+/CD8+and CD19+B of chronic hepatitis C patients were higher, the expressionlevels of CD8+T were lower, and the expression density of PD-1on T cell subsets(CD4T+、CD8T+)was significantly higher, there was significantly difference in allresults (P＜0.01).2. PD-1expression on T cell subsets(CD4T+、CD8T+) of peripheral blood may benegatively correlated with serum ALT levels、total bilirubin levels, but there was notsignificantly statistical difference.There was no correlation between the PD-1on T cellsubsets (CD4T+、CD8T+) of peripheral blood and HCV-RNA levels（r=-0.105，0.268，P>0．05）.3. Compared with those of RVR group, the expression levels of CD4+T, CD4+/CD8+and CD19+B of NR group after12weeks by peg-interferon therapy werehigher, the expression levels of CD8+T were lower (P＜0.01or＜0.05). And theexpression density of PD-1on T cell subsets（CD4T+、CD8T+） was higher, there is asignificantly statistical difference (P＜0.01).Conclusions1. It may exist that the unbalance of the T cell subsets and B cells of CHC patients,their immune function have been recovered after PEG-IFN therapy.2. The higher expression levels of PD-1may be associated with HCV persistentinfection and it may be an important reason for the response decline of T cell.3. There was no correlation between the PD-1on T cell subsets (CD4T+、CD8T+)of peripheral blood and HCV-RNA levels、ALT levels、total bilirubin levels.