| Background: Hepatitis B virus(HBV) is a small DNA virus belongs to hepadnaviridae family and HBV infection is a global public health problem. Approximately one third of the world's population has serological evidence of past or present infection with HBV and 350–400 million people are chronic HBV surface antigen(HBs Ag) carriers. HBV is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma(HCC), HBV-related end stage liver disease or HCC are responsible for over 0.5–1 million deaths per year. Effective suppression of HBV DNA to reduce the risk of developing cirrhosis and HCC is the primary treatment goal. Currently, two therapeutic agents have been approved for the treatment of adults with chronic hepatitis B(CHB), including interferon a(IFNa) and nucleoside/nucleotide analogs. It is now widely accepted that host adaptive immune responses, especially cellular immune response, play a central role in determining the outcome of hepatitis B virus(HBV) infection. Many cytokines/chemokines are involved in immune reactions in response to HBV infection. Hepatocellular carcinoma(HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death worldwide. A lack of sensitive and specific biomarkers for the early detection of this disease has greatly impeded the development and effectiveness of therapeutic strategies. To date, only a few serum biomarkers are available for the diagnosis of HCC, and the most commonly used circulating marker for HCC is alpha-fetoprotein(AFP). But the sensitivity and specificity of AFP are not sufficient to meet the requirements of a perfect tumor biomarker. There is an urgent need to identify novel biomarkers to improve the early detection of HCC before it has progressed to lethal, advanced stages. Therefore, we need to try to find new ways to treat CHB and stop it from progressing, and there is an urgent need of improved indicators for early and noninvasive diagnosis of HBV-related HCC.The cytokine interleukin-38(IL-38), a newly characterized cytokine of the IL-1 family, was discovered in silico in 2001. An antiinflammatory role was suggested based on sequence homology with IL-1Ra(41%) and IL-36Ra(43%). This assumption was supported by a study showing that binding of recombinant IL-38 to the IL-36 receptor was associated with inhibition of IL-8, IL-17, and IL-22 in human peripheral blood mononuclear cells(PBMCs) under inflammatory conditions. The authors concluded that IL-38 might function as a partial IL-36 receptor antagonist. Another study observed a marked increase in lupus-associated pro-inflammatory mediators following silencing of endogenous IL-38 in PBMCs, which supported the assumed anti-inflammatory function of IL-38. Several genetic association studies suggest an association of IL-38 with inflammatory diseases like spondyloarthritis, rheumatoid arthritis and psoriatic arthritis.Beta 2-Glycoprotein ?(?2GPI), also known as apolipoprotein H, was first described in 1961 and is primarily synthesized in the liver. It is a co-factor for autoantibody recognition of anionic phospholipid antigen in anti-phospholipid syndrome(APS) and is associated with thrombic events and recurrent miscarriage. The variability of ?2GPI expression in individuals with various metabolic syndromes and disease states suggests that it may have clinical importance. It has been reported that ?2GPI can bind to recombinant hepatitis B surface antigen(r HBs Ag), suggesting that it may facilitate entry of the virus into hepatocytes. And it was reported that the association of ?2GPI with HBs Ag is related to the presence of hepatitis B virus(HBV) markers and the ?2GPI-binding activity for HBs Ag was higher in serum from patients with virus in the active replication phase. In our past studies, we also verified that ?2GPI specifically binds to r HBs Ag. In addition, we provided the first proof that a protein exists on the SMMC- 7721 hepatocellular carcinoma(HCC) cell membrane, which can specifically bind ?2GPI. The binding protein was later identified as annexin ?I. What's more, our research suggested that high expression of ?2GPI enhances HBs Ag binding to cell surfaces, thus contributing to virus particle transfer to the sodiumtaurocholate co-transporting polypeptide(NTCP) receptor and interaction with annexin ?I for viral membrane fusion. Furthermore, we also found that ?2GPI may play a role in the development of HBV-related HCC by activating NF-?B via interaction of ?2GPI and HBs Ag. However, whether ?2GPI could be used as an indicator for HBV-related HCC, and its relations with CHB and acute hepatitis B(AHB) were still unclear.Aim: To investigate serum IL-38 level and its clinical role in predicting virological response(VR) to telbivudine(Ld T) in patients with CHB; To evaluate the role of plasma ?2GPI on HBV infection patients with HCC, CHB and acute hepatitis B(AHB).Methods: The study participants were divided into two groups; one group consisted of 43 healthy controls and the other group consisted of 46 patients with HBe Ag-positive CHB. All patients were administered 600 mg of oral Ld T daily for 52 weeks, and they visited physicians every 12 week for physical examination and laboratory tests. Serum IL-38 levels were determined using enzyme-linked immunosorbent assay(ELISA). A total of 12 healthy controls(HC) and 107 HBV infection patients, including 43 HCC, 54 CHB and 10 AHB were enrolled. The plasma concentrations of ?2GPI were determined by ELISA. Correlations between ?2GPI and clinicopathologic data were evaluated by Spearman rank correlation test, and the diagnostic values of ?2GPI were analyzed by receiver operating characteristic(ROC) curves. The concentrations of serum or plasma cytokines were measured using the cytometric bead array(CBA) method. The levels of serum ALT and AST were detected using a Biochemistry Automatic Analyzer. HBs Ag, HBs Ab, HBe Ag and HBe Ab were detected by chemiluminescent microparticle immunoassay. The amount of serum HBV DNA were measured by quantitative PCR assay using a luciferase quantization detection kit.Results:(1) Serum levels of IL-38 at baseline in all patients were higher than those in HCs;(2) the levels returned to normal after the first 12 week of treatment with Ld T;(3) Serum IL-38 levels at baseline were positively associated with serum aspartate aminotransferase levels in patients with CHB;(4) Higher levels of serum IL-38 at baseline were associated with a greater probability of VR to Ld T treatment at 24 week and 52 week;(5) The levels of serum IL-38 in patients with primary non-response at week 12 after treatment initiation were lower than those in patients with primary response;(6) Serum IL-38 levels were correlated with serum IL-6 and IL-12 levels in patients with CHB during treatment with Ld T;(7) The plasma level of ?2GPI was significantly elevated in HBV infection patients with HCC and CHB than HC, while no significantly different was revealed between AHB and HC;(8) Combination of ?-fetoprotein(AFP) and ?2GPI could significantly improve the diagnosis performance of HBV-related HCC;(9) ?2GPI was associated with Hbe Ag in CHB patients;(10) A positive correlation was reveled on ?2GPI and IFN-? in AHB patients.Conclusion:(1) The expression levels of IL-38 and ?2GPI have a clinical role in treating and diagnosing hepatitis B virus associated liver diseases.(2) Higher serum IL-38 levels before treatment indicate a greater probability of VR to Ld T treatment. Elevated serum IL-38 levels in untreated CHB patients reflect ongoing liver injury, which is an indicator of endogenous clearance of HBV infection. These findings are interesting because it might provide novel predictors for good response to antiviral therapy.(3) Plasma ?2GPI was closely associated with HBV-related HCC, which could be used as a novel diagnosis marker in clinical. And plasma ?2GPI levels may be associated with host immunity in patients with CHB and patients with AHB. |
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