C-X-C chemokine receptor type 5+CD8+T cells as immune regulators in hepatitis Be antigen-positive chronic hepatitis B under interferonalpha treatment

BACKGROUND C-X-C chemokine receptor type 5(CXCR5)+CD8+T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5+CD8+T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5+CD8+T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5+CD8+T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×104 copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8+T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5+CD8+T cells compared to healthy controls(P<0.01).Notably,CXCR5+CD8+T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5+CD8+T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5+CD8+T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.

Hepatitis B virus-persistent infection and innate immunity defect: Cell-related or virus-related?

The outcomes of hepatitis B virus(HBV) infection are closely related to the age at which infection was acquired. Infection acquired in adult life tends to be selflimited, in contrast to perinatal acquirement, for which chronic persistence of the HBV is a general outcome. Innate immunity plays an indispensable role in early virus infection, facilitating virus clearance. However, it has been reported that HBV is under-recognized and poorly eliminated by the innate immune system in the early stages of infection, possibly explaining the long-lasting persistence of viremia afterwards. Furthermore, due to the existence of covalently closed circular DNA, chronic HBV clearance is very difficult, even when patients are given interferon-α and nucleotide/nucleoside analogs for antiviral therapy. The mechanism by which HBV evades innate immune recognition and establishes persistent infection remains a subject of debate. Besides, some researchers are becoming more interested in how to eradicate chronic HBV infection by restoring or boosting innate immunity. This review aimed to summarize the current knowledge on how intrahepatocyte signaling pathways and innate immune cells act after the onset of HBV infection and how these actions are related to the persistence of HBV. We anticipate the insights presented herein to be helpful for future development of novel immune therapeutic strategies to fight HBV infection.

Novel HBV mutations and their value in predicting efficacy of conventional interferon

BACKGROUND： Accumulating studies assessing the impacts of hot spot mutations on conventional interferon（IFN） efficacy come to discrepant conclusions; studies regarding the mutations in S and RT regions are also unclear. The present study aimed to evaluate the impacts of HBV mutations on the efficacy of conventional IFN. METHODS： A total of 126 patients who received conventional IFN treatment for 48 weeks were enrolled. Biochemical and serological parameters were routinely tested. The sequences of HBV from 78 serum samples were amplified by nested-PCR; mutations were identified with sequence scanner V1.0 after ABI 3730 xl direct sequencing, HBV genotypes were determined according to RT gene sequences utilizing NCBI Genotyping Tool which was based on phylogenetic analysis.RESULTS： The baseline DNA levels of virological response（VR） group were significantly lower than those of no VR group [7.13±0.76 vs 7.69±0.56 lg（copies/m L）, P=0.001]. The baseline ALT levels were significantly higher in the HBe Ag clearance group（204.72±88.65 vs 162.80±85.81 IU/L, P〈0.05） andHBe Ag seroconversion group（204.89 ±95.68 vs 166.75±84.43 IU/L, P〈0.05）. Females and lower BMI levels（20.01±2.33 vs 21.65±3.66 kg/m^2, P〈0.05） were prone to acquired biochemical response（BR）. PC-W28STOP（ntG 1896A） was significantly higher in the combined response（CR） group than that in the no CR group（91.7% vs 39.7%, P=0.001）. Multivariate logistic regression analysis showed that baseline DNA, PC-P159T（ntC2288A）, BCP-N118T（ntA 1726C） and BCP-L134L（ntA 1775C/G/T） influenced VR independently. PC-G182C（nt G2357T）, PC-S64A/T（nt T2003G/A） and BMI were independent influence factors for HBe Ag clearance, HBe Ag seroconversion and BR, respectively. The new predicting model concluded that baseline DNA and new mutations for VR were established successfully, and ROC analysis showed that AUC was 0.842（P〈0.001） with a sensitivity of 0.652 and a specificity of 0.933.CONCLUSIONS： PC-P159T（ntC 2288A）, BCP-N118T（ntA 1726C）, BCP-L134L（nt A1775C/G/T）, PC-G182C（nt G2357T） and PCS64A/T（nt T2003G/A） were novel identified mutations that impacted IFN therapeutic efficacy. These novel mutations could serve as important predictors before conventional IFN treatment.

Diagnosis and management of fulminant Wilson's disease: a single center's experience

Background: Medical therapy is rarely effective inpatients with fulminant Wilson's disease (FWD). Livertransplantation is limited by the lack of donor liver inmost patients with FWD at the time of diagnosis. NewWilson's index, model for end-stage liver disease (MELD)and Child-Pugh score are useful tools for decisionmakingof liver transplantation;however, none of them isan independent decisive tool. It is worthwhile to explorea more effective and practical therapeutic strategy andreevaluate the prediction systems for patients with FWD.Methods: Nine patients with FWD associated withhemolytic crisis and fulminant hepatic failure (FHF) wereinvestigated. The clinical presentation, prognostic scoreand medical therapies of the patients were analyzed.Results: In 7 of the 9 patients with FWD who receivedthe comprehensive therapy of corticosteroid, copperchelatingagent (dimercaptopropansulfonate sodium)and therapeutic plasma exchange (TPE), 6 patientsrecovered from FHF. The remaining one had beenimproved through the comprehensive therapy but died ofsepticemia 51 days later. Two patients with spontaneousbacterial peritonitis (SBP) died from liver failure inthree or five hospital days without plasma exchangeor chelating therapy. All of the 9 patients with FWDpresented with acute hepatic failure, severe jaundice andmild to severe hemolytic anemia. No marked differencein the incidence of severe hemolytic anemia was detectedbetween the survival and deceased groups. However,the incidence and the degree of hepatic encephalopathy(HE) in the non-survival group were higher than thosein the survival group. Unlike the deceased group, thesurvival group had no complications induced by bacterialinfection. Compared to new Wilson's index, Child-Pughscore and MELD score, the variation of prothrombinactivity (PTA) between the survival and deceased groupswas more evident.Conclusions: For patients with FWD, the episodeof severe hepatic encephalopathy or/and spontaneousbacterial peritonitis indicates worse prognosis, andPTA is a recommendable predictor. An emergent livertransplantation should be considered for patients whosePTA is below 20%, or for those with severe HE or/and SBP. The comprehensive therapy of corticosteroid,copper-chelating agent and TPE is effective for patientswithout SBP and whose PTA is higher than 20%.