The complement system is crucial for maintaining immunological homeostasis in the liver, playing a significant role in both innate and adaptive immune responses. Dysregulation of this system is closely linked to the pathogenesis of various liver diseases. Modulating the complement system can affect the progression of these conditions. To provide insights into treating liver injury by targeting the regulation of the complement system, we conducted a comprehensive search of major biomedical databases, including MEDLINE, PubMed, EMBASE, and Web of Science, to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.

The main cause of the liver fibrosis (LF) remains hepatitis B virus (HBV) infection, especially in China. Histologically, liver fibrosis still occurs progressively in chronic hepatitis B (CHB) patients, even if HBV-DNA is negative or undetectable. The diagnosis of LF is beneficial to control the development of it, also it may promote the reversal of LF. Although liver biopsy is the gold standard of diagnosis in LF at present, it isa traumatic diagnosis. There are no diagnostic biomarkers as yet for the condition. It is badly in need of biomarkers clinically, which is simple to test, minimally invasive, highly specific, and sensitive. Early detection of HBV-LF development is crucial in the prevention, treatment, and prognosis prediction of HBV-LF. Cytokines are closely associated with both immune regulation and inflammation in the progression of hepatitis B virus associated-liver fibrosis (HBV-LF). In this bioinformatic study, we not only analyzed the relationship between HBV-LF and immune infiltration, but also identified key genes to uncover new therapeutic targets.

To find potential biomarkers for liver fibrosis in the development of chronic hepatic B patients.

We obtained two sets of data including CHB/healthy control and CHB/HBV-LF from the Integrated Gene Expression (GEO) database to select for differential expression analysis. Protein-protein interaction (PPI) network was also generated, while key genes and important gene modules involved in the occurrence and development of HBV-LF were identified. These key genes were analyzed by functional enrichment analysis, module analysis, and survival analysis. Furthermore, the relationship between these two diseases and immune infiltration was explored.

Among the identified genes, 150 were individually associated with CHB and healthy control in the differential gene expression (DGE) analysis. While 14 with CHB and HBV-LF. It was also analyzed in the Robust rank aggregation (RRA) analysis, 34 differential genes were further identified by Cytohubba. Among 34 differential genes, two core genes were determined: CCL20 and CD8A. CCL20 was able to predict CHB positivity (area under the receiver operating characteristic curve [AUC-ROC] = 0.883, 95% confidence interval [CI] 0.786-0.963), while HBV-LF positivity ([AUC-ROC] = 0.687, 95% confidence interval [CI] 0.592-0.779). And CD8A was able to predict CHB positivity ([AUC-ROC] = 0.960, 95% confidence interval [CI] 0.915-0.992), while HBV-LF positivity ([AUC-ROC] = 0.773, 95% confidence interval [CI] 0.680-0.856). Relationship between CCL20 gene expression and LF grades was P < 0.05, as well as CD8A.

CCL20 and CD8A were found to be potential biomarkers and therapeutic targets for HBV-LF. It is instructive for research on the progression of LF in HBV patients, suppression of chronic inflammation, and development of molecularly targeted-therapy for HBV-LF.

Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading microbes, plays an essential role for the functions of both classical (CP) and lectin (LP) complement pathways. Complement C4 is the most polymorphic protein in complement system. A plethora of research data demonstrated that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders. In this review, we will discuss the diversity of complement C4 proteins and its genetic structures. In addition, the current development of the regulation of complement C4 activation and its activation derivatives will be reviewed. Moreover, the review will provide the updates on the molecule interactions of complement C4 under the circumstances of bacterial and viral infections, as well as autoimmune diseases. Lastly, more evidence will be presented to support the paradigm that links microbial infections and autoimmune disorders under the condition of the deficiency of complement C4. We provide such an updated overview that would shed light on current research of complement C4. The newly identified targets of molecular interaction will not only lead to novel hypotheses on the study of complement C4 but also assist to propose new strategies for targeting microbial infections, as well as autoimmune disorders.

Chronic hepatitis B virus (CHB) infection is a burden on global healthcare and is associated with a higher risk of serious sequelae, including cirrhosis and hepatocellular carcinoma. The clinical application of entecavir as a treatment for CHB has produced positive outcomes, and so is an attractive form of pharmacological therapy. However, little data exists comparing the safety and efficacy of entecavir for the treatment of hepatitis B virus (HBV)-related compensated, and decompensated cirrhosis, respectively. The aim of the present study was to evaluate entecavir therapy as a treatment for patients with HBV-related compensated and decompensated cirrhosis. A retrospective analysis of 46 compensated patients (compensated group) and 51 decompensated cirrhotic patients (decompensated group) treated with entecavir was conducted. Baseline demographics, clinical outcomes, and adverse events during the treatment were compared. Treatment with entecavir for 96 weeks resulted in significant improvements in serum levels of HBV DNA (P=0.002), albumin (P=0.014), cholinesterase (CHE; P=0.001), HBV DNA negativity rate (P=0.004), Child-Turcotte-Pugh score (P=0.030), alanine aminotransferase normalized rate (P=0.039), and the degree of esophageal varices liver stiffness (P=0.002) in the two groups. However, statistical analysis revealed that the improvements were significantly higher in the compensated group compared with the decompensated group (P<0.05). The complement component (C)3 and C4 levels were also significantly increased in the compensated group compared with the decompensated group at weeks 24, 48 and 96 (P<0.05). In addition, the incidences of hepatocellular carcinoma, upper digestive tract hemorrhage and ascites were significantly higher in the decompensated group compared with the compensated group (P<0.05). In conclusion, treatment with 96-week entecavir therapy produced similar clinical outcomes in compensated and decompensated cirrhotic patients via inhibiting HBV-DNA viral load and recovering complement C3 and C4; however, entecavir exerts a better effect on patients with compensated cirrhosis, and so this therapy may improve the prognosis of such patients.

Alanine aminotransferase (ALT), hepatitis B virus (HBV) DNA levels and age are used commonly to assess liver histology in chronic hepatitis B. Increasing levels of HBV DNA are associated with the increasing prevalence of significant fibrosis in HBeAg-negative patients. It is unclear whether these data can be applied to HBeAg-positive patients. In present study, liver biopsies were performed and clinical parameters were measured in 234 treatment-naive chronic HBeAg-positive patients. The proportion of significant fibrosis in patients with ALT 1-2 × ULN was similar to in patients with ALT more than 2 × ULN (48.4% vs. 51.8%). Patients over 30 years of age (>30 years) had a higher prevalence of significant fibrosis than patients 30 years of age and younger (61.0% vs. 33.6%). Negative correlation between HBV DNA levels and significant fibrosis was observed in patients >30 years. The optimal level of serum HBV DNA to evaluate low risk of significant fibrosis was ≥6.7 log10 IU/ml. Patients with serum HBV DNA levels ≥8.5 log10 IU/ml all had no significant fibrosis, however, patients with HBV DNA levels <4.7 log10 IU/ml all had significant fibrosis. Logistic regressions showed that age, aspartate aminotransferase, platelet count, and HBV DNA levels were independent predictors of significant fibrosis. In summary, older age, elevated ALT, and lower HBV DNA levels are associated with significant fibrosis. Decreasing levels of HBV DNA are associated with increasing prevalence of significant fibrosis in patients >30 years. The threshold of HBV DNA levels for treatment of HBeAg-positive patients needs to be combined with age.

The inflammatory response mediated by the immune system is the major cause of hepatitis B virus (HBV)-associated liver injury. Here, we identified CD59, as a novel HBc-interacting protein in hepatocytes by tandem affinity purification (TAP) screening. The expression of CD59 was markedly down-regulated in HBc-transfected HepG2 or HepG2.215 cells, which resulted in an upshift of hepatocyte sensitivity to membrane attack complex (MAC)-induced cell lysis. These results were consistent with the accumulation of MACs in the liver of HBV-infected patients. Additional analyses using laser confocal microscopy, quantitative PCR and flow cytometry revealed that CD59 was specifically translocated to the nucleus upon binding to HBc, which induced the down-regulation of CD59 on both the mRNA and protein levels.

Liver fibrosis and its end-stage consequence, cirrhosis, represent the final common pathway of virtually all chronic liver diseases. Research into hepatic stellate cell activation, imbalance of the extracellular matrix synthesis and degradation and the contribution of cytokines and chemokines has further elucidated the mechanisms underlying fibrosis. Furthermore, clarification of changes in host adaptive and innate immune systems has accelerated our understanding of the association between liver inflammation and fibrosis. Continued elucidation of the mechanisms of hepatic fibrosis has provided a comprehensive model of fibrosis progression and regression. This review summarizes the current concepts of improvements that have been made in the field of fibrosis.