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Role of Innate Immune Regulatory Genes, FOXP3 and FOS in Chronic Hepatitis B Infection
Biswajyoti Borkakoty1, Mandakini Das Sarmah1, Tapan Majumdar2
1Regional VRDL, ICMR-Regional Medical Research Centre, NE Region, Dibrugarh, India.
Insights
Chronic hepatitis B (CHB) involves immune dysregulation, with FOS and FOXP3 genes upregulated in HBeAg-positive CHB. Targeting these genes may improve CHB management and prevent liver cancer.
Area of Science:
- Immunology
- Hepatology
- Genetics
Background:
- Hepatitis B virus (HBV) infection leads to chronic hepatitis B (CHB), a major cause of liver disease and mortality worldwide.
- The precise mechanisms driving HBV persistence and CHB remain incompletely understood.
- Immune regulatory genes are hypothesized to play a role in the progression of CHB.
Purpose of the Study:
- To investigate the role of immune regulatory genes in chronic hepatitis B (CHB) compared to spontaneously cleared HBV infection.
- To identify potential genetic markers associated with CHB persistence and its sequelae.
Main Methods:
- A case-control study involving 679 subjects from Northeast India.
- Real-Time Polymerase Chain Reaction Array used to analyze the relative gene expression of 26 innate immunity genes.
- Subjects categorized into CHB with HBeAg(+), CHB with HBeAg(-), spontaneously cleared HBV, and healthy controls.
Main Results:
- Proto-oncogene FOS was upregulated in CHB with HBeAg(+) (2.3-fold) and significantly in hepatocellular carcinoma (4.1-fold).
- FOXP3 gene showed significant upregulation (3.0-fold) in CHB with HBeAg(+) compared to spontaneously cleared HBV infection.
- A higher prevalence of CHB was observed in men (66.4%) than in women (33.6%).
Conclusions:
- CHB with HBeAg positivity is characterized by a disrupted immune response, evidenced by the upregulation of FOS and FOXP3 genes.
- Early induction of HBeAg seroconversion, potentially with FOS inhibitors, could offer new therapeutic strategies for CHB.
- These findings have clinical implications for managing CHB and preventing liver cirrhosis and hepatocellular carcinoma (HCC).
Abstract:
Persistence of hepatitis B virus (HBV) infection leading to chronic infection and its sequalae is responsible for over half a million deaths worldwide. The reason for persistence of chronic hepatitis B (CHB) infection is still not clearly understood. An attempt was made to understand the role of immune regulatory genes in CHB in comparison to spontaneously cleared HBV infection. Relative gene expression of 26 genes involved in innate immunity were studied using Real-Time Polymerase Chain Reaction Array. A total of 679 subjects from three different geographical regions of Northeast India (Assam, Arunachal Pradesh, and Tripura) were included in this case-control study. The cases were subdivided into CHB cases with HBeAg(+)(72), CHB with HBeAg(-)(278), spontaneously cleared controls (88), and healthy controls (228). Overall, 28.3% of the subjects had previous exposure with HBV, while 28.6% had protective antibodies IgG/IgM against HBV. There was a statistically higher number of CHB in men (66.4%) compared to women (33.6%) (p = 0.0001). Proto-oncogene FOS has been found to be moderately upregulated in CHB with HBeAg +ve (2.3-fold) and significantly upregulated (4.1-fold upregulation) in hepatocellular carcinoma. Further, FOXP3 was found to be significantly upregulated (3.0-fold, p = 0.01) in CHB with HBeAg (+) compared to spontaneously cleared HBV infection. In conclusion, CHB with HBeAg positivity was found to have disrupted immune response with upregulation of FOS and FOXP3. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogs along with FOS inhibitors can have important clinical implications in the management of CHB and preventing cirrhosis and HCC.
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