Research Closer to Finding Ways to Help Patients With Hepatitis
For healthcare workers, there has been a vaccine for Hepatitis B for some time now. T-cell immunity plays a vital role in pathogen infections. MicroRNA are small, single-stranded non-coding RNAs that regulate T-cell immunity by targeting key factors, signaling and proteins and cytokines associated with T-cell activation, differentiation, and function. This study of specific immune responses can provide new therapeutic opportunities against various infectious diseases.
The liver is the largest digestive gland and metabolic organ in the human body. It also functions of detoxification, immunity and hematopoietic (an immature cell that can develop into all types of blood cells). The liver is a vital organ and supports almost every other organ in the body. The liver however is also prone to a number of diseases. Most common is hepatitis. The viral form is the most common but non-viral factors such as autoimmunity can also cause hepatitis. Recent mounting drug research is looking at folk medicine in an effort to find treatment that is effective with low toxicity. Cynanchum atratum is a perennial herbaceous plant native to East Asia and widely distributed in China. When accessing mice treated with cynatratoside A one of the steroidal glycosides isolated from Baiwei, it reduced the numbers of common biological indexes used to monitor liver damage (ALT, AST, LDH, and TBil). The results from the study showed the substance from Baiwei was able to improve the diseased livers in the mice it was tested on. Further study is needed and entering human trials should occur soon (Yang et al, 2019).
Liver cells have an innate resistance to RNA viral infections like hepatitis A, dengue, and Zika thanks to a protein called IRF1 according to researchers at UNC-Chapel Hill and Tokyo Metropolitan Institute of Medical Science. When IRF1 is present in liver cells the protein regulates RARRES3, an enzyme, that when expressed in cells of hepatitis A virus is trying to set up shop and will attack the virus. Both research groups found IRF1 is a master regulator of intrinsic resistance to viruses in liver cells. If in liver cells IRF1 makes sure RARRES3 enzyme will act on the lipids making the cells hostile to hepatitis A infection. In future studies, it is hoped investigation of this innate immunity of liver cells to regulate infection through IRF1 and a better understanding of why it sparks certain cellular function to guard against particular RNA viruses (UNC-Chapel Hill, 2019).
Current Research and Treatments
Innate immune response creates interferon; proinflammatory cytokines complement activation and natural killer cells response. Although the host innate immune system senses and responds to eliminate virus infection hepatitis C virus evades the onslaught and establishes persistent infection in the liver. Approximately 177.5 million people in the world are infected by HCV and annually 1.3 to 3.7 million new cases of HCV occur. Chronic HCV often results in cirrhosis (a chronic disease of liver marked by degeneration of cells, inflammation, and fibrous thickening of tissue), and hepatocellular carcinoma (liver cancer). The immune system has developed two areas innate and adaptive immunity. They work together to prevent infection and also limiting the damage done by invading bugs. HCV makes successful strategies to antagonize the host immune responses and often persists as a chronic infection leading to end-stage life-threatening liver disease. HCV modulates inflammatory responses in different cell populations and microenvironments within the host. The liver is made up mostly of hepatocytes (⁓60-80%) and they can produce TNFα during chronic HCV infection. Natural killer cells are the bridge between innate and adaptive immune responses. The best outcome of this study is the discovery of interferon-free direct-acting antivirals with a sustained virological response (Patra, Ray & Ray, 2019).
Liver resection remains the popular treatment for hepatocellular carcinoma (HCC). The aim of this study was to explore alterations of immune cells in HCC patients with liver resections. The analysis showed that the percentage of CD4⁺ T-cells were not altered by the liver resection but the percentage of CD8⁺ T-cells was decreased at one-week post resection. Myeloid-derived suppressor cells (MDSC) decreased when checked at one-month post resection in patients with a high frequency of MDSC. HCC is aggressive cancer and one of the leading causes of death from cancer. Several therapeutic options have been used to treat HCC depending on what stage it is at. These options include surgical resection, liver transplant, local ablation, transcatheter arterial chemoembolization (TACE) and systemic treatment. Immunity is the most important protection system for a host to defend cancer development. Regulatory T-cells and MDSC are both immunosuppressive cells and stay with cancers. Regulatory T-cells are shown to increase the peripheral blood in HCC, gastric cancer, breast cancer, esophageal cancer, and lung cancer. Frequency of MDSC could be reduced by removal of the tumor. MDSC was reduced one month after surgery to normal levels (Lee et al, 2019).
A prominent role for complement has been identified in the linkage of innate and adaptive immunity. The liver is the main source of complement hepatocytes (liver cells) are the primary sites for synthesis of complement components in vivo (experimentation was done in live isolated cells rather than the whole organism). This study found that hepatitis C virus (HCV) impairs C4 and C3 synthesis. Liver damage may diminish the capacity of complement synthesis in patients. This study found that changes in measured complement components in chronically HCV infected patients do not correlate with liver fibrosis or rheumatoid factor present in the blood, serum albumin, or alkaline phosphatase levels. Complement component C3 is of critical importance in B cell activation and T-cell-dependent antibody response. C3 component activity is required for the expansion of CD8⁺ T-cells during systemic viral infection. Deficiencies in complement may predispose patients to infection via ineffective opsonization (a process by which bacteria or other antigen-bearing entities are made attractive to phagocytes by binding of opsonin to their surface) and defects in the lytic activity via membrane attack complex (Kwon & Ray, 2019).
The introduction of a preventative vaccine for Hepatitis B virus (HBV) has led to an overall reduction in the incidence of chronic infection. Unfortunately, this is not the case in many middle and low-income countries. In the past 20 years, it has been the only communicable disease with increased mortality. Both HBV and HCV contribute to end-stage liver disease and HCC. HCV remains prevalent in North America and Europe even though there is a novel direct-acting antiviral that provides 90% cure rates for patients with chronic HCV. The drug development in HBV is advancing and researchers are on the cusp of major changes in the treatment of chronic HBV. Recent clinical studies have shown the combination or addition of Peg-IFNα results in greater seroconversion. Thus their use in a clinical setting requires further consideration. Novel drug targets are entering clinical trials to determine how well they work (Gill & Kennedy, 2018).
Gill, U.S. & Kennedy, P.T.F. (2018). The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics. Journal of Viral Hepatitis.
Giri, B.R., Mahato, R.I. & Cheng, G. (2019). Roles of microRNAs in T cell immunity: Implications for strategy developments against infectious diseases. Medical Research Reviews, 39(2).
Kwon, Y-C & Ray, R. (2019). Complement regulation and immune evasion by Hepatitis C Virus. In: Law, M. (ed). Hepatitis C Virus Protecols. Methods in Molecular Biology, vol 1911, Humana Press, NY, NY,
Lee, W-C et al. (2019). Myeloid-derived suppressor cells in patients with liver resection for Hepatitis B virus-related hepatocellular carcinoma. Scientific Reports.
Patra, T., Ray, RB & Ray,R. (2019). Strategies to circumvent host innate immune response by hepatitis C virus. Cells, 8(3).
UNC-Chapel Hill. (2019). US and Japanese researchers identify how liver cells protect against viral attacks. University of North Carolina-Chapel Hill, Tokyo Metropolitan Institute of Medical Science.
Yang ,J. et al. (2019). A C₂₁-steroidal glycoside from cynanchum atratum attenuates concanavalin A-induced liver injury in mice. Molecules,24(6).