The liver is an immunologically tolerant organ that is uniquely equipped to limit hypersensitivity to food-derived antigens and bacterial products through the portal vein and can feasibly accept ...liver allografts. The adaptive immune response is a major branch of the immune system that induces organ/tissue-localized and systematic responses against pathogens and tumors while promoting self-tolerance. Persistent infection of the liver with a virus or other pathogen typically results in tolerance, which is a key feature of the liver. The liver's immunosuppressive microenvironment means that hepatic adaptive immune cells become readily tolerogenic, promoting the death of effector cells and the "education" of regulatory cells. The above mechanisms may result in the clonal deletion, exhaustion, or inhibition of peripheral T cells, which are key players in the adaptive immune response. These tolerance mechanisms are believed to be responsible for almost all liver diseases. However, optimal protective adaptive immune responses may be achieved through checkpoint immunotherapy and the modulation of hepatic innate immune cells in the host. In this review, we focus on the mechanisms involved in hepatic adaptive immune tolerance, the liver diseases caused thereby, and the therapeutic strategies needed to overcome this tolerance.
Immune checkpoint blockade has become a promising therapeutic approach to reverse immune cell exhaustion. Coinhibitory CD96 and T‐cell immunoglobulin and ITIM domain (TIGIT), together with ...costimulatory CD226, bind to common ligand CD155. The balancing between three receptors fine‐tunes immune responses against tumors. In this study, we investigated the expression of CD96, TIGIT, and CD226 in 55 fresh human hepatocellular carcinoma (HCC) samples, 236 paraffin‐embedded HCC samples, and 20 normal human livers. The cumulative percentage, absolute count, and mean fluorescence intensity (MFI) of CD96+ NK cells are significantly increased in the intratumoral tissues of HCC and break the balance between three receptors. Human CD96+ NK cells are functionally exhausted with impaired interferon‐gamma (IFN‐γ) and tumor necrosis factor‐alpha (TNF‐α) production, high gene expression of interleukin (IL)‐10 and transforming growth factor‐beta 1 (TGF‐β1), and low gene expression of T‐bet, IL‐15, perforin, and granzyme B. In addition, blocking CD96‐CD155 interaction specifically increases lysis of HepG2 cells by NK cells. HCC patients with a high level of CD96 or CD155 expression within tumor are strongly associated with deteriorating disease condition and shorter disease‐free survival (DFS) and overall survival times. Patients with a higher cumulative percentage of CD96+ NK cells within tumor also exhibit shorter DFS. High plasma level of TGF‐β1 in HCC patients up‐regulates CD96 expression and dynamically shifts the balance between CD96, TIGIT, and CD226 in NK cells. Blocking TGF‐β1 specifically restores normal CD96 expression and reverses the dysfunction of NK cells. Conclusion: These findings indicate that human intratumoral CD96+ NK cells are functionally exhausted and patients with higher intratumoral CD96 expression exhibit poorer clinical outcomes. Blocking CD96‐CD155 interaction or TGF‐β1 restores NK cell immunity against tumors by reversing NK cell exhaustion, suggesting a possible therapeutic role of CD96 in fighting liver cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Hepatitis B virus (HBV) can induce chronic inflammation, cirrhosis, and eventually hepatocellular carcinoma (HCC). Despite evidence suggesting a link between adaptive immunity and HBV-related ...diseases in humans, the immunopathogenic mechanisms involved are seldom described. Here we show that expression of TIGIT, a promising immune checkpoint in tumor immunotherapy, increases with age on hepatic CD8
T cells in HBsAg-transgenic (HBs-tg) mice whose adaptive immune system is tolerant to HBsAg. TIGIT blockade or deficiency leads to chronic hepatitis and fibrosis, along with the emergence of functional HBsAg-specific cytotoxic T lymphocytes (CTLs), suggesting adaptive immune tolerance could be broken by TIGIT blockade or deficiency. Importantly, HBsAg vaccination further induces nonresolving inflammation and HCC in a CD8
T cell-dependent manner in TIGIT-blocked or -deficient HBs-tg mice. Therefore, CD8
T cells play an important role in adaptive immunity-mediated tumor progression and TIGIT is critical in maintenance of liver tolerance by keeping CTLs in homeostatic balance.
With the development of white light-emitting diode (LED) technology, near-infrared (NIR) phosphor-converted (pc) LED is becoming a new emerging light source. However, due to the lack of long ...wavelength components of the phosphors, the application of NIR pc-LED is restricted. In this work, a continuous ultra-broadband NIR emission without the emission gap in the 850–950 nm region has been realized in the Mg4Nb2O9 (MNO):Cr3+, Yb3+ phosphor. Meanwhile, when compared to MNO:Cr3+, an improved internal quantum efficiency (from 55.4% to 72.6%) and thermal stability (from 39% to 63% at 100 °C) have been obtained for MNO:Cr3+, Yb3+, which is attributed to the combined effect of the efficient energy transfer from Cr3+ to its nearest Yb3+ and the unique energy levels of Yb3+. The performances of the fabricated pc-LED devices by combining MNO:Cr3+, Yb3+ with 460 nm LED chips were also given, and the results demonstrate that the MNO:Cr3+, Yb3+ phosphor may have potential for practical application in the NIR pc-LED.
Hepatitis B virus (HBV) prevalence is highest in Sub-Saharan Africa including Ethiopia. HBV genotypes have distinct geographic distributions and play a role in course of infection and treatment ...management. However, in Ethiopia there is paucity of information about distribution of HBV genotypes. This study was done to determine genotype, mutation and sero-virological profiles of HBV isolates in Southern Ethiopia. Cross-sectional, laboratory based study was conducted on 103HBsAg sero-positive samples from a total of 2,237 screened blood donors. HBV serological markers and biochemical assays were done. Serum viral load was measured using quantitative real-time PCR. Partial HBV S-gene was amplified with nested PCR and sequenced. Bioinformatics tools were utilized to determine genotypes, serotypes and mutations. Of 103 HBsAg reactive serum samples, 14.6% and 70.9% were sero-positive for HBeAg and HBeAb, respectively. Ninety-eight samples gave detectable viral load with a median of 3.46(2.62-4.82) log IU/ml. HBeAg sero-positive donors carried elevated levels of viral load. Eighty five isolates were successfully amplified, sequenced and genotyped into 58 (68.2%) genotype A (HBV/A) and 27 (31.8%) genotype D (HBV/D). HBV serotypes found were adw2 (74.1%), ayw2 (24.7%), and ayw3 (1.2%). In twenty-four (28.2%) samples mutations in the major hydrophilic region (MHR) were observed. Donors infected with HBV/A had higher viral load and more frequent MHR mutation than HBV/D infected donors. This study illustrated distribution of HBV genotype A and D among blood donors in southern Ethiopia. It also demonstrated occurrence HBV variants that may influence clinical aspects of HBV infection. The study contributes in narrowing the existing gap of HBV molecular study in Ethiopia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N
6
-methyladenosine (m
6
A) ...methylation) is unclear. Here we report decreased expression of the m
6
A “writer” METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of
Mettl3
in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m
6
A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m
6
A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.
This paper presents a novel three-time slot transmission protocol designed for energy-constrained two-way relay systems. In a departure from traditional energy sources, our approach serves a dual ...purpose by not only providing power to the system but also significantly enhancing its security. We leverage both physical-layer network coding (PNC) and bit-level Exclusive OR (XOR) technology to amplify system capacity and bolster security. Given the unavailability of exact closed-form solutions, we utilize tight upper bounds for the signal-to-noise ratio (SNR) to derive approximate closed-form results, specifically focusing on outage and intercept performance under Rayleigh channel conditions. We also provide performance bounds for outage and intercept probabilities in the high SNR regime. Our simulation results validate the accuracy of our derived probabilities, demonstrating consistency with Monte Carlo simulations. Furthermore, our investigation reveals that the time allocation factor has minimal impact on the security and reliability of the proposed protocol, particularly under high SNR conditions. In addition, we conduct a comparative analysis between the XOR scheme introduced in this article and non-XOR (NXOR) systems. This analysis underscores the superior security-reliability tradeoff of our approach, particularly in scenarios characterized by poor channel conditions between the energy source user and potential eavesdroppers.
Summary
Natural killer (NK) cells have a specialized function in peripheral organs, which is determined by the organ‐specific niches. We have attempted to explore whether lung NK cells display a ...particular phenotype according to their function in the unique pulmonary environment in health or during respiratory infection in mice. In healthy mice, higher frequencies of NK cells among lymphocytes were detected in the lung than in other tissues (lymph node, bone marrow, spleen, blood and liver), and lung NK cells maintained a more mature phenotype, implying that lung NK cells were critical for the pulmonary immune response. However, lung NK cells expressed higher levels of inhibitory receptors and lower levels of activating receptors, migration/adhesion‐associated molecules and co‐stimulatory molecules than splenic NK cells, implying that lung NK cells were quiescent, and the activation of lung NK cells was tightly regulated by the pulmonary environment in health. During respiratory infection, lung NK cells could be activated and express functional molecules (CD107a and interferon‐γ) to take part in the response to infection quickly. These results suggested that the unique pulmonary environment promotes the development of NK cells with a lung‐specific phenotype.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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