Juanjuan Zhao

Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients.

Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection. Although NK cells have been implicated in inducing hepatocellular damage in patients with chronic hepatitis virus infections, the roles that hepatic NK cells play in chronic hepatitis B virus (HBV) infections remain obscure. In this study, we comprehensively characterized intrahepatic and peripheral NK cells and investigated their impact on liver pathology in a cohort of HBV‐infected individuals; this cohort included 51 immune‐activated (IA) patients, 27 immune‐tolerant (IT) carriers, and 26 healthy subjects. We found that NK cells expressing NK receptors (activation receptors) preferentially accumulated in the livers of IA patients, in which they were activated and skewed toward cytolytic activity but without a concomitant increase in interferon‐γ production, in comparison with those of IT carriers and healthy subjects. Further analysis showed that the livers of IA patients, in comparison with those of IT and healthy subjects, expressed higher levels of interleukin‐12 (IL‐12), IL‐15, and IL‐18 in situ and lower levels of IL‐10, which in vitro can induce the activation and degranulation of NK cells from healthy individuals. Finally, hepatic NK cells displayed more cytolytic activity than peripheral NK cells, and this was found to be positively correlated with the liver histological activity index and serum alanine aminotransferase levels in these IA patients. Conclusion: In IA patients, hepatic NK cells are activated and preferentially skew toward cytolytic activity, which depends on an imbalanced cytokine milieu and correlates with liver injury during chronic HBV infection. (HEPATOLOGY 2011)

Pathological functions of interleukin‐22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment

It is well established that interleukin (IL)‐22 has hepatoprotective and antifibrotic functions in acute liver injury models; however, its function in patients with liver fibrosis and liver cirrhosis (LC) remains obscure. In the current study, we demonstrated that expression of numerous IL‐22 pathway‐associated genes was significantly up‐regulated in hepatitis B virus (HBV)‐infected liver tissues, compared to normal controls, through microarray analysis. In agreement with these findings, liver‐infiltrating IL‐22+ cells were largely increased in HBV‐infected patients with LC, compared to those without LC or healthy subjects, and were positively associated with liver fibrosis staging scores. Immunohistochemistry and flow cytometric analyses revealed that IL‐22 was produced by multiple intrahepatic immune cells and, preferentially, by T‐helper (Th) 17 cells in LC patients. In an HBV transgenic (Tg) mouse model of T‐cell‐mediated chronic liver inflammation and fibrosis, blockade of IL‐22 attenuated hepatic expression of chemokine (C‐X‐C motif) ligand 10 and chemokine (C‐C motif) ligand 20 (CCL20) and subsequently reduced Th17 recruitment and liver inflammation and fibrosis progression. In vitro treatment with IL‐22 stimulated hepatic stellate cells (HSCs) to secrete several chemokines and subsequently promoted Th17 cell chemotaxis. Blocking C‐X‐C chemokine receptor type 3 or CCL20 reduced Th17 cell chemotaxis by IL‐22‐treated HSCs. Conclusions: IL‐22 plays a pathological role in exacerbating chronic liver inflammation and fibrosis by recruiting hepatic Th17 cells in HBV‐infected patients and HBV Tg mice. (Hepatology 2014;59:1331‐1342)

Hot Corrosion of an Electrodeposited Ni-11 wt % Cr Nanocomposite under Molten Na2SO4 – K2SO4 – NaCl

A Ni-Cr nanocomposite with an average Cr concentration of 11 (wt %) was deposited onto nickel plate by simultaneous electrodeposition of Ni and Cr nanoparticles from a nickel sulfate bath. The nanocomposite consisted of a nanocrystalline Ni matrix and dispersed Cr nanoparticles with a mean size of 33 nm. For comparison, two Ni-Cr alloys, one with similar Cr content (10 wt %) and the other with much higher Cr content (20 wt %), were prepared using electro-arc melting. Hot corrosion testing under molten Na2SO4-K2SO4-NaCl in air at 700 degrees C showed that rapid formation of a continuous chromia-rich scale is essential for hot corrosion protection. This was the case only for the nanocomposite. Internal sulfidation was observed for arc-melted alloys, but not for the nanocomposite. The results demonstrate that it was not primarily the Cr content but the unique structure of the nanocomposite that was responsible for its superior hot corrosion resistance. The protection mechanism lies in the fast formation of a continuous chromia scale on the nanocomposite, due to the easy nucleation of chromia on both chromium nanoparticles and abundant nickel grain boundaries, and then fast linking of the nuclei as a result of enhanced diffusion of Cr through those grain boundaries. (c) 2005 The Electrochemical Society.

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

Group 3 innate lymphoid cells (ILC3s) have demonstrated roles in promoting antibacterial immunity, maintaining epithelial barrier function, and supporting tissue repair. ILC3 alterations are associated with chronic inflammation and inflammatory disease; however, the characteristics and relevant regulatory mechanisms of this cell population in HIV-1 infection are poorly understood due in part to a lack of a robust model. Here, we determined that functional human ILC3s develop in lymphoid organs of humanized mice and that persistent HIV-1 infection in this model depletes ILC3s, as observed in chronic HIV-1-infected patients. In HIV-1-infected mice, effective antiretroviral therapy reversed the loss of ILC3s. HIV-1-dependent reduction of ILC3s required plasmacytoid dendritic cells (pDCs), IFN-I, and the CD95/FasL pathway, as targeted depletion or blockade of these prevented HIV-1-induced ILC3 depletion in vivo and in vitro, respectively. Finally, we determined that HIV-1 infection induces CD95 expression on ILC3s via a pDC- and IFN-I-dependent mechanism that sensitizes ILC3s to undergo CD95/FasL-mediated apoptosis. We conclude that chronic HIV-1 infection depletes ILC3s through pDC activation, induction of IFN-I, and CD95-mediated apoptosis.

Natural Killer Cells Are Characterized by the Concomitantly Increased Interferon-γ and Cytotoxicity in Acute Resolved Hepatitis B Patients

Natural killer (NK) cells are abundant in the liver and have been implicated in inducing hepatocellular damage in patients with chronic hepatitis B virus (HBV) infection. However, the role of NK cells in acute HBV infection remains to be elucidated. We comprehensively characterized NK cells and investigated their roles in HBV clearance and liver pathology in 19 chronic hepatitis B (CHB) patients and 21 acute hepatitis B (AHB) patients as well as 16 healthy subjects. It was found that NKp46+ NK cells were enriched in the livers of AHB and CHB patients. We further found that peripheral NK cells from AHB patients expressed higher levels of activation receptors and lower levels of inhibitory receptors than those from CHB patients and HC subjects, thus displaying the increased cytolytic activity and interferon-γ production. NK cell activation levels were also correlated positively with serum alanine aminotransferase levels and negatively with plasma HBV DNA levels in AHB patients, which is further confirmed by the longitudinal follow-up of AHB patients. Serum pro-inflammatory cytokine and chemokine levels were also increased in AHB patients as compared with CHB and HC subjects. Thus, the concomitantly increased interferon-γ and cytotoxicity of NK cells were associated with liver injury and viral clearance in AHB patients.

Prior Electrodeposition of Nanocrystalline Ni – CeO2 Film Fabricating an Oxidation-Resistant Chromized Coating on Carbon Steels

With the prior electrodeposition of nanocrystalline Ni film without or with the dispersions of CeO2 nanoparticles, a carbon steel was chromized using a conventional pack-cementation method but at a greatly decreased temperature (700 degrees C). The chromized coating on the Ni-CeO2 film had a considerable thickness, throughout which chromium was continuously distributed, and an extremely low scaling rate during oxidation at 700 degrees C in air. The study offers a novel approach for fabricating a low- temperature chromized coating with a desired oxidation performance on conventional steels. (c) 2006 The Electrochemical Society.

Vaccines Targeting PreS1 Domain Overcome Immune Tolerance in HBV Carrier Mice

Strong tolerance to hepatitis B virus (HBV) surface antigens limits the therapeutic effect of the conventional hepatitis B surface antigen (HBsAg) vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of the preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1‐polypeptide rather than HBsAg vaccination induced robust immune responses in HBV carrier mice. The anti‐preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1‐polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1‐polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg/hepatitis B surface antibody serological conversion and clear chronic HBV infection in carrier mice. Conclusion: These results suggest that preS1 can function as a therapeutic vaccine for the control of CHB. (Hepatology 2017;66:1067‐1082)

Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice

Strong tolerance to hepatitis B virus (HBV) surface antigens limits the therapeutic effect of the conventional hepatitis B surface antigen (HBsAg) vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of the preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1‐polypeptide rather than HBsAg vaccination induced robust immune responses in HBV carrier mice. The anti‐preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1‐polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1‐polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg/hepatitis B surface antibody serological conversion and clear chronic HBV infection in carrier mice. Conclusion: These results suggest that preS1 can function as a therapeutic vaccine for the control of CHB. (Hepatology 2017;66:1067‐1082)

Photosynthesis, leaf morphology and chemistry of Pinus koraiensis and Quercus mongolica in broadleaved Korean pine mixed forest

Leaf traits and physiology are species-specific and various with canopy position and leaf age. Leaf photosynthesis, morphology and chemistry in the upper and lower canopy positions of Pinus koraiensis Sieb. et Zucc and Quercus mongolica Fisch. ex Turoz in broadleaved Korean pine forest were determined in September 2009. Canopy position did not significantly affect light-saturated photosynthetic rate based on unit area (Parea) and unit dry mass (Pmass), apparent quantum yield (α), light compensation point (LCP), light saturation point (LSP); total nitrogen (Nm), phosphorus (Pm), carbon (Cm), and chlorophyll content (Chlm) per unit dry mass; leaf dry mass per unit area (LMA) and photosynthetic nitrogen-use efficiency (PNUE) for P. koraiensis current-year needles and Q. mongolica leaves. While in P. koraiensis one-year-old needles, Parea, Pmass, α and LCP in the upper canopy were lower than those in the lower canopy. The needles of P. koraiensis had higher Cm and LMA than leaves of Q. mongolica, but Pmass, Chlm and PNUE showed opposite trend. There were no differences in Parea, LSP, Nm, and Pm between the two species. Needle age significantly influenced photosynthetic parameters, chemistry and LMA of P. koraiensis needles except LCP, LSP and Cm. In contrast to LMA, Parea, Pmass, Nm, Pm, Chlm, and PNUE of one-year-old needles were significantly lower than those of current-year needles for P. koraiensis. The negative correlations between LMA and Pmass, Nm, Pm, Chlm, and positive correlations between Pmass and Nm, Pm, Chlm were found for P. koraiensis current-year needles and Q. mongolica leaves. Our results indicate that leaf nitrogen and phosphorus contents and nutrient absorption from soil are similar for mature P. koraiensis and Q. mongolica growing in the same environment, while difference in carbon content between P. koraiensis and Q. mongolica may be attributed to inherent growth characteristics.

Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients

Natural killer (NK) cells can induce liver fibrosis remission by killing hepatic stellate cells (HSCs) and producing interferon (IFN)-γ in a mouse model; however, their anti-fibrotic immune-characteristics and regulatory mechanisms by HSCs remain to be determined, especially in livers from HBV-infected liver cirrhosis (LC) patients. We analyzed frequency, phenotype and anti-fibrotic function of hepatic and peripheral NK subsets in 43 HBV-LC patients. We found that hepatic NK subsets from LC patients displayed a decreased frequency, activation status and anti-fibrotic activity compared with those from chronic hepatitis B patients, which were mainly mediated by increased intrahepatic tumour-growth factor (TGF)-β because blockade of TGF-β significantly reversed NK anti-fibrotic function in vitro. In vivo, hepatic NK cells were enriched in proximity to the α-smooth muscle actin (α-SMA+) area within mild fibrosis regions; while in severe fibrotic areas, they were either directly attached to or separated from the α-SMA+ region. NK cells from LC patients could enter HSCs to form emperipolesis (a cell-in-cell structure) and become apoptotic; anti-TGF-β treatment ameliorated this emperipolesis. This finding suggested a novel mechanism by which activated HSCs impair NK cells’ anti-fibrosis capacity through a TGF-β-dependent emperipolesis in LC patients, providing an anti-fibrotic rational by enhancing NK cell activity.