ABSTRACT
Ocular infection of herpes simplex virus-1 (HSV1) can result in herpetic stromal keratitis (HSK),which impairs vision and is a common cause of human blindness.Studies indicated that HSK lesions are mainly orchestrated by CD4+ T cells.Herpesvirus entry mediator (HVEM),a tumor necrosis factor receptor superfamily member,facilitates virus entry through interactions with viral glycoprotein D (gD).HVEM,a widely expressed tumor necrosis factor (TNF) receptor superfamily member with diverse roles in immune signaling.Intriguingly,HVEM has five receptors:two costimulatory molecules (LIGHT and LT-α),two coinhibitory molecules (BTLA and CD160),and the HSV-gD.HVEM is referred to as a molecular switch because of its capacity to deliver costimulatory signals when bound to LIGHT/LT-α and to produce inhibitory signals when bound to BTLA/CD160.In this paper,the researching progress of the five receptors functions of HVEM and CD160/BTLA-HVEM-LIGHT/LT-α signaling pathway in the HSK were reviewed.We have to provide an insight into the pathogenesis of HSK and clinical ideas for the effective treatment of HSK.Through effective clinical intervention,the inflammatory immune response is reduced,thereby achieving therapeutic effects on recurrence of autoimmune diseases and chronic immune diseases.
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Objective To evaluate effects of a fusion protein LTβR-Fc, which can block the herpesvirus entry mediator ligand (LIGHT-HVEM)signaling pathway, on ovalbumin-induced dermatitis in a mouse model. Methods Thirty BALB/c mice were randomly and equally divided into 3 groups: blank control group treated with 100 μl of sodium chloride physiological solution, model group sensitized with 100 μl of sodium chloride physiological solution containing 100 μg ovalbumin, blocker group firstly blocked with 100 μl of sodium chloride physiological solution containing 100 μg LTβR-Fc followed by sensitization with 100 μl of sodium chloride physiological solution containing 100 μg ovalbumin at 24 hours after the blocking. Disease severity was evaluated by eczema area and severity index (EASI)score, and lesional size was measured on day 0, 4, 8, 12, 15, 20, 23, 27, 31 and 34 after the first sensitization. A total of three sessions of sensitization were carried out. At the end of treatment, all the mice were sacrificed after serum was obtained from their orbital cavities. Thereafter, tissue specimens were obtained from skin lesions, and single cell suspensions of the spleen were prepared. RT-PCR was performed to detect mRNA expressions of interferon γ (IFN-γ), interleukin 4 (IL-4)and IL-5 in murine lesions, ELISA to measure IFN-γ, IL-4 and IL-5 levels in culture supernatants of murine splenocytes, as well as ovalbumin-specific and total IgE and IgG1 levels in murine sera. Results LTβR-Fc significantly suppressed inflammatory response in the mouse model of dermatitis induced by ovalbumin. Compared with the model group, the blocker group showed significantly decreased lesion area and EASI score (both P < 0.05). In addition, a significant decrease was observed in the mRNA expressions of IL-4 (0.88 ± 0.25 vs. 1.81 ± 0.25, P < 0.05), IL-5 (0.75 ± 0.15 vs. 1.24 ± 0.26, P < 0.05)and IFN-γ (0.62 ± 0.09 vs. 1.11 ± 0.19, P < 0.05)in murine lesions, and in supernatant levels of IL-4 (9.58 ± 1.44 ng/L vs. 20.12 ± 5.39 ng/L, P < 0.05), IL-5 (11.37 ± 2.02 ng/L vs. 22.77 ± 4.07 ng/L, P < 0.05)and IFN-γ (16 167 ± 950.40 ng/L vs. 23 930 ± 44.20 ng/L, P < 0.05)in the blocker group compared with the model group. The serum levels of both total IgE and ovalbumin-specific IgE were significantly lower in the blocker group than in the model group(total IgE: 27 466.67 ± 2 052.64 μg/L vs. 32 277 ± 407.53 μg/L, P < 0.05; ovalbumin-specific IgE: 1 296.33 ± 32.72 μg/L vs. 2 323.33 ± 502.43 μg/L, P < 0.05), so were those of total IgG1 (0.46 ± 0.11 μg/L vs. 0.84 ± 0.11 μg/L, P < 0.05)and ovalbumin-specific IgG1 (0.62 ± 0.11 μg/L vs. 0.86 ± 0.07 μg/L, P < 0.05). Conclusion The fusion protein LTβR-Fc can alleviate symptoms of ovalbumin-induced dermatitis in the mouse model likely by suppressing the LIGHT-HVEM signaling pathway, suggesting that this signaling pathway may serve as a target for the treatment of dermatitis(such as atopic dermatitis).
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Objective:To explore the role of TNFSF14 and its receptors LTβR and HVEM in the pathogenesis of virus hepatitis.Methods:Marine fulminant viral hepatitis model was established by infecting mice with MHV-3.Liver tissue destruction in LIGHT KO and WT mice were analyzed by HE staining and ALT levels in serum by automatic biochemical analyzer .The mRNA levels of HVEM and LTβR in the liver and spleen tissues in the indicated time points ( 0 h, 12 h, 24 h, 48 h, 72 h ) were detected by quantitative-PCR.The expression of HVEM and LTβR on PBMC in patients with severe hepatitis were measured by flow cytometry.Results:In the MHV-3-induced murine fulminant hepatitis model ,liver injury in LIGHT KO mice was obviously decreased than that of WT mice,and ALT levels was also significantly lower than that of WT mice (P<0.01).The mRNA of HVEM and LTβR in the spleen were increased significantly after 48 h postinfection with MHV-3 ( P<0.05 );The level of LTβR mRNA in liver was significantly up-regulated in 12 h postinfection with MHV-3(P<0.01).Compared to healthy volunteers,the expression of both HVEM and LTβR on PBMC in patients with severe hepatitis was remarkably enhanced .Conclusion: TNFSF14 and its receptors LTβR and HVEM play a critical role in the pathogenesis of viral fulminant hepatitis .
ABSTRACT
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. The deterioration of subcellular organelles, including the mitochondria, is another major ultrastructural characteristic of AD pathogenesis, in addition to amyloid plaque deposition. However, the three-dimensional (3-D) study of mitochondrial structural alteration in AD remains poorly understood. Therefore, ultrastructural analysis, 3-D electron tomography, and immunogold electron microscopy were performed in the present study to clarify the abnormal structural alterations in mitochondria caused by the progression of AD in APP/PSEN1 transgenic mice, expressing human amyloid precursor protein, as a model for AD. Amyloid β (Aβ) plaques accumulated and dystrophic neurites (DN) developed in the hippocampus of transgenic AD mouse brains. We also identified the loss of peroxiredoxin 3, an endogenous cytoprotective antioxidant enzyme and the accumulation of Aβ in the hippocampal mitochondria of transgenic mice, which differs from those in age-matched wild-type mice. The mitochondria in Aβ plaque-detected regions were severely disrupted, and the patterns of ultrastructural abnormalities were classified into three groups: disappearance of cristae, swelling of cristae, and bulging of the outer membrane. These results demonstrated that morpho-functional alterations of mitochondria and AD progression are closely associated and may be beneficial in investigating the function of mitochondria in AD pathogenesis.
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Objective To explore the effect of blocking BTLA-HVEM (herpesvirus entry mediator-B and T lymphocyte attenuator) pathway on dendritic cell function and the related immunological mechanisms. Methods Murine BTLA extracellular domain eukaryotic expression vector psBTLA was constructed by gene recombination and transfected CHO by Lipofection method. Mouse bone marrow cells were induced to differentiate into DCs by GM-CSF plus IL-4. Expression of BTLA and HVEM on DCs was detected after HSPT0-TC-1 peptide complex stimulation by FACS. Expression of BT-1 and secretion of IL-12 were detected after HSP70-TC-1 peptide complex plus psBTLA transfected CHO culture supernatant stimulation on DCs. Pretreated DCs co-cultured with the same genetic background mouse splenocytes and lymphocytes proliferation and cytokine secretion were detected. Effect of psBTLA gene transfer in vivo on BT-1 expression of DCs and tumor growth on tumor-bearing mice was detected. Results Extracellular domain of murine BTLA was successfully constructed, psBTLA stable transfection CHO cells were obtained and expression of BTLA extracellular domain(sBTLA) was detected the in its culture supernatant. BTLA and HVEM expression of DCs were increased after stimulation by the antigen peptide complex. When DCs were treated with antigen peptide complex plus culture supernatant containing sBTLA, B7-1 expression and IL-12 secretion were increased. Co-cultured with splenocytes, lymphocytes proliferation and cytokine secretion, such as IL-2 and IFN-γ,, were also increased. Gene transfection with psBTLA in vivo promoted B7-1 expression on DCs and inhibited cervical cancer cells growth. Conclusion Blockade of BTLA-HVEM inhibitory pathway with sBTLA can further improve DCs function, activation of lymphocytes and promote antitumor immune response.