In this study, a novel polyurethane membrane, modified by superfine silk-fibroin powder, was prepared for small-diameter vascular grafting. Scanning electron microscopy, transmission electron microscopy, and histologi...In this study, a novel polyurethane membrane, modified by superfine silk-fibroin powder, was prepared for small-diameter vascular grafting. Scanning electron microscopy, transmission electron microscopy, and histological examination were applied to evaluate histocompatibility of this polyurethane membrane. The polyurethane membrane was compared with polytetrafluoroethylene material. A pseudomembrane and gap formed between polytetrafluoroethylene and the surrounding tissues, and no cells infiltrated or grew into the polytetrafluoroethylene material. On the contrary, superfine silk-fibroin powder/polyurethane blend membrane merged tightly with the surrounding tissues without gaps, and cells infiltrated and grew into the material. Moreover, the negative effects of superfine silk-fibroin powder/polyurethane blend membrane on cells were less than those of its polytetrafluoroethylene counterpart. Our findings indicated that the superfine silk-fibroin powder/polyurethane blend membrane has better histocompatibility than polytetrafluoroethylene membrane. It is concluded that the superfine silk-fibroin powder/polyurethane blend membrane is a promising biomaterial for small-diameter prosthesis.展开更多
AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells(DCs) in chronic hepatitis C(CHC) patients infected with genotype 3 virus.METHODS: This prospective study was c...AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells(DCs) in chronic hepatitis C(CHC) patients infected with genotype 3 virus.METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c(BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus(HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR.RESULTS: Non-responders [sustained virological response(SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1(6-fold) and negative regulators of JAK-STAT pathway such as SOCS(6-fold) as compared to responders(SVR+ve) to antiviral therapy. The downregulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex(MHC) Class-Ⅱ family as HLA-DP, HLA-DQ(2-fold) and superoxide dismutase(2-fold). Cells grown in the presence of HCV viral proteins had genes downregulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors(4-fold) were upregulated as compared to cells grown in absence of viral proteins.CONCLUSION: Underexpressed MHC class-Ⅱ genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs.展开更多
The major histocompatibility complex(MHC) is the exclusive chaperone that presents intracellular antigens,either self or foreign to T cells.Interestingly,aberrant expression of MHC molecules has been reported in vario...The major histocompatibility complex(MHC) is the exclusive chaperone that presents intracellular antigens,either self or foreign to T cells.Interestingly,aberrant expression of MHC molecules has been reported in various autoimmune target tissues such as thyroid follicular cells in Grave's disease.Herein,we review the discovery of an unexpected effect of cytosolic doublestranded DNA(ds DNA),despite its origins,to induce antigen processing and presenting genes,including MHC molecules,in non-immune cells.Moreover,we highlight several recent studies that suggest cell injury endows thyroid epithelial cells with a phenotype of mature antigen presenting cells by inducing multiple antigen processing and presenting genes via releasing genomic DNA fragments into the cytosol.We discuss the possibility that such cytosolic ds DNA,in naked form without binding to histone proteins,might be involved in the development of cell damage-triggered autoimmune responses.We also discuss the possible molecular mechanism by which cytosolic ds DNA can induce MHC molecules.It is reasonable to speculate that cytosolic ds DNA-induced MHC class Ⅰ is partially due to an autocrine/paracrine effect of type Ⅰ interferon(IFN).While the mechanism of cytosolic ds DNA-induced MHC class Ⅱ expression appears,at least partially,distinct from that mediated by IFN-γ.Further in-depth are required to clarify this picture.展开更多
Background:Atherosclerosis is a chronic cardiovascular disease of great concern.However,it is difficult to establish a direct connection between conventional small animal models and clinical practice.The pig's gen...Background:Atherosclerosis is a chronic cardiovascular disease of great concern.However,it is difficult to establish a direct connection between conventional small animal models and clinical practice.The pig's genome,physiology,and anatomy reflect human biology better than other laboratory animals,which is crucial for studying the pathogenesis of atherosclerosis.Methods:We used whole-genome sequencing data from nine Bama minipigs to perform a genome-wide linkage analysis,and further used bioinformatic tools to filter and identify underlying candidate genes.Candidate gene function prediction was performed using the online prediction tool STRING 12.0.Immunohistochemistry and immunofluorescence were used to detect the expression of proteins encoded by candidate genes.Results:We mapped differential single nucleotide polymorphisms(SNPs)to genes and obtained a total of 102 differential genes,then we used GO and KEGG pathway enrichment analysis to identify four candidate genes,including SLA-1,SLA-2,SLA-3,and TAP2.nsSNPs cause changes in the primary and tertiary structures of SLA-I and TAP2 proteins,the primary structures of these two proteins have undergone amino acid changes,and the tertiary structures also show slight changes.In addition,immunohistochemistry and immunofluorescence results showed that the expression changes of TAP2 protein in coronary arteries showed a trend of increasing from the middle layer to the inner layer.Conclusions:We have identified SLA-I and TAP2 as potential susceptibility genes of atherosclerosis,highlighting the importance of antigen processing and immune response in atherogenesis.展开更多
Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug r...Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.展开更多
Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens (...Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens (HLA) and anti-major histocompatibility complex class I-related chain A (MICA) antibody expression after kidney transplantation. Methods We obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine (SCr) levels were evaluated at each follow-up. Patients were divided into 4 groups: HLA(+) MICA(-), HLA(-)MICA(+), HLA(+)MICA(+) and HLA(-)MICA(-). The impact of post-transplant antibody level on kidney allograft function was evaluated. Results Antibodies were detected in 38.1% (32/84) of the renal allograft recipients. HLA, MICA and HLA+MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were All, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% (10/84) of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti- MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value. Conclusions Anti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival.展开更多
Background Sensitized recipients have a high risk of immunological graft loss due to hyperacute rejection and/or accelerated acute rejection. The presence of major histocompatibility complex class I-related chain A (...Background Sensitized recipients have a high risk of immunological graft loss due to hyperacute rejection and/or accelerated acute rejection. The presence of major histocompatibility complex class I-related chain A (MICA) antibodies has also been described associated with an increased rate of kidney-allograft rejection. The aim of this study was to describe the expression of MICA antibodies in sensitized recipients of renal transplantation and evaluate its influence on the kidney transplantation recipients.Methods A total of 29 sensitized recipients were included in this study. All patients received the MICA antibodies detection before and after protein A immunoadsorption. Panel reactive antibody (PRA), HLA-matches, acute rejection and postoperative one to four-week serum creatinine level were also collected and analyzed, respectively. No prisoners were used in this study.Results Eight patients (27.6%) in all 29 sensitized recipients expressed the MICA antibodies but did not show higher acute rejection rate than the non-expressed patients (3/8, 37.5% vs. 8/21, 38.1%; P=1.000). Recipients with PRA 〉40% showed higher expression levels of MICA antibodies than the recipients with PRA 〈40% (7/16, 43.8% vs. 1/13, 8.3%; P=0.044). HLA mismatch did not have any effect on the expression of MICA antibodies (P=1.000). MICA antibodies positive group had higher serum creatinine level than the control in postoperative one week ((135.4±21.4) μmol/L vs. (108.6±31.6) μmol/L, P=0.036), but no significant difference in postoperative four weeks ((89.0±17.1) μmol/L vs. (77.1±15.9) μmol/L, P=0.089). MICA antibodies decreased significantly after protein A immunoadsorption.Conclusions MICA antibodies increase in the sensitized recipients, which have significant effects on the function of aliograft in early postoperative period. Protein A immunoadsorption can decrease MICA antibodies effectively in sensitized recipients.展开更多
Objective To review the role of polymorphism of major histocompatibility complex class I-related chain A (MICA) gene and antibodies against MICA antigens in transplant immunology. Data sources The data used in this ...Objective To review the role of polymorphism of major histocompatibility complex class I-related chain A (MICA) gene and antibodies against MICA antigens in transplant immunology. Data sources The data used in this review were mainly from our own results and from the relevant English language literatures published from 1999 to 2010. Some data presented in this review are in press.Study selection Articles regarding MICA gene discovery and pioneering finding of antibodies against MICA antigen and allograft rejection were selected. This review chronicles the development of our understanding of the role that MICA antigens and antibodies may play in organ transplantation.Results Polymorphic glycoprotein MICA antigens were detected on freshly isolated human umbilical cord endothelial cells, but not on peripheral lymphocytes. Antibodies were found and typing of recipients and donors by sequencing the MICA alleles has established that de novo antibodies produced in kidney transplant recipients are directed at mismatched MICA epitopes and are associated with acute rejection and chronic transplant failure. The specificity of antibodies against the epitopes of MICA antigens were well characterized by donor MICA typing, single antigen array testing with antibody absorption and elution. Acute graft-versus-host disease was observed in stem-cell recipients who were mismatched for MICA.Conclusions Immunization against mismatched MICA epitopes encountered in donor organs after transplantation may result in antibodies against MICA alleles. Testing for MICA donor-specific antibodies (DSA) which are associated with early failure of kidney transplants may be helpful for identifying some of the targets of antibodies against antigens other than the human leukocyte antigen (HLA) and for improving transplantation outcome.展开更多
The major histocompatibility complex(MHC)is closely associated with numerous diseases,but its high degree of polymorphism complicates the discovery of disease-associated variants.In principle,recombination and de novo...The major histocompatibility complex(MHC)is closely associated with numerous diseases,but its high degree of polymorphism complicates the discovery of disease-associated variants.In principle,recombination and de novo mutations are two critical factors responsible for MHC polymorphisms.However,direct evidence for this hypothesis is lacking.Here,we report the generation of fine-scale MHC recombination and de novo mutation maps of~5 Mb by deep sequencing(>100×)of the MHC genome for 17 MHC recombination and 30 non-recombination Han Chinese families(a total of 190 individuals).Recombination hotspots and Han-specific breakpoints are located in close proximity at haplotype block boundaries.The average MHC de novo mutation rate is higher than the genome-wide de novo mutation rate,particularly in MHC recombinant individuals.Notably,mutation and recombination generated polymorphisms are located within and outside linkage disequilibrium regions of the MHC,respectively,and evolution of the MHC locus was mainly controlled by positive selection.These findings provide insights on the evolutionary causes of the MHC diversity and may facilitate the identification of disease-associated genetic variants.展开更多
The highly polymorphic genes within the major histocompatibility complex(MHC)not only play a major role in immunity resistance,but also seem to provide hints for mate choice in some animal populations.In the pres...The highly polymorphic genes within the major histocompatibility complex(MHC)not only play a major role in immunity resistance,but also seem to provide hints for mate choice in some animal populations.In the present study we investigated MHC-related mate choice in a small natural population(group size 40-55 individuals)of a polygynous primate,the Sichuan snub-nosed monkey(Rhinopithecus roxellana).We found that there was no evidence either for MHC-disassortative mating,or for females to mate with males based on MHC heterozygosity or specific alleles.Nevertheless,of the 11 alleles identified,we found that the frequencies of 2 alleles,Rhro-DRB2(P<0.01)and Rhro-DRB5(P<0.05)were higher in offspring than in their parents.These findings suggest that MHC-DRB in this population of R.roxellana is unlikely to be associated with mating preferences.Limited female opportunities for mate choice are likely due,in part,to the harem breeding structure present in R.roxellana,and the relatively small number of resident adult males in our study band(N=4-6).In addition,we suggest that differences in the frequency of particular alleles across generations may be linked to parasite resistance in a fluctuating environment;however,confirmation of this finding requires further study.展开更多
The variation of the exon 2 of the major histo-compatibility complex(MHC)class II gene DRB locus in three feline species were examined on clouded leopard(Neofelis nebulosa),leopard(Panthera pardus)and Amur tiger(Panth...The variation of the exon 2 of the major histo-compatibility complex(MHC)class II gene DRB locus in three feline species were examined on clouded leopard(Neofelis nebulosa),leopard(Panthera pardus)and Amur tiger(Panthera tigris altaica).A pair of degenerated primers was used to amplify DRB locus covering almost the whole exon 2.Exon 2 encodes theβ1 domain which is the most vari-able fragments of the MHC class II molecule.Single-strand conformational polymorphism(SSCP)analysis was applied to detect different MHC class II DRB haplotypes.Fifteen recombinant plasmids for each individual were screened out,isolated,purified and sequenced finally.Totally eight distinct haplotypes of exon 2 were obtained in four individuals.With-in 237 bp nucleotide sequences from four samples,30 vari-able positions were found,and 21 putative peptide-binding positions were disclosed in 79 amino acid residues.The ratio of nonsynonymous substitutions(d_(N))was much higher than that of synonymous substitutions(d_(S)),which indicated that balancing selection probably maintain the variation of exon 2.MEGA neighbor joining(NJ)and PAUP maximum parsimo-ny(MP)methods were used to reconstruct phylogenetic trees among species,respectively.Results displayed a more close relationship between leopard and tiger;however,clouded leopard has a comparatively distant relationship form the other two.展开更多
The genes of the major histocompatibility complex(MHC) encode cell surface proteins that are essential for adaptive immunity. MHC genes show the most prominent genetic diversity in vertebrates,reflecting the adaptatio...The genes of the major histocompatibility complex(MHC) encode cell surface proteins that are essential for adaptive immunity. MHC genes show the most prominent genetic diversity in vertebrates,reflecting the adaptation of populations to their evolving environment, population survival and reproduction. In the present study, we used nextgeneration sequencing(NGS) to study the loci polymorphism of exon 3 of the MHC class Ⅰ genes in an ovoviviparous skink, the many-lined sun skink,Eutropis multifasciata and five other species of Scincidae, to quantify genetic variation. In addition,we genotyped the same MHC class Ⅰ genes of E.multifasciata using clone sequencing, to directly compare the effectiveness of both analytical techniques for MHC genotyping. NGS detected 20MHC class Ⅰ alleles in E. multifasciata, and 2 to 15 alleles in the other five Scincidae species. However,clone sequencing detected only 15 of those MHC class Ⅰ alleles in E. multifasciata. In addition, transspecies polymorphism of MHC class Ⅰ genes was studied by constructing a phylogenetic tree using the gene sequences obtained by NGS. Phylogenetic analysis revealed that MHC class I alleles were shared among different species of Scincidae with trans-species polymorphism, and did not exhibit specific genealogical inheritance. These results have important implications for understanding polymorphism interspecies diversity in the MHC genes of Scincidae, and the evolution of the MHC more broadly.展开更多
A novel in vitro cellular model prodicting recipient donor histocompatibility in allograft was developed to select the donor validly. Fifteen couples of blood samples of donor and recipient in human BMT were examined...A novel in vitro cellular model prodicting recipient donor histocompatibility in allograft was developed to select the donor validly. Fifteen couples of blood samples of donor and recipient in human BMT were examined using the model, and skin allograft in mice was performed to test the model. The results showed that the less the differences of histocompatibility evaluated by the model were, the later GVHR in human BMT occurred and the longer the survival time of skin allografts in mice. It was suggested that the model could be used to predict correctly histocompatibility between donor and recipient.展开更多
Autism and autism spectrum disorders(ASD) refer to a range of conditions characterized by impaired social and communication skills and repetitive behaviors caused by different combinations of genetic and environmental...Autism and autism spectrum disorders(ASD) refer to a range of conditions characterized by impaired social and communication skills and repetitive behaviors caused by different combinations of genetic and environmental influences. Although the pathophysiology underlying ASD is still unclear, recent evidence suggests that immune dysregulation and neuroinflammation play a role in the etiology of ASD. In particular, there is direct evidence supporting a role for maternal immune activation during prenatal life in neurodevelopmental conditions. Currently, the available options of behavioral therapies and pharmacological and supportive nutritional treatments in ASD are only symptomatic. Given the disturbing rise in the incidence of ASD, and the fact that there is no effective pharmacological therapy for ASD, there is an urgent need for new therapeutic options. Mesenchymal stem cells(MSCs) possess immunomodulatory properties that make them relevant to several diseases associated with inflammation and tissue damage. The paracrine regenerative mechanisms of MSCs are also suggested to be therapeutically beneficial for ASD.Thus the underlying pathology in ASD, including immune system dysregulation and inflammation, represent potential targets for MSC therapy. This review willfocus on immune dysfunction in the pathogenesis of ASD and will further discuss the therapeutic potential for MSCs in mediating ASD-related immunological disorders.展开更多
Background:There are remarkable genetic differences between animal major histocompatibility complex(MHC)systems and the human leukocyte antigen(HLA)system.HLA transgenic humanized mouse model systems offer a much bett...Background:There are remarkable genetic differences between animal major histocompatibility complex(MHC)systems and the human leukocyte antigen(HLA)system.HLA transgenic humanized mouse model systems offer a much better method to study the HLA-A-related principal mechanisms for vaccine development and HLA-Arestricted responses against infection in human.Methods:A recombinant gene encoding the chimeric HLA-A30 monochain was constructed.This HHD molecule contains the following:α1-α2 domains of HLA-A30,α3 and cytoplasmic domains of H-2D~b,linked at its N-terminus to the C-terminus of humanβ2m by a 15-amino-acid peptide linker.The recombinant gene encoding the chimeric HLA-A30 monochain cassette was introduced into bacterial artificial chromosome(BAC)CH502-67J3 containing the HLA-A01 gene locus by Red-mediated homologous recombination.Modified BAC CH502-67J3 was microinjected into the pronuclei of wild-type mouse oocytes.This humanized mouse model was further used to assess the immune responses against influenza A virus(H1N1)pdm09 clinically isolated from human patients.Immune cell population,cytokine production,and histopathology in the lung were analyzed.Results:We describe a novel humanβ2m-HLA-A30(α1α2)-H-2D~b(α3 transmembrane cytoplasmic)(HHD)monochain transgenic mouse strain,which contains the intact HLA-A01 gene locus including 49 kb 5’-UTR and 74 kb 3’-UTR of HLA-A01*01.Five transgenic lines integrated into the large genomic region of HLA-A gene locus were obtained,and the robust expression of exogenous transgene was detected in various tissues from A30-18#and A30-19#lines encompassing the intact flanking sequences.Flow cytometry revealed that the introduction of a large genomic region in HLA-A gene locus can influence the immune cell constitution in humanized mice.Pdm09 infection caused a similar immune response among HLA-A30 Tg humanized mice and wild-type mice,and induced the rapid increase of cytokines,including IFN-γ,TNF-α,and IL-6,in both HLA-A30 humanized Tg mice and wild-type mice.The expression of HLA-A30 transgene was dramatically promoted in tissues from A30-9#line at 3 days post-infection(dpi).Conclusions:We established a promising preclinical research animal model of HLA-A30 Tg humanized mouse,which could accelerate the identification of novel HLA-A30-restricted epitopes and vaccine development,and support the study of HLA-A-restricted responses against infection in humans.展开更多
The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurre...The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s disease.However,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway.In the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse model.The findings revealed that MHC-I was expressed in both models.To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated mice.The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T cells.Moreover,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal death.To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells.Taken together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and degeneration.This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation.All animal experiments were approved by the Southern Medical University Ethics Committee(No.81802040,approved on February 25,2018).展开更多
Recent nationwide clinico-epidemiological surveys in Japan showed that the occurrence of cardiomyopathies was most frequently seen in the age of sixties, and that cardiomyopathies are important causes of heart failure...Recent nationwide clinico-epidemiological surveys in Japan showed that the occurrence of cardiomyopathies was most frequently seen in the age of sixties, and that cardiomyopathies are important causes of heart failure in the elderly. Viral infection was conventionally considered to cause myocarditis, which resulted in the development of dilated cardiomyopathy. Recent studies suggest that hepatitis C virus (HCV) is involved in the development of dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy in addition to myocarditis. Furthermore, left ventricular aneurysm represents the same morbid state not only after myocardial infarction but also after myocarditis. There were wide variations in the frequency of detection of HCV genomes in cardiomyopathy in different regions and in different populations. Major histocompatibility complex class Ⅱ genes may play a role in the susceptibility to HCV infection, and may influence the development of different phenotypes of cardiomyopathy. If in fact the myocardial damage is caused by HCV, it might be expected that interferon (IFN) administration would be useful for its treatment. Hepatitis patients receiving IFN treatment for hepatitis were screened by thallium myocardial scintigraphy, and an abnormality was discovered in half of the patients. Treatment with IFN resulted in a disappearance of the image abnormality. It has thus been suggested that mild myocarditis and myocardial damage may be cured with IFN. We have recently found that high concentrations of circulating cardiac troponin T are a specific marker of cardiac involvement in HCV infection. By measuring cardiac troponin T in patients with HCV infection, the prevalence of cardiac involvement in HCV infection will be clarified. We are proposing a collaborative work on a global network on myocarditis/cardiomyopathies due to HCV infection. (J Geriatr Cardiol 2004;1(2):83-89. )展开更多
AIM: To investigate the biocompatibility and therapeutic effects of polyetheretherketone(PEEK) on recovery of a rabbit orbital defect.METHODS: Totally 16 New Zealand rabbits were used to establish an orbital bone defe...AIM: To investigate the biocompatibility and therapeutic effects of polyetheretherketone(PEEK) on recovery of a rabbit orbital defect.METHODS: Totally 16 New Zealand rabbits were used to establish an orbital bone defect model and then randomly divided into two groups. PEEK was implanted in the experimental group. The control group was blank, and no substance was implanted. The model rabbits were sacrificed at 4 and 8 wk, and examined by general observations, histology, electron microscopy, Western blotting, and realtime polymerase chain reaction.RESULTS: No infection or rejection occurred after PEEK implantation, and biocompatibility was good. The relative expression of vascular endothelial growth factor(VEGF) protein in the experimental group was significantly higher than that in the control group postoperatively(P<0.05). Bone defect repair in the experimental group was significantly better than that in the control group in the same period and some osteogenesis was observed.CONCLUSION: PEEK has good biocompatibility and efficacy for the treatment of orbital bone defects in a rabbit model.展开更多
Porcine reproductive and respiratory syndrome(PRRS) is one of the most important diseases of swine industry. The causal agent, PRRS-virus(PRRSV), is able to evade the host immune response and survive in the organism c...Porcine reproductive and respiratory syndrome(PRRS) is one of the most important diseases of swine industry. The causal agent, PRRS-virus(PRRSV), is able to evade the host immune response and survive in the organism causing transient infections. Despite all scientific efforts, there are still some gaps in the knowledge of the pathogenesis of this disease. Antigen presenting cells(APCs), as initiators of the immune response, are located in the first line of defense against microorganisms, and are responsible for antigen recognition, processing and presentation. Dendritic cells(DCs) are the main type of APC involved in antigen presentation and they are susceptible to PRRSV infection. Thus, PRRSV replication in DCs may trigger off different mechanisms to impair the onset of a host effective immune response against the virus. On the one side, PRRSV may impair the basic functions of DCs by regulating the expression of major histocompatibility complex class Ⅱ and CD80/86. Other strategy followed by the virus is the induction of cell death of APCs by apoptosis, necrosis or both of them. The impairment and/or cell death ofAPCs could lead to a failure in the onset of an efficient immune response, as long as cells could not properly activate T cells. Future aspects to take into account are also discussed in this review.展开更多
基金supported by a grant from the 973 Programof Ministry of Science and Technology of China(No.2009CB526400)
文摘In this study, a novel polyurethane membrane, modified by superfine silk-fibroin powder, was prepared for small-diameter vascular grafting. Scanning electron microscopy, transmission electron microscopy, and histological examination were applied to evaluate histocompatibility of this polyurethane membrane. The polyurethane membrane was compared with polytetrafluoroethylene material. A pseudomembrane and gap formed between polytetrafluoroethylene and the surrounding tissues, and no cells infiltrated or grew into the polytetrafluoroethylene material. On the contrary, superfine silk-fibroin powder/polyurethane blend membrane merged tightly with the surrounding tissues without gaps, and cells infiltrated and grew into the material. Moreover, the negative effects of superfine silk-fibroin powder/polyurethane blend membrane on cells were less than those of its polytetrafluoroethylene counterpart. Our findings indicated that the superfine silk-fibroin powder/polyurethane blend membrane has better histocompatibility than polytetrafluoroethylene membrane. It is concluded that the superfine silk-fibroin powder/polyurethane blend membrane is a promising biomaterial for small-diameter prosthesis.
基金Supported by Council of Scientific and Industrial Research,No.27(0262)12/EMR-II
文摘AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells(DCs) in chronic hepatitis C(CHC) patients infected with genotype 3 virus.METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c(BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus(HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR.RESULTS: Non-responders [sustained virological response(SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1(6-fold) and negative regulators of JAK-STAT pathway such as SOCS(6-fold) as compared to responders(SVR+ve) to antiviral therapy. The downregulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex(MHC) Class-Ⅱ family as HLA-DP, HLA-DQ(2-fold) and superoxide dismutase(2-fold). Cells grown in the presence of HCV viral proteins had genes downregulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors(4-fold) were upregulated as compared to cells grown in absence of viral proteins.CONCLUSION: Underexpressed MHC class-Ⅱ genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs.
基金Scientific Research from the Japan Society for the Promotion of Science to Suzuki K,No.15K09444
文摘The major histocompatibility complex(MHC) is the exclusive chaperone that presents intracellular antigens,either self or foreign to T cells.Interestingly,aberrant expression of MHC molecules has been reported in various autoimmune target tissues such as thyroid follicular cells in Grave's disease.Herein,we review the discovery of an unexpected effect of cytosolic doublestranded DNA(ds DNA),despite its origins,to induce antigen processing and presenting genes,including MHC molecules,in non-immune cells.Moreover,we highlight several recent studies that suggest cell injury endows thyroid epithelial cells with a phenotype of mature antigen presenting cells by inducing multiple antigen processing and presenting genes via releasing genomic DNA fragments into the cytosol.We discuss the possibility that such cytosolic ds DNA,in naked form without binding to histone proteins,might be involved in the development of cell damage-triggered autoimmune responses.We also discuss the possible molecular mechanism by which cytosolic ds DNA can induce MHC molecules.It is reasonable to speculate that cytosolic ds DNA-induced MHC class Ⅰ is partially due to an autocrine/paracrine effect of type Ⅰ interferon(IFN).While the mechanism of cytosolic ds DNA-induced MHC class Ⅱ expression appears,at least partially,distinct from that mediated by IFN-γ.Further in-depth are required to clarify this picture.
基金supported by the Special Scientific Research Project of Army Laboratory Animals(No.SYDW[2020]01)National Natural Science Foundation of ChinaNo.32370568。
文摘Background:Atherosclerosis is a chronic cardiovascular disease of great concern.However,it is difficult to establish a direct connection between conventional small animal models and clinical practice.The pig's genome,physiology,and anatomy reflect human biology better than other laboratory animals,which is crucial for studying the pathogenesis of atherosclerosis.Methods:We used whole-genome sequencing data from nine Bama minipigs to perform a genome-wide linkage analysis,and further used bioinformatic tools to filter and identify underlying candidate genes.Candidate gene function prediction was performed using the online prediction tool STRING 12.0.Immunohistochemistry and immunofluorescence were used to detect the expression of proteins encoded by candidate genes.Results:We mapped differential single nucleotide polymorphisms(SNPs)to genes and obtained a total of 102 differential genes,then we used GO and KEGG pathway enrichment analysis to identify four candidate genes,including SLA-1,SLA-2,SLA-3,and TAP2.nsSNPs cause changes in the primary and tertiary structures of SLA-I and TAP2 proteins,the primary structures of these two proteins have undergone amino acid changes,and the tertiary structures also show slight changes.In addition,immunohistochemistry and immunofluorescence results showed that the expression changes of TAP2 protein in coronary arteries showed a trend of increasing from the middle layer to the inner layer.Conclusions:We have identified SLA-I and TAP2 as potential susceptibility genes of atherosclerosis,highlighting the importance of antigen processing and immune response in atherogenesis.
基金Research Projects-Joint Fund for Applied Basic Research of Kunming Medical University,Yunnan Provincial Department of Science and Technology(No.2018FE001(-113),No.202301AY070001-098)Open project of Yunnan Clinical Medical Center(Nos.2020LCZXKF-XY02,XY06,XY16+1 种基金2022LCZXKF-XY02)Yunnan Health Training Project of High Level Talents(No.D–2018018).
文摘Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.
基金the grants from the the National Science Foundation of China,the Key Discipline of Medicine of Jiangsu Province,the Outstanding Medical Academic Leader Program of Jiangsu Province,the Science Foundation of Jiangsu Province,the Key Laboratory Foundation of Suzhou
文摘Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens (HLA) and anti-major histocompatibility complex class I-related chain A (MICA) antibody expression after kidney transplantation. Methods We obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine (SCr) levels were evaluated at each follow-up. Patients were divided into 4 groups: HLA(+) MICA(-), HLA(-)MICA(+), HLA(+)MICA(+) and HLA(-)MICA(-). The impact of post-transplant antibody level on kidney allograft function was evaluated. Results Antibodies were detected in 38.1% (32/84) of the renal allograft recipients. HLA, MICA and HLA+MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were All, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% (10/84) of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti- MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value. Conclusions Anti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival.
文摘Background Sensitized recipients have a high risk of immunological graft loss due to hyperacute rejection and/or accelerated acute rejection. The presence of major histocompatibility complex class I-related chain A (MICA) antibodies has also been described associated with an increased rate of kidney-allograft rejection. The aim of this study was to describe the expression of MICA antibodies in sensitized recipients of renal transplantation and evaluate its influence on the kidney transplantation recipients.Methods A total of 29 sensitized recipients were included in this study. All patients received the MICA antibodies detection before and after protein A immunoadsorption. Panel reactive antibody (PRA), HLA-matches, acute rejection and postoperative one to four-week serum creatinine level were also collected and analyzed, respectively. No prisoners were used in this study.Results Eight patients (27.6%) in all 29 sensitized recipients expressed the MICA antibodies but did not show higher acute rejection rate than the non-expressed patients (3/8, 37.5% vs. 8/21, 38.1%; P=1.000). Recipients with PRA 〉40% showed higher expression levels of MICA antibodies than the recipients with PRA 〈40% (7/16, 43.8% vs. 1/13, 8.3%; P=0.044). HLA mismatch did not have any effect on the expression of MICA antibodies (P=1.000). MICA antibodies positive group had higher serum creatinine level than the control in postoperative one week ((135.4±21.4) μmol/L vs. (108.6±31.6) μmol/L, P=0.036), but no significant difference in postoperative four weeks ((89.0±17.1) μmol/L vs. (77.1±15.9) μmol/L, P=0.089). MICA antibodies decreased significantly after protein A immunoadsorption.Conclusions MICA antibodies increase in the sensitized recipients, which have significant effects on the function of aliograft in early postoperative period. Protein A immunoadsorption can decrease MICA antibodies effectively in sensitized recipients.
文摘Objective To review the role of polymorphism of major histocompatibility complex class I-related chain A (MICA) gene and antibodies against MICA antigens in transplant immunology. Data sources The data used in this review were mainly from our own results and from the relevant English language literatures published from 1999 to 2010. Some data presented in this review are in press.Study selection Articles regarding MICA gene discovery and pioneering finding of antibodies against MICA antigen and allograft rejection were selected. This review chronicles the development of our understanding of the role that MICA antigens and antibodies may play in organ transplantation.Results Polymorphic glycoprotein MICA antigens were detected on freshly isolated human umbilical cord endothelial cells, but not on peripheral lymphocytes. Antibodies were found and typing of recipients and donors by sequencing the MICA alleles has established that de novo antibodies produced in kidney transplant recipients are directed at mismatched MICA epitopes and are associated with acute rejection and chronic transplant failure. The specificity of antibodies against the epitopes of MICA antigens were well characterized by donor MICA typing, single antigen array testing with antibody absorption and elution. Acute graft-versus-host disease was observed in stem-cell recipients who were mismatched for MICA.Conclusions Immunization against mismatched MICA epitopes encountered in donor organs after transplantation may result in antibodies against MICA alleles. Testing for MICA donor-specific antibodies (DSA) which are associated with early failure of kidney transplants may be helpful for identifying some of the targets of antibodies against antigens other than the human leukocyte antigen (HLA) and for improving transplantation outcome.
基金supported by grants from the National Key Basic Research Development Program of China(grants No.2009CB522401 and 2003CB515509,and AWS14C014)。
文摘The major histocompatibility complex(MHC)is closely associated with numerous diseases,but its high degree of polymorphism complicates the discovery of disease-associated variants.In principle,recombination and de novo mutations are two critical factors responsible for MHC polymorphisms.However,direct evidence for this hypothesis is lacking.Here,we report the generation of fine-scale MHC recombination and de novo mutation maps of~5 Mb by deep sequencing(>100×)of the MHC genome for 17 MHC recombination and 30 non-recombination Han Chinese families(a total of 190 individuals).Recombination hotspots and Han-specific breakpoints are located in close proximity at haplotype block boundaries.The average MHC de novo mutation rate is higher than the genome-wide de novo mutation rate,particularly in MHC recombinant individuals.Notably,mutation and recombination generated polymorphisms are located within and outside linkage disequilibrium regions of the MHC,respectively,and evolution of the MHC locus was mainly controlled by positive selection.These findings provide insights on the evolutionary causes of the MHC diversity and may facilitate the identification of disease-associated genetic variants.
基金This project was supported by the Project of Public Benefit(No.201104073)the Natural Science Foundation of China(No.30970427,31130061)the National Key Technology R&D Program of China(2013BAD03B02).
文摘The highly polymorphic genes within the major histocompatibility complex(MHC)not only play a major role in immunity resistance,but also seem to provide hints for mate choice in some animal populations.In the present study we investigated MHC-related mate choice in a small natural population(group size 40-55 individuals)of a polygynous primate,the Sichuan snub-nosed monkey(Rhinopithecus roxellana).We found that there was no evidence either for MHC-disassortative mating,or for females to mate with males based on MHC heterozygosity or specific alleles.Nevertheless,of the 11 alleles identified,we found that the frequencies of 2 alleles,Rhro-DRB2(P<0.01)and Rhro-DRB5(P<0.05)were higher in offspring than in their parents.These findings suggest that MHC-DRB in this population of R.roxellana is unlikely to be associated with mating preferences.Limited female opportunities for mate choice are likely due,in part,to the harem breeding structure present in R.roxellana,and the relatively small number of resident adult males in our study band(N=4-6).In addition,we suggest that differences in the frequency of particular alleles across generations may be linked to parasite resistance in a fluctuating environment;however,confirmation of this finding requires further study.
基金This research was funded by the grants from Special Fund for Anhui Young Leaders Fellowship(No.04043049)Key Laboratory of Biotic Environment and Ecological Safety in Anhui Province,and Anhui Scholar Special Fund in Science and Technology.
文摘The variation of the exon 2 of the major histo-compatibility complex(MHC)class II gene DRB locus in three feline species were examined on clouded leopard(Neofelis nebulosa),leopard(Panthera pardus)and Amur tiger(Panthera tigris altaica).A pair of degenerated primers was used to amplify DRB locus covering almost the whole exon 2.Exon 2 encodes theβ1 domain which is the most vari-able fragments of the MHC class II molecule.Single-strand conformational polymorphism(SSCP)analysis was applied to detect different MHC class II DRB haplotypes.Fifteen recombinant plasmids for each individual were screened out,isolated,purified and sequenced finally.Totally eight distinct haplotypes of exon 2 were obtained in four individuals.With-in 237 bp nucleotide sequences from four samples,30 vari-able positions were found,and 21 putative peptide-binding positions were disclosed in 79 amino acid residues.The ratio of nonsynonymous substitutions(d_(N))was much higher than that of synonymous substitutions(d_(S)),which indicated that balancing selection probably maintain the variation of exon 2.MEGA neighbor joining(NJ)and PAUP maximum parsimo-ny(MP)methods were used to reconstruct phylogenetic trees among species,respectively.Results displayed a more close relationship between leopard and tiger;however,clouded leopard has a comparatively distant relationship form the other two.
基金This work was supported by grants from the National Natural Science Foundation of China(32171495 and 31971414)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘The genes of the major histocompatibility complex(MHC) encode cell surface proteins that are essential for adaptive immunity. MHC genes show the most prominent genetic diversity in vertebrates,reflecting the adaptation of populations to their evolving environment, population survival and reproduction. In the present study, we used nextgeneration sequencing(NGS) to study the loci polymorphism of exon 3 of the MHC class Ⅰ genes in an ovoviviparous skink, the many-lined sun skink,Eutropis multifasciata and five other species of Scincidae, to quantify genetic variation. In addition,we genotyped the same MHC class Ⅰ genes of E.multifasciata using clone sequencing, to directly compare the effectiveness of both analytical techniques for MHC genotyping. NGS detected 20MHC class Ⅰ alleles in E. multifasciata, and 2 to 15 alleles in the other five Scincidae species. However,clone sequencing detected only 15 of those MHC class Ⅰ alleles in E. multifasciata. In addition, transspecies polymorphism of MHC class Ⅰ genes was studied by constructing a phylogenetic tree using the gene sequences obtained by NGS. Phylogenetic analysis revealed that MHC class I alleles were shared among different species of Scincidae with trans-species polymorphism, and did not exhibit specific genealogical inheritance. These results have important implications for understanding polymorphism interspecies diversity in the MHC genes of Scincidae, and the evolution of the MHC more broadly.
文摘A novel in vitro cellular model prodicting recipient donor histocompatibility in allograft was developed to select the donor validly. Fifteen couples of blood samples of donor and recipient in human BMT were examined using the model, and skin allograft in mice was performed to test the model. The results showed that the less the differences of histocompatibility evaluated by the model were, the later GVHR in human BMT occurred and the longer the survival time of skin allografts in mice. It was suggested that the model could be used to predict correctly histocompatibility between donor and recipient.
基金Supported by National Nature Science Foundation of China,No.81660381
文摘Autism and autism spectrum disorders(ASD) refer to a range of conditions characterized by impaired social and communication skills and repetitive behaviors caused by different combinations of genetic and environmental influences. Although the pathophysiology underlying ASD is still unclear, recent evidence suggests that immune dysregulation and neuroinflammation play a role in the etiology of ASD. In particular, there is direct evidence supporting a role for maternal immune activation during prenatal life in neurodevelopmental conditions. Currently, the available options of behavioral therapies and pharmacological and supportive nutritional treatments in ASD are only symptomatic. Given the disturbing rise in the incidence of ASD, and the fact that there is no effective pharmacological therapy for ASD, there is an urgent need for new therapeutic options. Mesenchymal stem cells(MSCs) possess immunomodulatory properties that make them relevant to several diseases associated with inflammation and tissue damage. The paracrine regenerative mechanisms of MSCs are also suggested to be therapeutically beneficial for ASD.Thus the underlying pathology in ASD, including immune system dysregulation and inflammation, represent potential targets for MSC therapy. This review willfocus on immune dysfunction in the pathogenesis of ASD and will further discuss the therapeutic potential for MSCs in mediating ASD-related immunological disorders.
基金supported by the followed funds:National Science and Technology Major Project(2017ZX10304402-001-006,2017ZX10304402-001-012,2016YFD0500208)Shanghai Science and Technology Commission“R&D public service platform and institutional capacity improvement project”(21DZ2291300)+1 种基金Shanghai scientific research projects(19140905300)Shanghai Public Health Clinical Center projects(KY-GW-2019-11,KY-GW-2019-19,and KY-GW-2021-39)。
文摘Background:There are remarkable genetic differences between animal major histocompatibility complex(MHC)systems and the human leukocyte antigen(HLA)system.HLA transgenic humanized mouse model systems offer a much better method to study the HLA-A-related principal mechanisms for vaccine development and HLA-Arestricted responses against infection in human.Methods:A recombinant gene encoding the chimeric HLA-A30 monochain was constructed.This HHD molecule contains the following:α1-α2 domains of HLA-A30,α3 and cytoplasmic domains of H-2D~b,linked at its N-terminus to the C-terminus of humanβ2m by a 15-amino-acid peptide linker.The recombinant gene encoding the chimeric HLA-A30 monochain cassette was introduced into bacterial artificial chromosome(BAC)CH502-67J3 containing the HLA-A01 gene locus by Red-mediated homologous recombination.Modified BAC CH502-67J3 was microinjected into the pronuclei of wild-type mouse oocytes.This humanized mouse model was further used to assess the immune responses against influenza A virus(H1N1)pdm09 clinically isolated from human patients.Immune cell population,cytokine production,and histopathology in the lung were analyzed.Results:We describe a novel humanβ2m-HLA-A30(α1α2)-H-2D~b(α3 transmembrane cytoplasmic)(HHD)monochain transgenic mouse strain,which contains the intact HLA-A01 gene locus including 49 kb 5’-UTR and 74 kb 3’-UTR of HLA-A01*01.Five transgenic lines integrated into the large genomic region of HLA-A gene locus were obtained,and the robust expression of exogenous transgene was detected in various tissues from A30-18#and A30-19#lines encompassing the intact flanking sequences.Flow cytometry revealed that the introduction of a large genomic region in HLA-A gene locus can influence the immune cell constitution in humanized mice.Pdm09 infection caused a similar immune response among HLA-A30 Tg humanized mice and wild-type mice,and induced the rapid increase of cytokines,including IFN-γ,TNF-α,and IL-6,in both HLA-A30 humanized Tg mice and wild-type mice.The expression of HLA-A30 transgene was dramatically promoted in tissues from A30-9#line at 3 days post-infection(dpi).Conclusions:We established a promising preclinical research animal model of HLA-A30 Tg humanized mouse,which could accelerate the identification of novel HLA-A30-restricted epitopes and vaccine development,and support the study of HLA-A-restricted responses against infection in humans.
基金This work was supported by the National Natural Science Foundation of China,Nos.81671240(to SZZ),81560220(to GHL)the Youth Science Foundation of Jiangxi Province of China,No.20151BAB215014(to GHL)Health and Family Planning Commission of Jiangxi Province of China,No.20195109(to GHL)。
文摘The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s disease.However,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway.In the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse model.The findings revealed that MHC-I was expressed in both models.To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated mice.The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T cells.Moreover,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal death.To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells.Taken together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and degeneration.This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation.All animal experiments were approved by the Southern Medical University Ethics Committee(No.81802040,approved on February 25,2018).
文摘Recent nationwide clinico-epidemiological surveys in Japan showed that the occurrence of cardiomyopathies was most frequently seen in the age of sixties, and that cardiomyopathies are important causes of heart failure in the elderly. Viral infection was conventionally considered to cause myocarditis, which resulted in the development of dilated cardiomyopathy. Recent studies suggest that hepatitis C virus (HCV) is involved in the development of dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy in addition to myocarditis. Furthermore, left ventricular aneurysm represents the same morbid state not only after myocardial infarction but also after myocarditis. There were wide variations in the frequency of detection of HCV genomes in cardiomyopathy in different regions and in different populations. Major histocompatibility complex class Ⅱ genes may play a role in the susceptibility to HCV infection, and may influence the development of different phenotypes of cardiomyopathy. If in fact the myocardial damage is caused by HCV, it might be expected that interferon (IFN) administration would be useful for its treatment. Hepatitis patients receiving IFN treatment for hepatitis were screened by thallium myocardial scintigraphy, and an abnormality was discovered in half of the patients. Treatment with IFN resulted in a disappearance of the image abnormality. It has thus been suggested that mild myocarditis and myocardial damage may be cured with IFN. We have recently found that high concentrations of circulating cardiac troponin T are a specific marker of cardiac involvement in HCV infection. By measuring cardiac troponin T in patients with HCV infection, the prevalence of cardiac involvement in HCV infection will be clarified. We are proposing a collaborative work on a global network on myocarditis/cardiomyopathies due to HCV infection. (J Geriatr Cardiol 2004;1(2):83-89. )
基金Supported by the Liaoning Province Natural Science Foundation Guidance Program(No.20170520286)。
文摘AIM: To investigate the biocompatibility and therapeutic effects of polyetheretherketone(PEEK) on recovery of a rabbit orbital defect.METHODS: Totally 16 New Zealand rabbits were used to establish an orbital bone defect model and then randomly divided into two groups. PEEK was implanted in the experimental group. The control group was blank, and no substance was implanted. The model rabbits were sacrificed at 4 and 8 wk, and examined by general observations, histology, electron microscopy, Western blotting, and realtime polymerase chain reaction.RESULTS: No infection or rejection occurred after PEEK implantation, and biocompatibility was good. The relative expression of vascular endothelial growth factor(VEGF) protein in the experimental group was significantly higher than that in the control group postoperatively(P<0.05). Bone defect repair in the experimental group was significantly better than that in the control group in the same period and some osteogenesis was observed.CONCLUSION: PEEK has good biocompatibility and efficacy for the treatment of orbital bone defects in a rabbit model.
基金Supported by The Spanish Ministry of Education and Science,No.AGL2009-12438/GAN
文摘Porcine reproductive and respiratory syndrome(PRRS) is one of the most important diseases of swine industry. The causal agent, PRRS-virus(PRRSV), is able to evade the host immune response and survive in the organism causing transient infections. Despite all scientific efforts, there are still some gaps in the knowledge of the pathogenesis of this disease. Antigen presenting cells(APCs), as initiators of the immune response, are located in the first line of defense against microorganisms, and are responsible for antigen recognition, processing and presentation. Dendritic cells(DCs) are the main type of APC involved in antigen presentation and they are susceptible to PRRSV infection. Thus, PRRSV replication in DCs may trigger off different mechanisms to impair the onset of a host effective immune response against the virus. On the one side, PRRSV may impair the basic functions of DCs by regulating the expression of major histocompatibility complex class Ⅱ and CD80/86. Other strategy followed by the virus is the induction of cell death of APCs by apoptosis, necrosis or both of them. The impairment and/or cell death ofAPCs could lead to a failure in the onset of an efficient immune response, as long as cells could not properly activate T cells. Future aspects to take into account are also discussed in this review.