Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 91
Filter
1.
Molecules ; 26(17)2021 Aug 26.
Article in English | MEDLINE | ID: mdl-34500611

ABSTRACT

Human natural killer-1 (HNK-1) is a sulfated glyco-epitope regulating cell adhesion and synaptic functions. HNK-1 and its non-sulfated forms, which are specifically expressed in the brain and the kidney, respectively, are distinctly biosynthesized by two homologous glycosyltransferases: GlcAT-P in the brain and GlcAT-S in the kidney. However, it is largely unclear how the activity of these isozymes is regulated in vivo. We recently found that bisecting GlcNAc, a branching sugar in N-glycan, suppresses both GlcAT-P activity and HNK-1 expression in the brain. Here, we observed that the expression of non-sulfated HNK-1 in the kidney is unexpectedly unaltered in mutant mice lacking bisecting GlcNAc. This suggests that the biosynthesis of HNK-1 in the brain and the kidney are differentially regulated by bisecting GlcNAc. Mechanistically, in vitro activity assays demonstrated that bisecting GlcNAc inhibits the activity of GlcAT-P but not that of GlcAT-S. Furthermore, molecular dynamics simulation showed that GlcAT-P binds poorly to bisected N-glycan substrates, whereas GlcAT-S binds similarly to bisected and non-bisected N-glycans. These findings revealed the difference of the highly homologous isozymes for HNK-1 synthesis, highlighting the novel mechanism of the tissue-specific regulation of HNK-1 synthesis by bisecting GlcNAc.


Subject(s)
CD57 Antigens/biosynthesis , Glucuronosyltransferase/metabolism , Animals , Brain/metabolism , COS Cells , Cell Line , Chlorocebus aethiops , Epitopes/metabolism , Glycosyltransferases/metabolism , HEK293 Cells , Humans , Kidney/metabolism , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Polysaccharides/metabolism
2.
Pathol Res Pract ; 213(9): 1097-1101, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28778496

ABSTRACT

Peri-implantitis is an infectious disease characterized by inflammation of the tissues surrounding the implant, bleeding on probing with or without suppuration, and bone loss. Peri-implant lesions contain a leukocyte infiltrate of plasma cells, lymphocytes, macrophages and neutrophils. A survey of the literature did not show any studies reporting an association between hypoxia and peri-implantitis. The aim of the present cross-sectional study was to evaluate histological changes and immunostaining for CD15, CD57 and HIF-1α in the peri-implant mucosa of patients with and without peri-implantitis. Mucosal biopsies were obtained from 18 patients with peri-implantitis and 10 control subjects without peri-implantitis at a private health care center between 2010 and 2012. The sections were fixed in 10% buffered formalin, processed and embedded in paraffin for histopathological and immunohistochemical study. Acanthosis, spongiosis and exocytosis were observed in both groups, with no significant difference between them. The peri-implantitis group showed increased immunostaining for CD15, a neutrophil marker, and HIF-1α, a tissue hypoxia marker, but no significant difference in immunostaining for CD57, a Natural Killer cell marker. The increase in neutrophil (CD15) and hypoxia (HIF-1α) markers in patients with peri-implantitis suggests an active participation of neutrophils and hypoxia in the pathogenesis of this disease. Since the present study was the first to evaluate the expression of CD15, CD57 and HIF-1α in peri-implant tissues, further studies should be performed to better understand the role of these molecules in peri-implantitis.


Subject(s)
Dental Implants/adverse effects , Peri-Implantitis/immunology , Stomatitis/immunology , Aged , Biomarkers/analysis , Biopsy , CD57 Antigens/analysis , CD57 Antigens/biosynthesis , Cross-Sectional Studies , Female , Fucosyltransferases/analysis , Fucosyltransferases/biosynthesis , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/analysis , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Lewis X Antigen/analysis , Lewis X Antigen/biosynthesis , Male , Middle Aged
3.
AIDS Res Hum Retroviruses ; 33(12): 1205-1213, 2017 12.
Article in English | MEDLINE | ID: mdl-28810810

ABSTRACT

HIV-1 viremia has been shown to induce several phenotypic and functional abnormalities in natural killer (NK) cells. To assess immune defects associated with HIV viremia, we examined NK cell function, differentiation status, and phenotypic alterations based on expression of inhibitory and activating receptors on NK cells in HIV-1 subtype C chronically infected participants from Durban, South Africa. NK cell phenotypic profiles were characterized by assessing sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7), NKG2A, and NKG2C markers on frozen peripheral blood mononuclear cells from viremic, antiretroviral therapy (ART)-naive HIV-1 chronically infected participants (n = 23), HIV-1 chronically infected participants who had been on combination antiretroviral therapy (cART) for at least 12 months (n = 23) compared with healthy donors (n = 23). NK cell differentiation was assessed by measurement of killer immunoglobulin receptor (KIR) and NKG2A expression; CD57 and CD107a measurements were carried out in HIV viremic and healthy donors. All phenotypic and functional assessments were analyzed by using multicolor flow cytometry. HIV-1-infected participants displayed greater frequencies of the CD56-CD16+ (CD56negative) NK cell subset compared with healthy donors (p < .0001). Downregulation of Siglec-7 and NKG2A and upregulation of NKG2C were more pronounced in the CD56negative NK cell subset of viremic participants. The CD56negative subset demonstrated a differentiated (KIR+NKG2A-) phenotype with reduced CD57 expression and lower degranulation capacity in HIV-1-infected participants compared with healthy donors. HIV-1 infection induces the expansion of the CD56negative NK cell subset marked by altered receptor expression profiles that are indicative of impaired function and may explain the overall NK cell dysfunction observed in chronic HIV-1 infection.


Subject(s)
Antigens, Differentiation, Myelomonocytic/biosynthesis , CD57 Antigens/biosynthesis , HIV Infections/pathology , Killer Cells, Natural/immunology , Lectins/biosynthesis , Lysosomal-Associated Membrane Protein 1/biosynthesis , NK Cell Lectin-Like Receptor Subfamily C/biosynthesis , Adolescent , Adult , Anti-HIV Agents/therapeutic use , Down-Regulation/immunology , Female , Flow Cytometry , HIV-1 , Humans , Killer Cells, Natural/pathology , Leukocytes, Mononuclear/metabolism , South Africa , Up-Regulation/immunology , Viremia/pathology , Viremia/virology , Young Adult
4.
J Oral Pathol Med ; 45(1): 58-62, 2016 Jan.
Article in English | MEDLINE | ID: mdl-25808210

ABSTRACT

BACKGROUND: Natural killer (NK) cells are important immune effector cells against tumors especially in the absence or reducing MHC class I antigen. Downregulation of CD16 receptor is accompanied by decreasing NK cell-killing activity. It has also been shown that some of tumor cells can evade from immune system through producing transforming growth factor beta (TGF-ß) and affect prognosis. The objective of this study was to evaluate the prognostic significance of CD57(+) and CD16(+) cells and TGF-ß expression in samples of oral squamous cell carcinoma (OSCC). METHODS: CD57, CD16, and TGF-ß expressions were examined immunohistochemically in 57 cases of OSCC. The relationship between markers' expression and clinicopathologic data using bivariate and multivariate analysis was assessed. RESULTS: Multivariate analysis revealed that CD57 expression [HR 17.34 (95% CI 3.815-78.830); P < 0.001] and mode of invasion [HR 0.362 (95% CI 0.138-0.947); P = 0.038] correlated with survival rate, but no relation between CD57 expression and mode of invasion was seen (P = 0.96). Furthermore, no correlation between CD57, CD16, and TGF-ß expression was found. CONCLUSION: These findings suggest that CD57 expression and mode of invasion are independent prognostic factors of survival in OSCC patients.


Subject(s)
CD57 Antigens/biosynthesis , Carcinoma, Squamous Cell/metabolism , Head and Neck Neoplasms/metabolism , Mouth Neoplasms/metabolism , Receptors, IgG/biosynthesis , Transforming Growth Factor beta/biosynthesis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/biosynthesis , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Down-Regulation , Female , GPI-Linked Proteins/biosynthesis , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Immunohistochemistry , Iran/epidemiology , Killer Cells, Natural/metabolism , Male , Middle Aged , Mouth Neoplasms/mortality , Mouth Neoplasms/pathology , Prognosis , Squamous Cell Carcinoma of Head and Neck , Survival Rate
5.
Cell Immunol ; 297(1): 19-32, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26071876

ABSTRACT

The role of T-cell immunosenescence and functional CD8(+) T-cell responses in HIV/TB co-infection is unclear. We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of HIV/TB co-infected, HIV-infected and healthy controls. Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects relative to HIV-infected, and also a closer association with changes in the expression of CD38, a cyclic ADP ribose hydrolase and CD57, which were consistently expressed on late-senescent CD8(+) T cells. Up-regulation of CD57 and CD38 were directly proportional to lack of co-stimulatory markers on CD8(+) T cells, besides diminished expression of CD127 (IL-7Rα) on CD57(+)CD4(+) T cells. Notably, intracellular IFN-γ, perforin and granzyme B levels in HIV-specific CD8(+) T cells of HIV/TB co-infected subjects were diminished. Intracellular CD57 levels in HIV gag p24-specific CD8(+) T cells were significantly increased in HIV/TB co-infection. We suggest that HIV-TB co-infection contributes to senescence associated with chronic immune activation, which could be due to functional insufficiency of CD8(+) T cells.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cellular Senescence/immunology , HIV Infections/immunology , Immunosenescence/immunology , Tuberculosis, Pulmonary/immunology , ADP-ribosyl Cyclase 1/biosynthesis , Adult , CD4-CD8 Ratio , CD57 Antigens/biosynthesis , CD57 Antigens/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/pathology , Cell Differentiation/immunology , Cell Proliferation , Coinfection/immunology , Disease Progression , Female , Granzymes/metabolism , HLA-DR alpha-Chains/immunology , Humans , Interferon-gamma/metabolism , Interleukin-7 Receptor alpha Subunit/biosynthesis , Lymphocyte Activation/immunology , Male , Membrane Glycoproteins/biosynthesis , Perforin/metabolism
6.
J Immunol ; 195(3): 965-72, 2015 Aug 01.
Article in English | MEDLINE | ID: mdl-26091716

ABSTRACT

Recent studies suggested that human CD56(bright)CD16(-) NK cells may play a role in the regulation of the immune response. Since the mechanism(s) involved have not yet been elucidated, in the present study we have investigated the role of nucleotide-metabolizing enzymes that regulate the extracellular balance of nucleotides/nucleosides and produce the immunosuppressive molecule adenosine (ADO). Peripheral blood CD56(dim)CD16(+) and CD56(bright)CD16(-) NK cells expressed similar levels of CD38. CD39, CD73, and CD157 expression was higher in CD56(bright)CD16(-) than in CD56(dim)CD16(+) NK cells. CD57 was mostly expressed by CD56(dim)CD16(+) NK cells. CD203a/PC-1 expression was restricted to CD56(bright)CD16(-) NK cells. CD56(bright)CD16(-) NK cells produce ADO and inhibit autologous CD4(+) T cell proliferation. Such inhibition was 1) reverted pretreating CD56(bright)CD16(-) NK cells with a CD38 inhibitor and 2) increased pretreating CD56(bright)CD16(-) NK cells with a nucleoside transporter inhibitor, which increase extracellular ADO concentration. CD56(bright)CD16(-) NK cells isolated from the synovial fluid of juvenile idiopathic arthritis patients failed to inhibit autologous CD4(+) T cell proliferation. Such functional impairment could be related to 1) the observed reduced CD38/CD73 expression, 2) a peculiar ADO production kinetics, and 3) a different expression of ADO receptors. In contrast, CD56(bright)CD16(-) NK cells isolated from inflammatory pleural effusions display a potent regulatory activity. In conclusion, CD56(bright)CD16(-) NK cells act as "regulatory cells" through ADO produced by an ectoenzymes network, with a pivotal role of CD38. This function may be relevant for the modulation of the immune response in physiological and pathological conditions, and it could be impaired during autoimmune/inflammatory diseases.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , Adenosine/biosynthesis , CD4-Positive T-Lymphocytes/immunology , CD56 Antigen/genetics , Killer Cells, Natural/immunology , Membrane Glycoproteins/metabolism , 5'-Nucleotidase/biosynthesis , ADP-ribosyl Cyclase/biosynthesis , ADP-ribosyl Cyclase 1/antagonists & inhibitors , Antigens, CD/biosynthesis , Apyrase/biosynthesis , Arthritis, Juvenile/genetics , Arthritis, Juvenile/immunology , CD57 Antigens/biosynthesis , Cell Proliferation/genetics , GPI-Linked Proteins/biosynthesis , Humans , Killer Cells, Natural/cytology , Lymphocyte Activation/immunology , Membrane Glycoproteins/antagonists & inhibitors , Receptors, IgG/immunology , Synovial Fluid/cytology
7.
Arch Pathol Lab Med ; 139(4): 543-6, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25822764

ABSTRACT

CONTEXT: Neuroblastoma (NB) is the most common extracranial tumor of childhood. Although most cases have a distinctive histology, a subset of primitive cases require immunohistochemical studies to distinguish them from other small round blue cell tumors of childhood. Immunohistochemistry is also used to detect small amounts of tumor metastatic to the bone marrow and in posttreatment samples with obscuring fibrosis, calcification, or inflammation. The transcription factor PHOX2B is essential for the differentiation and survival of sympathetic neurons and chromaffin cells, and therefore is highly specific for the peripheral autonomic nervous system. OBJECTIVE: To determine the diagnostic utility of PHOX2B immunohistochemistry as a marker of primary, treated, and metastatic NB. DESIGN: Neuroblastoma tissue microarrays were stained with PHOX2B, CD57, and synaptophysin. Arrays containing rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor were stained with PHOX2B, and negative bone marrow samples were stained with PHOX2B and CD57. RESULTS: PHOX2B and CD57 were similar to synaptophysin in their ability to detect NB. PHOX2B and CD57 similarly showed robust staining in posttreatment NB and NB metastatic to the bone marrow. In contrast to the cytoplasmic staining pattern seen with synaptophysin and CD57, clear and strong nuclear PHOX2B permitted identification of individual tumor cells. PHOX2B staining was absent in all cases of rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor, and in the negative bone marrow. CONCLUSIONS: PHOX2B and CD57 are useful markers of NB. PHOX2B is specific for NB in its differential diagnosis with other small round cell tumors, and its nuclear staining may be helpful for accurate bone marrow tumor quantification.


Subject(s)
Bone Marrow Neoplasms/metabolism , Homeodomain Proteins/biosynthesis , Neuroblastoma/metabolism , Transcription Factors/biosynthesis , Bone Marrow Neoplasms/secondary , CD57 Antigens/biosynthesis , Diagnosis, Differential , Humans , Immunohistochemistry/methods , Neuroblastoma/diagnosis , Neuroblastoma/surgery , Reproducibility of Results , Rhabdomyosarcoma/diagnosis , Rhabdomyosarcoma/metabolism , Sarcoma, Ewing/diagnosis , Sarcoma, Ewing/metabolism , Sensitivity and Specificity , Synaptophysin/biosynthesis , Tissue Array Analysis , Wilms Tumor/diagnosis , Wilms Tumor/metabolism
8.
Toxicol Appl Pharmacol ; 274(1): 42-54, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24211274

ABSTRACT

Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8+CD57+ cytotoxic T cells but not CD4+CD57+ cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1ß, and IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8+CD57+ T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH.


Subject(s)
CD57 Antigens/biosynthesis , CD8-Positive T-Lymphocytes/metabolism , Cytochrome P-450 CYP2E1/deficiency , Environmental Exposure/adverse effects , Fatty Liver/metabolism , Leptin/deficiency , Animals , CD8-Positive T-Lymphocytes/drug effects , Cytokines/biosynthesis , Fatty Liver/chemically induced , Gene Expression Regulation , Inflammation Mediators/metabolism , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease , Obesity/chemically induced , Obesity/metabolism , Oxidative Stress/drug effects , Oxidative Stress/physiology , Trihalomethanes/toxicity
9.
Transpl Int ; 25(9): 948-55, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22784509

ABSTRACT

The role of Cytomegalovirus (CMV) in carcinogenesis is controversial. We studied whether CMV may contribute to cancer occurrence in renal transplant recipients. We studied a prospective cohort of 455 consecutive patients who received a kidney transplant between January 1995 and December 2006. All cancers and types of cancers were assessed. Lymphocyte phenotype and cytokines production were analysed according to CMV status in a subset population of this cohort. Mean follow-up was 84 ± 29 months. One hundred and nineteen cancers (26.2%) occurred during the study follow-up. There was a higher cumulated incidence of cancers in CMV-exposed patients (30.4% vs. 20%; P=0.018). Mean time to cancer occurrence was shorter in CMV-exposed patients than in CMV-naïve patients (4.7 ± 2.6 vs. 6.7 ± 2.8; P = 0.001). Cox regression analysis revealed that both pretransplant CMV exposure (HR, 1.83; 95% CI, 1.17-2.88; P = 0.009) and post-transplant CMV replication (HR, 2.17; 95% CI, 1.02-4.59; P = 0.044) were risk factors for cancer. Among CD8+ T cells, exhausted T cells assessed as CD57+CD28- were expanded in CMV-exposed patients (26 ± 20 vs. 9 ± 8%; P < 0.0001), whereas CD8+CD57+IL2- cells were more frequent in CMV-exposed patients. Our results highly suggest that CMV increases the risk of cancer after transplantation.


Subject(s)
Cytomegalovirus/metabolism , Neoplasms/complications , Neoplasms/immunology , Renal Insufficiency/therapy , Adult , Aged , CD28 Antigens/biosynthesis , CD57 Antigens/biosynthesis , Cohort Studies , Female , Humans , Immune System , Lymphocytes/metabolism , Male , Middle Aged , Neoplasms/virology , Phenotype , Prospective Studies , Regression Analysis , Renal Insufficiency/complications , Renal Insufficiency/virology , Risk , Treatment Outcome
10.
Cell Mol Life Sci ; 69(24): 4135-47, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22669261

ABSTRACT

Human natural killer-1 (HNK-1) carbohydrate, comprising a unique trisaccharide HSO(3)-3GlcAß1-3Galß1-4GlcNAc, shows well-regulated expression and unique functions in the nervous system. Recent studies have revealed sophisticated and complicated expression mechanisms for HNK-1 glycan. Activities of biosynthetic enzymes are controlled through the formation of enzyme-complexes and regulation of subcellular localization. Functional aspects of HNK-1 carbohydrate were examined by overexpression, knockdown, and knockout studies of these enzymes. HNK-1 is involved in several neural functions such as synaptic plasticity, learning and memory, and the underlying molecular mechanisms have been illustrated upon identification of the target carrier glycoproteins of HNK-1 such as the glutamate receptor subunit GluA2 or tenascin-R. In this review, we describe recent findings about HNK-1 carbohydrate that provide further insights into the mechanism of its expression and function in the nervous system.


Subject(s)
CD57 Antigens/physiology , Nervous System/metabolism , Animals , CD57 Antigens/biosynthesis , CD57 Antigens/chemistry , Chick Embryo , Dendritic Spines/metabolism , Dendritic Spines/physiology , Epitopes/biosynthesis , Epitopes/chemistry , Gene Expression Regulation, Developmental , Glucuronosyltransferase/genetics , Glucuronosyltransferase/physiology , Humans , Mice , Models, Biological , Nervous System/growth & development , Nervous System Diseases/genetics , Neuronal Plasticity , Polysaccharides/biosynthesis , Polysaccharides/chemistry , Polysaccharides/physiology , Rats
11.
Brain Behav Immun ; 26(1): 177-86, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21933704

ABSTRACT

NK-cells and γδ T-cells are cytotoxic effectors of the immune system that are preferentially mobilized into the blood compartment in response to acute stress and exercise. While infection history is known to alter the phenotype and exercise-responsiveness of CD8+ T-cells, the influence of latent cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections on the phenotypes and exercise-responsiveness of NK-cells and γδ T-cells are unknown. Twenty healthy males (age: 28.4±5.4 years) cycled for 30 min at 85% peak power. Blood lymphocytes isolated before, immediately after, and 1 h after exercise were surface stained for CD3, CD4, CD8, CD56, CD57, CD158a, KLRG1, and γδ-TCR antigens by four-color flow cytometry. CMV and EBV serostatus (pos/neg) was determined by ELISA. CMVpos had lower proportions of NK-cells expressing inhibitory receptors (KLRG1+ and CD158a+) and higher proportions of terminally differentiated NK-cells (KLRG1-/CD57+) compared to CMVneg. CMVpos mobilized far fewer (132 cells/µL vs. 245 cells/µL) NK-cells in response to exercise despite having similar baseline NK-cell counts and physiological responses to exercise as CMVneg, although terminally differentiated NK-cells were equally responsive to exercise regardless of CMV serostatus (p=0.658). EBVpos had higher proportions of CD8+ NK-cells, but cellular responses to exercise were not influenced by EBV. The frequency and exercise-responsiveness of γδ T-cells was not affected by CMV or EBV serostatus (p>0.05). In conclusion, latent CMV infection is associated with lowered numbers of NK-cells expressing inhibitory receptors and a blunted mobilization of NK-cells in response to acute exercise. This may indicate a compromised immune response to "fight-or-flight" situations in those infected with CMV.


Subject(s)
Cytomegalovirus Infections/metabolism , Exercise/physiology , Killer Cells, Natural/metabolism , Killer Cells, Natural/physiology , Lectins, C-Type/biosynthesis , Receptors, KIR2DL1/biosynthesis , Trans-Activators/biosynthesis , Adult , Anaerobic Threshold/physiology , Antibodies, Monoclonal/immunology , Bicycling/physiology , CD57 Antigens/biosynthesis , CD57 Antigens/genetics , CD8-Positive T-Lymphocytes/metabolism , Epstein-Barr Virus Infections/metabolism , Flow Cytometry , Humans , Lectins, C-Type/genetics , Lymphocyte Count , Male , Membrane Proteins/metabolism , Phenotype , Receptors, Immunologic , Receptors, KIR2DL1/genetics , T-Lymphocytes/physiology , Trans-Activators/genetics , Young Adult
12.
Dis Markers ; 31(6): 337-42, 2011.
Article in English | MEDLINE | ID: mdl-22182806

ABSTRACT

HIV-infected individuals responding to antiretroviral therapy (ART) after severe CD4+ T-cell depletion may retain low responses to recall antigens [eg: cytomegalovirus (CMV)] and altered expression of T-cell co-stimulatory molecules consistent with immunosenescence. We investigated the capacity of phenotypically senescent cells to generate cytokines in HIV patients receiving long-term ART (n = 18) and in healthy controls (n = 10). Memory T-cells were assessed by interferon (IFN)-γ ELISpot assay and flow cytometrically via IFN-γ or IL-2. Proportions of CD57(bright)CD28(null) CD4+ T-cells correlated with IFN-γ responses to CMV (p =0.009) and anti-CD3 (p =0.002) in HIV patients only. Proportions of CD57(bright)CD28(null) CD8+T-cells and CD8+ T-cell IFN-γ responses to CMV peptides correlated in controls but not HIV patients. IL-2 was predominantly produced by CD28+T-cells from all donors, whereas IFN-γ was mostly produced by CD57+ T-cells. The findings provide evidence of an accumulation of immunosenescent T-cells able to make IFN-γ. This may influence the pathogenesis of secondary viral infections in HIV patients receiving ART.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD57 Antigens/biosynthesis , Cellular Senescence/immunology , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , HIV Infections/immunology , HIV/immunology , Adult , Aged , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Australia , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , CD57 Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Case-Control Studies , Cell Proliferation , Coinfection , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/metabolism , Cytomegalovirus Infections/pathology , Cytomegalovirus Infections/virology , Female , HIV Infections/drug therapy , HIV Infections/metabolism , HIV Infections/pathology , HIV Infections/virology , Humans , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Interleukin-2/biosynthesis , Interleukin-2/immunology , Male , Middle Aged
13.
Proc Natl Acad Sci U S A ; 108(36): 14725-32, 2011 Sep 06.
Article in English | MEDLINE | ID: mdl-21825173

ABSTRACT

During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94-NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56(dim)CD16(+) NK cell compartment. Here we demonstrate the preferential expansion of a unique subset of NK cells coexpressing the activating CD94-NKG2C receptor and CD57 in CMV(+) donors. These CD57(+)NKG2C(hi) NK cells degranulated in response to stimulation through their NKG2C receptor. Furthermore, CD57(+)NKG2C(hi) NK cells preferentially lack expression of the inhibitory NKG2A receptor and the inhibitory KIR3DL1 receptor in individuals expressing its HLA-Bw4 ligand. Moreover, in solid-organ transplant recipients with active CMV infection, the percentage of CD57(+)NKG2C(hi) NK cells in the total NK cell population preferentially increased. During acute CMV infection, the NKG2C(+) NK cells proliferated, became NKG2C(hi), and finally acquired CD57. Thus, we propose that CD57 might provide a marker of "memory" NK cells that have been expanded in response to infection.


Subject(s)
CD57 Antigens/immunology , Cell Proliferation , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Killer Cells, Natural/immunology , NK Cell Lectin-Like Receptor Subfamily C/immunology , Acute Disease , Biomarkers/metabolism , CD56 Antigen/immunology , CD56 Antigen/metabolism , CD57 Antigens/biosynthesis , Cell Degranulation/immunology , Cytomegalovirus/metabolism , Cytomegalovirus Infections/metabolism , GPI-Linked Proteins/immunology , GPI-Linked Proteins/metabolism , Gene Expression Regulation/immunology , HLA-B Antigens/immunology , HLA-B Antigens/metabolism , Humans , Immunologic Memory , Killer Cells, Natural/metabolism , NK Cell Lectin-Like Receptor Subfamily C/biosynthesis , Organ Transplantation , Receptors, IgG/immunology , Receptors, IgG/metabolism , Receptors, KIR3DL1/immunology , Receptors, KIR3DL1/metabolism , Tissue Donors , Transplantation, Homologous
14.
J Biol Chem ; 286(36): 31337-46, 2011 Sep 09.
Article in English | MEDLINE | ID: mdl-21771787

ABSTRACT

Human natural killer-1 (HNK-1) carbohydrate is highly expressed in the nervous system and is involved in synaptic plasticity and dendritic spine maturation. This unique carbohydrate, consisting of a sulfated trisaccharide (HSO(3)-3GlcAß1-3Galß1-4GlcNAc-), is biosynthesized by the successive actions of ß-1,4-galactosyltransferase (ß4GalT), glucuronyltransferase (GlcAT-P and GlcAT-S), and sulfotransferase (HNK-1ST). A previous study showed that mice lacking ß4GalT-II, one of seven ß4GalTs, exhibited a dramatic loss of HNK-1 expression in the brain, although ß4GalT-I-deficient mice did not. Here, we investigated the underlying molecular mechanism of the regulation of HNK-1 expression. First, focusing on a major HNK-1 carrier, neural cell adhesion molecule, we found that reduced expression of an N-linked HNK-1 carbohydrate caused by a deficiency of ß4GalT-II is not likely due to a general loss of the ß1,4-galactose residue as an acceptor for GlcAT-P. Instead, we demonstrated by co-immunoprecipitation and endoplasmic reticulum-retention analyses using Neuro2a (N2a) cells that ß4GalT-II physically and specifically associates with GlcAT-P. In addition, we revealed by pulldown assay that Golgi luminal domains of ß4GalT-II and GlcAT-P are sufficient for the complex to form. With an in vitro assay system, we produced the evidence that the kinetic efficiency k(cat)/K(m) of GlcAT-P in the presence of ß4GalT-II was increased about 2.5-fold compared with that in the absence of ß4GalT-II. Finally, we showed that co-expression of ß4GalT-II and GlcAT-P increased HNK-1 expression on various glycoproteins in N2a cells, including neural cell adhesion molecule. These results indicate that the specific enzyme complex of ß4GalT-II with GlcAT-P plays an important role in the biosynthesis of HNK-1 carbohydrate.


Subject(s)
CD57 Antigens/biosynthesis , Galactosyltransferases/metabolism , Glucuronosyltransferase/metabolism , Animals , Cell Line , Galactosyltransferases/deficiency , Gene Expression Regulation , Glucuronosyltransferase/deficiency , Humans , Kinetics , Metabolic Networks and Pathways , Mice , Mice, Knockout
15.
Appl Immunohistochem Mol Morphol ; 19(3): 239-45, 2011 May.
Article in English | MEDLINE | ID: mdl-21475039

ABSTRACT

It is not easy to reach a differential diagnosis between keratoacanthoma (KA) and squamous cell carcinoma (SCC) and furthermore there is still considerable discussion about the relationship of these 2 tumors with immunity. To facilitate such a diagnosis, we assessed the Glut-1 antibody, reported to be strongly and diffusely expressed in SCC but never assessed in KA. We studied 43 lesions of immunocompetent patients: 17 SCCs, 13 typical KAs (tKAs), and 13 atypical KAs (aKAs), with histologic features of SCC in less than 30% of the lesions. In tKA, Glut-1 stained only the basal layers of the squamous nests (basal pattern) whereas in SCC the squamous nests were randomly and diffusely stained (diffuse pattern). In aKA, a biphasic pattern was observed, with the typical KA areas showing the basal pattern and the SCC-like areas showing the diffuse pattern. Glut-1, therefore, helps to distinguish tKAs from SCCs and highlights the intermediate aKA group, supporting the hypothesis of a progression from KA to SCC. Finally, we used CD1a, CD57, CD4, CD8, CD3, and CD20 antibodies to assess whether or not the progression might be related to an in situ immunologic deficit. Significant differences were found both in CD1a+ cells, more numerous in tKA than in SCC and in CD57+ cells, more numerous in tKA than in aKA and in SCC. This suggests a local immunological failure in aKA and SCC, probably related to the action of UV rays, leading us to consider KA as a model for the study of the interaction of skin cancer and immunity.


Subject(s)
Carcinoma, Squamous Cell/diagnosis , Excitatory Amino Acid Transporter 2/metabolism , Keratoacanthoma/diagnosis , Skin Diseases/diagnosis , Skin Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Antigens, CD1/biosynthesis , Biomarkers, Tumor/metabolism , CD57 Antigens/biosynthesis , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/physiopathology , Diagnosis, Differential , Disease Progression , Excitatory Amino Acid Transporter 2/genetics , Excitatory Amino Acid Transporter 2/immunology , Female , Humans , Immunity , Keratoacanthoma/pathology , Keratoacanthoma/physiopathology , Male , Middle Aged , Skin Diseases/pathology , Skin Diseases/physiopathology , Skin Neoplasms/pathology , Skin Neoplasms/physiopathology
16.
Oncol Rep ; 26(1): 201-8, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21491089

ABSTRACT

Although CD57+ lymphocytes are closely correlated with prognosis in various cancers, the role of subsets of CD57+ cells in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is unclear. In the present study, peripheral blood (PB) from HCV-related HCC patients was analyzed. Plasma cytokine levels and in vitro cytokine-producing capabilities were analyzed with enzyme-linked immunosorbent assays, and CD57+ cell subsets were studied using a multi-color FACS system. Interferon (IFN)-γ was undetectable in the plasma of patients with tumors at any stage, whereas the plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-10 and IL-18, but not that of IL-12, were significantly higher in stage IV patients compared to patients with earlier-stage tumors. In contrast, the IFN-γ-producing capability of PB was highest in stage I patients and gradually decreased with tumor progression. The IL-10-, IL-18- and IL-12-producing capabilities of PB increased from stage I to III. However, PB-TNF-α, IL-10- and IL-18-producing capabilities were reduced in stage IV patients, probably due to repeated anti-cancer treatments. The percentage of CD4+CD57+αßTCR+ cells (CD4+CD57+ T cells) in peripheral blood lymphocytes (PBLs) increased with tumor progression. Moreover, the percentage of CD4+CD57+ T cells in PBLs and the ratio of CD4+CD57+ T cells to CD4+αßTCR+ cells (CD4+ T cells), but not that of CD4+CD57+ T cells to CD57+αßTCR+ cells (CD57+ T cells), showed a significant inverse correlation with PB-IFN-γ-producing capability. The present results suggest that an increase in CD4+CD57+ T cells controls the capability of PB to produce the anti-tumor cytokine IFN-γ and that PB-IFN-γ production is impaired with HCC tumor progression.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , Carcinoma, Hepatocellular/metabolism , Cytokines/biosynthesis , Gene Expression Regulation, Neoplastic , Hepacivirus/metabolism , Liver Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , CD57 Antigens/biosynthesis , Carcinoma, Hepatocellular/virology , Cell Separation , Female , Flow Cytometry , Humans , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-12/metabolism , Interleukin-18/metabolism , Liver Neoplasms/virology , Male , Middle Aged , Tumor Necrosis Factor-alpha/metabolism
17.
Atherosclerosis ; 217(1): 207-13, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21492857

ABSTRACT

OBJECTIVES: HIV disease is associated with increased arterial stiffness, which may be related to inflammation provoked by HIV-related immune perturbation. We assessed the association of T cell markers of immune activation and immunosenescence with carotid artery stiffness among HIV-infected women. METHODS: Among 114 HIV-infected and 43 HIV-uninfected women, we measured CD4+ and CD8+ T cell populations expressing activation (CD38+HLA-DR+) and senescence (CD28-CD57+) markers. We then related these measures of immune status with parameters of carotid artery stiffness, including decreased distensibility, and increased Young's elastic modulus, as assessed by B-mode ultrasound. RESULTS: HIV infection was associated with increased CD4+ T cell activation, CD8+ T cell activation and CD8+ T cell senescence. Among HIV-infected women, adjusted for age, HIV medications, and vascular risk factors, higher CD4+CD38+HLA-DR+ T cell frequency was associated with decreased carotid artery distensibility (ß=-2.00, 95% confidence interval [CI]=-3.86, -0.14, P=0.04) and increased Young's modulus (ß=1.00, 95% CI=0.03, 1.97, P=0.04). These associations were affected little by further adjustment for CD4+ T cell count and viral load. Among HIV-infected women, higher frequencies of immunosenescent T cells, including CD4+CD28-CD57+ and CD8+CD28-CD57+ T cells, were also associated with decreased arterial distensibility. Among HIV-uninfected women, frequencies of activated or senescent T cells were not significantly associated with measures of carotid stiffness. DISCUSSION: T cell activation and senescence are associated with arterial stiffness, suggesting that pro-inflammatory populations of T cells may produce functional or structural vascular changes in HIV-infected women.


Subject(s)
Carotid Arteries/pathology , HIV Infections/complications , Lymphocyte Activation , T-Lymphocytes/cytology , Vascular Stiffness , ADP-ribosyl Cyclase 1/biosynthesis , Adult , CD28 Antigens/biosynthesis , CD4-Positive T-Lymphocytes/metabolism , CD57 Antigens/biosynthesis , CD8-Positive T-Lymphocytes/metabolism , Cellular Senescence , Female , HIV Infections/pathology , HLA-DR Antigens/biosynthesis , Humans , Inflammation , Middle Aged , Models, Statistical , Prospective Studies , Risk Factors
18.
Anticancer Res ; 31(2): 699-703, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21378359

ABSTRACT

BACKGROUND: The objective of this study was to evaluate the recurrence-preventing effect of intravesical instillations of interleukin-2 (IL-2) in patients with non-muscle-invasive bladder carcinoma. In addition, this study aimed to determine the significance of immune parameters for recurrence-free interval. PATIENTS AND METHODS: Twenty-six patients with non-muscle-invasive bladder carcinoma were treated with intravesical instillations of IL-2 (Proleukin®, Novartis, formerly Chiron) in doses of 9 × 10(6) IU on 5 consecutive days, beginning on the second day after transurethral resection (TUR) of tumours. CD8(high)CD57(+) lymphocytes in peripheral blood were determined before TUR and compared with the recurrence-free interval after treatment. RESULTS: The multivariate analysis showed that CD8(high)CD57(+) lymphocytes had a prognostic significance in combination with number of bladder tumours, prior recurrence rate and age of patients. CONCLUSION: Peripheral blood CD8(high)CD57(+) lymphocytes have prognostic significance for recurrence-free survival in patients with non-muscle-invasive bladder carcinoma after TUR and intravesical IL-2.


Subject(s)
CD57 Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , Interleukin-2/administration & dosage , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/immunology , Administration, Intravesical , Adult , Aged , Aged, 80 and over , CD57 Antigens/biosynthesis , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Prognosis , Urinary Bladder Neoplasms/blood , Urinary Bladder Neoplasms/surgery
19.
Carbohydr Res ; 346(2): 348-51, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21176892

ABSTRACT

This work reports the synthesis and the biological validation of a trisaccharide analogue of the HNK-1 epitope. The 3-O-sulfo-ß-d-GlcpA-(1→3)-ß-d-Galp-(1→4)-ß-d-Glcp-allyl has been prepared by enzymatic glucuronylation of allyl lactoside by an engineered recombinant Escherichia coli strain followed by a chemoselective sulfation. Subsequent covalent attachment of the ozone-oxidised trisaccharide to bovine serum albumin provided a neo-glycoconjugate, which has been interrogated with antibodies specific to the human natural killer carbohydrate epitope HNK-1. ELISA assays confirmed the absolute requirement of the sulfate group for protein recognition and the potential application of this synthetic oligosaccharide as HNK-1 surrogate.


Subject(s)
Allyl Compounds/metabolism , CD57 Antigens/biosynthesis , Escherichia coli/enzymology , Immunodominant Epitopes/biosynthesis , Oligosaccharides/biosynthesis , Trisaccharides/biosynthesis , Allyl Compounds/chemistry , Allyl Compounds/immunology , Brain/immunology , CD57 Antigens/chemistry , CD57 Antigens/immunology , Carbohydrate Sequence , Enzyme-Linked Immunosorbent Assay , Escherichia coli/genetics , Humans , Immunodominant Epitopes/chemistry , Immunodominant Epitopes/immunology , Molecular Sequence Data , Oligosaccharides/chemistry , Oligosaccharides/immunology , Serum Albumin, Bovine/chemistry , Trisaccharides/chemistry , Trisaccharides/immunology
20.
PLoS One ; 5(12): e15343, 2010 Dec 13.
Article in English | MEDLINE | ID: mdl-21179445

ABSTRACT

West Nile virus (WNV) infection can result in severe neuroinvasive disease, particularly in persons with advanced age. As rodent models demonstrate that T cells play an important role in limiting WNV infection, and strong T cell responses to WNV have been observed in humans, we postulated that inadequate antiviral T cell immunity was involved in neurologic sequelae and the more severe outcomes associated with age. We previously reported the discovery of six HLA-A*0201 restricted WNV peptide epitopes, with the dominant T cell targets in naturally infected individuals being SVG9 (Env) and SLF9 (NS4b). Here, memory phenotype and polyfunctional CD8+ T cell responses to these dominant epitopes were assessed in 40 WNV seropositive patients displaying diverse clinical symptoms. The patients' PBMC were stained with HLA-I multimers loaded with the SVG9 and SLF9 epitopes and analyzed by multicolor flow cytometry. WNV-specific CD8+ T cells were found in peripheral blood several months post infection. The number of WNV-specific T cells in older individuals was the same, if not greater, than in younger members of the cohort. WNV-specific T cells were predominantly monofunctional for CD107a, MIP-1ß, TNFα, IL-2, or IFNγ. When CD8+ T cell responses were stratified by disease severity, an increased number of terminally differentiated, memory phenotype (CD45RA+ CD27- CCR7- CD57+) T cells were detected in patients suffering from viral neuroinvasion. In conclusion, T cells of a terminally differentiated/cytolytic profile are associated with neuroinvasion and, regardless of age, monofunctional T cells persist following infection. These data provide the first indication that particular CD8+ T cell phenotypes are associated with disease outcome following WNV infection.


Subject(s)
T-Lymphocytes/virology , West Nile virus/genetics , Age Factors , CD57 Antigens/biosynthesis , CD8-Positive T-Lymphocytes/metabolism , Epitopes/chemistry , HLA-A Antigens/genetics , Humans , Immunologic Memory , Leukocyte Common Antigens/metabolism , Ligands , Phenotype , Receptors, CCR7/metabolism , Tumor Necrosis Factor Receptor Superfamily, Member 7/biosynthesis , West Nile Fever/pathology , West Nile Fever/virology
SELECTION OF CITATIONS
SEARCH DETAIL
...