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1.
Front Immunol ; 15: 1342335, 2024.
Article in English | MEDLINE | ID: mdl-38596688

ABSTRACT

Introduction: Human leukocyte antigen (HLA) I molecules present antigenic peptides to activate CD8+ T cells. Type 1 Diabetes (T1D) is an auto-immune disease caused by aberrant activation of the CD8+ T cells that destroy insulin-producing pancreatic ß cells. Some HLA I alleles were shown to increase the risk of T1D (T1D-predisposing alleles), while some reduce this risk (T1D-protective alleles). Methods: Here, we compared the T1D-predisposing and T1D-protective allotypes concerning peptide binding, maturation, localization and surface expression and correlated it with their sequences and energetic profiles using experimental and computational methods. Results: T1D-predisposing allotypes had more peptide-bound forms and higher plasma membrane levels than T1D-protective allotypes. This was related to the fact that position 116 within the F pocket was more conserved and made more optimal contacts with the neighboring residues in T1D-predisposing allotypes than in protective allotypes. Conclusion: Our work uncovers that specific polymorphisms in HLA I molecules potentially influence their susceptibility to T1D.


Subject(s)
Diabetes Mellitus, Type 1 , Humans , CD8-Positive T-Lymphocytes , Histocompatibility Antigens Class I , Peptides/metabolism , Histocompatibility Antigens Class II/metabolism , HLA Antigens/metabolism , Histocompatibility Antigens/metabolism
2.
Eur J Immunol ; 54(6): e2350683, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38549458

ABSTRACT

HLA-B*39:06, HLA-B*39:01, and HLA-B*38:01 are closely related HLA allotypes differentially associated with type 1 diabetes (T1D) risk and progression. B*39:06 is highly predisposing, while B*39:01 and B*38:01 are weakly predisposing and protective allotypes, respectively. Here, we aimed to decipher molecular mechanisms underlying the differential association of these allotypes with T1D pathogenesis. We addressed peptide binding and conformational stability of HLA-B allotypes using computational and experimental approaches. Computationally, we found that B*39:06 and B*39:01 allotypes had more rigid peptide-binding grooves and were more promiscuous in binding peptides than B*38:01. Peptidomes of B*39:06 and B*39:01 contained fewer strong binders and were of lower affinity than that of B*38:01. Experimentally, we demonstrated that B*39:06 and B*39:01 had a higher capacity to bind peptides and exit to the cell surface but lower surface levels and were degraded faster than B*38:01. In summary, we propose that promiscuous B*39:06 and B*39:01 may bind suboptimal peptides and transport them the cell surface, where such unstable complexes may contribute to the pathogenesis of T1D.


Subject(s)
Diabetes Mellitus, Type 1 , HLA-B Antigens , Peptides , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Humans , Peptides/chemistry , Peptides/genetics , Peptides/immunology , HLA-B Antigens/genetics , HLA-B Antigens/metabolism , Polymorphism, Genetic , Protein Binding , Alleles , Protein Stability , Genetic Predisposition to Disease
4.
EMBO J ; 42(1): e111139, 2023 01 04.
Article in English | MEDLINE | ID: mdl-36382711

ABSTRACT

Hirschsprung disease (HSCR), one of several neurocristopathies in children, is characterized by nerve loss in the large intestine and is mainly treated by surgery, which causes severe complications. Enteric neural crest-derived cell (ENCC) transplantation is a potential therapeutic strategy; however, so far with poor efficacy. Here, we assessed whether and how fecal microbiota transplantation (FMT) could improve ENCC transplantation in a rat model of hypoganglionosis; a condition similar to HSCR, with less intestinal innervation. We found that the hypoganglionosis intestinal microenvironment negatively influenced the ENCC functional phenotype in vitro and in vivo. Combining 16S rDNA sequencing and targeted mass spectrometry revealed microbial dysbiosis and reduced short-chain fatty acid (SCFA) production in the hypoganglionic gut. FMT increased the abundance of Bacteroides and Clostridium, SCFA production, and improved outcomes following ENCC transplantation. SCFAs alone stimulated ENCC proliferation, migration, and supported ENCC transplantation. Transcriptome-wide mRNA sequencing identified MAPK signaling as the top differentially regulated pathway in response to SCFA exposure, and inhibition of MEK1/2 signaling abrogated the SCFA-mediated effects on ENCC. This study demonstrates that FMT improves cell therapy for hypoganglionosis via short-chain fatty acid metabolism-induced MEK1/2 signaling.


Subject(s)
Fecal Microbiota Transplantation , Hirschsprung Disease , Rats , Animals , Hirschsprung Disease/therapy , Hirschsprung Disease/genetics , Hirschsprung Disease/metabolism , Signal Transduction , Fatty Acids, Volatile/metabolism , Cell- and Tissue-Based Therapy
5.
Cell Cycle ; 22(23-24): 2584-2601, 2023.
Article in English | MEDLINE | ID: mdl-38197217

ABSTRACT

The family of high mobility group box (HMGB) proteins participates in various biological processes including immunity, inflammation, as well as cancer formation and progression. However, its role in thyroid cancer remains to be clarified. We performed quantitative RT-PCR (qRT-PCR), western blot, enzyme-linked immunosorbent, immunohistochemistry, and immunofluorescence assays to evaluate the expression level and subcellular location of HMGB3. The effects of HMGB3 knockdown on malignant biological behaviors of thyroid cancer were determined by cell proliferation assays, cell cycle and apoptosis assays, and transwell chamber migration and invasion assays. Differential expression genes (DEGs) altered by HMGB3 were analyzed using the Ingenuity Pathway Analysis (IPA) and TRRUST v2 database. HMGB3 correlated pathways predicted by bioinformatic analysis were then confirmed using western blot, co-immunoprecipitation, dual-luciferase reporter assay, and flow cytometry. We found that HMGB3 is overexpressed and its downregulation inhibits cell viability, promotes cell apoptosis and cell cycle arrest, and suppresses cell migration and invasion in thyroid cancer. In PTC, both tissue and serum levels of HMGB3 are elevated and are correlated with lymph node metastasis and advanced tumor stage. Mechanistically, we observed the translocation of HMGB3 in PTC, induced at least partially by hypoxia. Cytoplasmic HMGB3 activates nucleic-acid-mediated TLR3/NF-κB signaling and extracellular HMGB3 interacts with the transmembrane TREM1 receptor in PTC. This study demonstrates the oncogenic role of HMGB3 cytoplasmic and extracellular translocation in papillary thyroid cancers; we recommend its future use as a potential circulating biomarker and therapeutic target for PTC.


Subject(s)
HMGB3 Protein , MicroRNAs , Thyroid Neoplasms , Humans , Thyroid Cancer, Papillary/genetics , Thyroid Cancer, Papillary/pathology , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/metabolism , Cell Line, Tumor , Triggering Receptor Expressed on Myeloid Cells-1/genetics , Triggering Receptor Expressed on Myeloid Cells-1/metabolism , Thyroid Neoplasms/genetics , HMGB3 Protein/genetics , HMGB3 Protein/metabolism , Cell Proliferation/genetics , MicroRNAs/genetics , Cell Movement/genetics , Gene Expression Regulation, Neoplastic
6.
Front Immunol ; 13: 902135, 2022.
Article in English | MEDLINE | ID: mdl-35958592

ABSTRACT

Peptide-loaded Major Histocompatibility Complex (pMHC) class I molecules can be expressed in a single chain trimeric (SCT) format, composed of a specific peptide fused to the light chain beta-2 microglobulin (ß2m) and MHC class I heavy chain (HC) by flexible linker peptides. pMHC SCTs have been used as effective molecular tools to investigate cellular immunity and represent a promising vaccine platform technology, due to their intracellular folding and assembly which is apparently independent of host cell folding pathways and chaperones. However, certain MHC class I HC molecules, such as the Human Leukocyte Antigen B27 (HLA-B27) allele, present a challenge due to their tendency to form HC aggregates. We constructed a series of single chain trimeric molecules to determine the behaviour of the HLA-B27 HC in a scenario that usually allows for efficient MHC class I molecule folding. When stably expressed, a pMHC SCT incorporating HLA-B27 HC formed chaperone-bound homodimers within the endoplasmic reticulum (ER). A series of HLA-B27 SCT substitution mutations revealed that the F pocket and antigen binding groove regions of the HLA-B27 HC defined the folding and dimerisation of the single chain complex, independently of the peptide sequence. Furthermore, pMHC SCTs can demonstrate variability in their association with the intracellular antigen processing machinery.


Subject(s)
HLA-B27 Antigen , Histocompatibility Antigens Class I , Antigen Presentation , Genes, MHC Class I , HLA-B27 Antigen/genetics , Histocompatibility Antigens Class I/genetics , Humans , Molecular Chaperones/genetics , Peptides/genetics
7.
Front Endocrinol (Lausanne) ; 13: 842254, 2022.
Article in English | MEDLINE | ID: mdl-35712250

ABSTRACT

Objective: This cross-sectional study aimed to determine the relationship between clinical blood pressures and blood pressures measured using Doppler with blood glucose in pregnancy by ethnicity. Methods: We recruited 179 (52% White European, 48% Asian) pregnant women at 24-28 weeks of gestation who underwent a glucose tolerance test in an antenatal clinic in Bradford Royal Infirmary, the UK, from 2012 to 2013. Systolic blood pressures in the arm (left and right brachial) and ankle [left and right posterior tibial (PT) and dorsalis pedalis (DP)] blood pressures were measured using a Doppler probe. The inter-arm (brachial) and inter-ankle (PT and DP) systolic blood pressure differences were obtained. A multivariate linear regression model adjusted for age, body mass index, and diabetes risk was used to assess the relationship between blood pressures and blood glucose. Results: Asian pregnant women had higher blood glucose but lower ankle blood pressures than White Europeans. In White Europeans, brachial blood pressures and clinical blood pressures were positively associated with fasting blood glucose (FBG), but brachial blood pressures did not perform better as an indicator of FBG than clinical blood pressures. In Asians, increased inter-ankle blood pressure difference was associated with increased FBG. For each 10 mmHg increase in the inter-ankle blood pressure difference, FBG increased by 0.12 mmol/L (Beta=0.12, 95%CI: 0.01-0.23). Conclusion: The relationship between blood pressures with blood glucose differed by ethnicity. In Asians, inter-ankle systolic blood pressure difference was positively associated with blood glucose. This is first ever report on ankle blood pressures with blood glucose in pregnancy which suggests future potential as a non-invasive gestational diabetes risk screening tool.


Subject(s)
Ankle , Pregnant Women , Asian People , Blood Glucose , Blood Pressure/physiology , Cross-Sectional Studies , Fasting , Female , Humans , Pregnancy
8.
Neoplasma ; 69(2): 443-455, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35068162

ABSTRACT

Human leukocyte antigen class I (HLA class I) antigen processing and presentation pathway (APP) defines anti-tumor immune response. ERAP, TAP, tapasin (TAPBP), and IFNγ modulate APP: control HLA class I expression in the tumor and the repertoire of presented tumor antigens. At the same time, vascular endothelial growth factor (VEGF) acts as an immunomodulator in the tumor microenvironment. The objective of the current study was to examine the association of single nucleotide polymorphisms (SNPs) in the ERAP1, ERAP2, TAP1, TAP2, TAPBP, IFNG genes with the corresponding mRNA expression in bladder cancer (BC) risk and recurrence after transurethral resection of BC. Moreover, we assessed the relationship between HLA class I and VEGF plasma levels and BC recurrence. We analyzed 9 SNPs in 124 BC patients using TaqMan genotyping and compared them with the data from 503 healthy individuals from the 1000 Genomes Project. In addition, we quantified the effects of SNPs on the corresponding mRNA expression in tumor and non-tumor adjacent tissue in 60 BC patients with primary and 30 with recurrent tumor by quantitative real-time PCR. Furthermore, the plasma HLA class I and VEGF levels were analyzed in BC patients and healthy controls by ELISA. IFNG (rs1861493) was associated with BC risk, TAPBP (rs3106189, rs2071888) with recurrence-free survival (RFS). Moreover, TAPBP mRNA expression was lower in tumors than in the adjacent tissue. The SNPs ERAP2 (rs251339) and TAP2 (rs241447, rs241448) variants affected mRNA expression in BC tissue. In tumor tissue, the high mRNA expression of ERAP1 was more common in BC patients with single tumors, ERAP2 in non-smokers, and TAP2 mRNA in recurrence. The lower HLA and higher VEGF plasma levels were observed in BC patients compared with healthy controls. We conclude that the genetic elements responsible for MHC class I APP may influence the BC risk, risk of recurrence, and RFS.


Subject(s)
Urinary Bladder Neoplasms , Vascular Endothelial Growth Factor A , Aminopeptidases/genetics , Aminopeptidases/metabolism , Antigen Presentation/genetics , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/metabolism , Humans , Minor Histocompatibility Antigens/genetics , Neoplasm Recurrence, Local/genetics , Tumor Microenvironment , Urinary Bladder Neoplasms/genetics
9.
J Med Chem ; 64(14): 9677-9710, 2021 07 22.
Article in English | MEDLINE | ID: mdl-34236862

ABSTRACT

A fundamental role of pancreatic ß-cells to maintain proper blood glucose level is controlled by the Ras superfamily of small GTPases that undergo post-translational modifications, including prenylation. This covalent attachment with either a farnesyl or a geranylgeranyl group controls their localization, activity, and protein-protein interactions. Small GTPases are critical in maintaining glucose homeostasis acting in the pancreas and metabolically active tissues such as skeletal muscles, liver, or adipocytes. Hyperglycemia-induced upregulation of small GTPases suggests that inhibition of these pathways deserves to be considered as a potential therapeutic approach in treating T2D. This Perspective presents how inhibition of various points in the mevalonate pathway might affect protein prenylation and functioning of diabetes-affected tissues and contribute to chronic inflammation involved in diabetes mellitus (T2D) development. We also demonstrate the currently available molecular tools to decipher the mechanisms linking the mevalonate pathway's enzymes and GTPases with diabetes.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Monomeric GTP-Binding Proteins/antagonists & inhibitors , Animals , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Hypoglycemic Agents/chemistry , Molecular Structure , Monomeric GTP-Binding Proteins/metabolism , Structure-Activity Relationship
10.
Ann Transl Med ; 9(7): 564, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33987262

ABSTRACT

BACKGROUND: To investigate the association between marriage and the prevalence of overweight and obesity in China. METHODS: We conducted cross-sectional and retrospective cohort analyses using a nationwide sample of 36,310 individuals from the China Health and Nutrition Survey [2004-2015]. RESULTS: The prevalence of overweight and obesity increased from 28.7% to 36.7% and from 8.0% to 14.5% between 2004 and 2015, respectively. The cross-sectional analysis showed that married individuals were at a higher risk of being overweight (OR =2.18; 95% CI, 1.90-2.51) or obese (OR =1.95; 1.57-2.43) than never-married individuals. Divorced/widowed individuals were also at a greater risk of being overweight (OR =1.80; 1.51-2.13) or obese (OR =1.67; 1.28-2.17) than never-married individuals. Retrospective cohort analysis showed that individuals who married during the study were 1.55 (1.13-2.11) times more likely to be overweight than those who remained never-married. Compared to those who remained never-married, individuals who remained married were 1.71 (1.42-2.07) and 1.45 (1.11-1.89) times more likely to be overweight and obese. Individuals who became divorced or widowed were more likely to be overweight (RR =1.59; 1.18-2.15) or obese (RR =1.63; 1.08-2.46) than those who remained never-married. However, the risk of being overweight or obese among those who became divorced or widowed did not differ significantly from the risk among those who remained married. CONCLUSIONS: Marriage contributes to an increased risk of overweight and obesity in China; however, this risk is not significantly reduced by exiting a marriage.

11.
Front Cell Infect Microbiol ; 11: 598672, 2021.
Article in English | MEDLINE | ID: mdl-33680988

ABSTRACT

Objective: Mounting evidence has suggested a link between gut microbiome characteristics and type 2 diabetes (T2D). To determine whether these alterations occur before the impairment of glucose regulation, we characterize gut microbiota in normoglycemic individuals who go on to develop T2D. Methods: We designed a nested case-control study, and enrolled individuals with a similar living environment. A total of 341 normoglycemic individuals were followed for 4 years, including 30 who developed T2D, 33 who developed prediabetes, and their matched controls. Fecal samples (developed T2D, developed prediabetes and controls: n=30, 33, and 63, respectively) collected at baseline underwent metagenomics sequencing. Results: Compared with matched controls, individuals who went on to develop T2D had lower abundances of Bifidobacterium longum, Coprobacillus unclassified, and Veillonella dispar and higher abundances of Roseburia hominis, Porphyromonas bennonis, and Paraprevotella unclassified. The abundance of Bifidobacterium longum was negatively correlated with follow-up blood glucose levels. Moreover, the microbial Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of carbohydrate metabolism, methane metabolism, amino acid metabolism, fatty acid metabolism, and membrane transport were changed between the two groups. Conclusions: We found that fecal microbiota of healthy individuals who go on to develop T2D had already changed when they still were normoglycemic. These alterations of fecal microbiota might provide insights into the development of T2D and a new perspective for identifying individuals at risk of developing T2D.


Subject(s)
Diabetes Mellitus, Type 2 , Microbiota , Case-Control Studies , Clostridiales , Humans , Porphyromonas , Veillonella
12.
Biochem Biophys Res Commun ; 534: 659-665, 2021 01 01.
Article in English | MEDLINE | ID: mdl-33239168

ABSTRACT

Apolipoprotein A4 (ApoA4) regulates lipid and glucose metabolism and exerts anti-inflammatory effects in atherogenesis and colitis. The present study explored the presumed protective role of ApoA4 in carbon tetrachloride (CCl4)-induced acute liver injury (ALI) in mice. The ALI model in wild type (WT), ApoA4 knock-out (ApoA4-KO) and ApoA4 transgenic (ApoA4-TG) mice was induced by a single intraperitoneal administration of CCl4. Liver and blood were harvested from mice to assess liver functions, immunohistological changes, immune cell populations and cytokine profiles. ApoA4 deficiency aggravated, and ApoA4 overexpression alleviated CCl4-inflicted liver damage by controlling levels of anti-oxidant enzymes. ApoA4 deletion increased the recruitment of monocytes/macrophages into the injured liver and upregulated the plasma levels of IL-6, TNF-α and MCP-1, but lower IL-10 and IFN-γ. ApoA4 over-expression rescued this effect and resulted in lower percentages of monocytes/macrophages and dendritic cells, the ratio of blood pro-inflammatory to anti-inflammatory monocytes and reduced plasma concentrations of IL-6, but enhanced IL-10 and IFN-γ. We propose ApoA4 as a potential new therapeutic target for the management of liver damage.


Subject(s)
Apolipoproteins A/metabolism , Carbon Tetrachloride/antagonists & inhibitors , Carbon Tetrachloride/toxicity , Chemical and Drug Induced Liver Injury/prevention & control , Animals , Antioxidants/metabolism , Apolipoproteins A/deficiency , Apolipoproteins A/genetics , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Cytokines/blood , Cytokines/genetics , Inflammation Mediators/blood , Liver/drug effects , Liver/immunology , Liver/metabolism , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout, ApoE , Mice, Transgenic , Monocytes/immunology , Up-Regulation
13.
Int J Cancer ; 148(8): 1808-1820, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33105025

ABSTRACT

Aging is associated with an insufficient immune response that may lead to the initiation and progression of various malignancies. Bladder cancer (BC), prevalent in elderly patients, predominantly presents as recurrent nonmuscle invasive BC that requires further treatment. There is much interest in the activation of patients' immune cells with the focus on CD8+ T cells. Successful therapy should also ensure the efficient presentation of BC antigens by major histocompatibility complex (MHC) class I molecules. The purpose of this systematic review is to present the existing literature on the role of MHC class I in BC research and therapy. The bibliographic databases PubMed and Web of Science were searched for articles published between January 2009 and September 2020 that addressed MHC class I relationship to BC. We searched for available relevant publications on MHC class I and its role and regulation in BC, aging and MHC class I importance in BC immunotherapy. Based on the provided evidence, we propose that the loss of MHC class I expression in BC may lead to its recurrence after the transurethral resection and unresponsiveness to Bacillus Calmette-Guerin immunotherapy. We discuss different ways to enhance MHC class I antigen presentation to CD8+ T cells in BC treatment. The immune status characterized by MHC class I expression patterns and cancer-infiltrating immune cells may provide valuable prognostic information about which patients may benefit from transurethral resection of BC and additional immunotherapy.


Subject(s)
Aging/immunology , Antigen Presentation/immunology , CD8-Positive T-Lymphocytes/immunology , Histocompatibility Antigens Class I/immunology , Urinary Bladder Neoplasms/immunology , Aged , Humans , Immunotherapy/methods , Models, Immunological , Neoplasm Recurrence, Local , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/therapy
14.
JCI Insight ; 5(7)2020 04 09.
Article in English | MEDLINE | ID: mdl-32191644

ABSTRACT

C5a is a potent inflammatory mediator that binds C5aR1 and C5aR2. Although pathogenic roles of the C5a/C5aR1 axis in inflammatory disorders are well documented, the roles for the C5a/C5aR2 axis in inflammatory disorders and underlying mechanisms remain unclear. Here, we show that the C5a/C5aR2 axis contributes to renal inflammation and tissue damage in a mouse model of acute pyelonephritis. Compared with WT littermates, C5ar2-/- mice had significantly reduced renal inflammation, tubular damage, and renal bacterial load following bladder inoculation with uropathogenic E. coli. The decrease in inflammatory responses in the kidney of C5ar2-/- mice was correlated with reduced intrarenal levels of high mobility group box-1 protein (HMGB1), NLRP3 inflammasome components, cleaved caspase-1, and IL-1ß. In vitro, C5a stimulation of macrophages from C5ar1-/- mice (lacking C5aR1 but expressing C5aR2) led to significant upregulation of HMGB1 release, NLRP3/cleaved caspase-1 inflammasome activation, and IL-1ß secretion. Furthermore, blockade of HMGB1 significantly reduced C5a-mediated upregulation of NLRP3/cleaved caspase-1 inflammasome activation and IL-1ß secretion in the macrophages, implying a HMGB1-dependent upregulation of NLRP3/cleaved caspase-1 inflammasome activation in macrophages. Our findings demonstrate a pathogenic role for the C5a/C5aR2 axis in renal injury following renal infection and suggest that the C5a/C5aR2 axis contributes to renal inflammation and tissue damage through upregulation of HMGB1 and NLRP3/cleaved caspase-1 inflammasome.


Subject(s)
Complement C5a/metabolism , Kidney Diseases/metabolism , Kidney/metabolism , Receptor, Anaphylatoxin C5a/metabolism , Animals , Caspase 1/genetics , Caspase 1/metabolism , Complement C5a/genetics , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Inflammation/genetics , Inflammation/metabolism , Inflammation/pathology , Kidney/pathology , Kidney Diseases/genetics , Kidney Diseases/pathology , Mice , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Receptor, Anaphylatoxin C5a/genetics
15.
Mol Immunol ; 117: 201-215, 2020 01.
Article in English | MEDLINE | ID: mdl-31835202

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) expand in tumor-bearing host. They suppress anti-tumor immune response and promote tumor growth. Chemokines play a vital role in recruiting MDSCs into tumor tissue. They can also induce the generation of MDSCs in the bone marrow, maintain their suppressive activity, and promote their proliferation and differentiation. Here, we review CCL2/CCL12-CCR2, CCL3/4/5-CCR5, CCL15-CCR1, CX3CL1/CCL26-CX3CR1, CXCL5/2/1-CXCR2, CXCL8-CXCR1/2, CCL21-CCR7, CXCL13-CXCR5 signaling pathways, their role in MDSCs recruitment to tumor tissue, and their correlation with tumor development, metastasis and prognosis. Targeting chemokines and their receptors may serve as a promising strategy in immunotherapy, especially combined with other strategies such as chemotherapy, cyclin-dependent kinase or immune checkpoints inhibitors.


Subject(s)
Myeloid-Derived Suppressor Cells/immunology , Neoplasms/immunology , Receptors, Chemokine/immunology , Tumor Escape/immunology , Tumor Microenvironment/immunology , Animals , Cell Movement/immunology , Humans , Myeloid-Derived Suppressor Cells/metabolism , Receptors, Chemokine/metabolism
16.
Curr Protoc Immunol ; 126(1): e85, 2019 09.
Article in English | MEDLINE | ID: mdl-31483102

ABSTRACT

Cytotoxic CD8+ T cells mediate cellular immunity through recognition of specific antigens presented by MHC class I on all nucleated cells. Studying T cell interactions and responses provides invaluable information on infection, autoimmunity and cancer. Fluorescently labeled multimers of MHC I can be used to quantify, characterize, and isolate specific CD8+ T cells by flow cytometry. Here we describe the production and use of conditional MHC I multimers that can be loaded with peptides of choice by incubating them at a defined temperature. Multimers are folded with a template peptide that forms a stable complex at low temperature, but dissociates at a defined elevated temperature. Using this technology multiple MHC I multimers can be generated in parallel, to allow staining and isolation of large sets of antigen-specific CD8+ T cells, especially when combined with barcoding technologies. © 2019 The Authors.


Subject(s)
Antigens/metabolism , CD8-Positive T-Lymphocytes/immunology , Cell Separation/methods , Histocompatibility Antigens Class I/metabolism , Peptides/metabolism , Staining and Labeling/methods , T-Lymphocytes, Cytotoxic/immunology , Animals , Cell Culture Techniques , Flow Cytometry , Fluorescent Dyes , Humans , Mice , Protein Binding , Protein Multimerization
17.
Front Immunol ; 9: 949, 2018.
Article in English | MEDLINE | ID: mdl-29765378

ABSTRACT

Recent work in a murine model of ascending urinary tract infection has suggested that C5a/C5aR1 interactions play a pathogenic role in the development of renal infection through enhancement of bacterial adhesion/colonization to renal tubular epithelial cells (RTECs). In the present study, we extended these observations to human. We show that renal tubular epithelial C5aR1 signaling is involved in promoting uropathogenic Escherichia coli (UPEC) adhesion/invasion of host cells. Stimulation of primary cultures of RTEC with C5a resulted in significant increases in UPEC adhesion/invasion of the RTEC. This was associated with enhanced expression of terminal α-mannosyl residues (Man) (a ligand for type 1 fimbriae of E. coli) in the RTEC following C5a stimulation. Mechanism studies revealed that C5aR1-mediated activation of ERK1/2/NF-κB and upregulation of proinflammatory cytokine production (i.e., TNF-α) is at least partly responsible for the upregulation of Man expression and bacterial adhesion. Clinical sample studies showed that C5aR1 and Man were clearly detected in the renal tubular epithelium of normal human kidney biopsies, and UPEC bound to the epithelium in a d-mannose-dependent manner. Additionally, C5a levels were significantly increased in urine of urinary tract infection patients compared with healthy controls. Our data therefore demonstrate that, in agreement with observations in mice, human renal tubular epithelial C5aR1 signaling can upregulate Man expression in RTEC, which enhances UPEC adhesion to and invasion of RTEC. It also suggests the in vivo relevance of upregulation of Man expression in renal tubular epithelium by C5a/C5aR1 interactions and its potential impact on renal infection.


Subject(s)
Bacterial Adhesion , Epithelial Cells/metabolism , Epithelial Cells/microbiology , Kidney Tubules/metabolism , Receptor, Anaphylatoxin C5a/metabolism , Signal Transduction , Uropathogenic Escherichia coli/physiology , Biomarkers , Cells, Cultured , Cytokines/metabolism , Humans , Immunohistochemistry , Inflammation Mediators/metabolism , Kidney Tubules/cytology , Protein Binding
18.
J Exp Med ; 215(5): 1493-1504, 2018 05 07.
Article in English | MEDLINE | ID: mdl-29666167

ABSTRACT

Adaptive immunity is initiated by T cell recognition of specific antigens presented by major histocompatibility complexes (MHCs). MHC multimer technology has been developed for the detection, isolation, and characterization of T cells in infection, autoimmunity, and cancer. Here, we present a simple, fast, flexible, and efficient method to generate many different MHC class I (MHC I) multimers in parallel using temperature-mediated peptide exchange. We designed conditional peptides for HLA-A*02:01 and H-2Kb that form stable peptide-MHC I complexes at low temperatures, but dissociate when exposed to a defined elevated temperature. The resulting conditional MHC I complexes, either alone or prepared as ready-to-use multimers, can swiftly be loaded with peptides of choice without additional handling and within a short time frame. We demonstrate the ease and flexibility of this approach by monitoring the antiviral immune constitution in an allogeneic stem cell transplant recipient and by analyzing CD8+ T cell responses to viral epitopes in mice infected with lymphocytic choriomeningitis virus or cytomegalovirus.


Subject(s)
Epitopes/immunology , Histocompatibility Antigens Class I/metabolism , Protein Multimerization , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Amino Acid Sequence , Animals , CD8-Positive T-Lymphocytes/immunology , Cytomegalovirus/physiology , HLA-A Antigens/immunology , Herpesvirus 4, Human/physiology , Humans , Mice, Inbred C57BL , Monitoring, Immunologic , Peptides/chemistry , Peptides/metabolism , Temperature
19.
Oncotarget ; 9(1): 1266-1278, 2018 Jan 02.
Article in English | MEDLINE | ID: mdl-29416693

ABSTRACT

PURPOSE: To evaluate the association of serum levels of adipokines and cytokines with psoriasis. MATERIALS AND METHODS: A comprehensive literature search was performed in PubMed, ScienceDirect and Web of Science for the available relevant studies published before December 1, 2016. Differences in serum marker levels between patients and controls were pooled as standardized mean differences (SMDs) with 95% confidence interval to combine the effect estimations. We also conducted stratified analysis, meta-regression analysis and sensitivity analysis. RESULTS: Sixty-three studies containing 2876 psoriasis patients and 2237 healthy controls were included in this meta-analysis. The pooled serum levels of TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-18, IL-22, chemerin, lipocalin-2, resistin, sE-selectin, fibrinogen and C3 were higher in psoriasis patients compared with healthy controls (all P < 0.05). In contrast, adiponectin levels were lower. Serum levels of IL-1ß, IL-4, IL-10, IL-12, IL-17, IL-21, IL-23, visfatin and omentin were not significantly different between psoriasis patients and controls (all P > 0.05). However, increased serum levels of IL-17 correlated with psoriasis in men. For other biomarkers, age, gender and psoriasis area and severity index did not explain the differences in effect size between the studies. CONCLUSIONS: Serum levels of TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-18, IL-22, chemerin, lipocalin-2, resistin, sE-selectin, fibrinogen, complement 3, and adiponectin correlate with psoriasis and can be used as potential biomarkers for psoriasis and response to the treatment. Future studies are needed to identify additional players involved in the pathogenesis of psoriasis and to fully decipher the underlying mechanism.

20.
J Immunol Res ; 2017: 6073961, 2017.
Article in English | MEDLINE | ID: mdl-29226158

ABSTRACT

[This corrects the article DOI: 10.1155/2017/8193932.].

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