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2.
Adv Virus Res ; 95: 149-95, 2016.
Article in English | MEDLINE | ID: mdl-27112282

ABSTRACT

Autophagy is an important cellular catabolic process conserved from yeast to man. Double-membrane vesicles deliver their cargo to the lysosome for degradation. Hence, autophagy is one of the key mechanisms mammalian cells deploy to rid themselves of intracellular pathogens including viruses. However, autophagy serves many more functions during viral infection. First, it regulates the immune response through selective degradation of immune components, thus preventing possibly harmful overactivation and inflammation. Additionally, it delivers virus-derived antigens to antigen-loading compartments for presentation to T lymphocytes. Second, it might take an active part in the viral life cycle by, eg, facilitating its release from cells. Lastly, in the constant arms race between host and virus, autophagy is often hijacked by viruses and manipulated to their own advantage. In this review, we will highlight key steps during viral infection in which autophagy plays a role. We have selected some exemplary viruses and will describe the molecular mechanisms behind their intricate relationship with the autophagic machinery, a result of host-pathogen coevolution.


Subject(s)
Autophagy/immunology , Immunity, Innate , Virion/immunology , Virus Diseases/immunology , Virus Replication/immunology , Viruses/immunology , Adaptive Immunity , Animals , Autophagy/genetics , Cell Differentiation , Gene Expression Regulation/immunology , Host-Pathogen Interactions , Humans , Phagosomes/immunology , Phagosomes/metabolism , Phagosomes/virology , Receptors, Pattern Recognition/genetics , Receptors, Pattern Recognition/immunology , T-Lymphocytes/immunology , T-Lymphocytes/virology , Virion/genetics , Virus Diseases/virology , Viruses/genetics
3.
Mult Scler ; 16(3): 355-8, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20203149

ABSTRACT

The objective of this study was to determine the immune responses to candidate viral triggers of multiple sclerosis in patients and healthy siblings raised in the same family household. Virus antigen-specific IgG responses to Epstein-Barr virus-derived gene products as well as to human herpersvirus-6, human cytomegalovirus, and measles virus were evaluated in 25 multiple sclerosis patients and compared with 49 healthy full-siblings. IgG responses to the latent Epstein-Barr virus-encoded nuclear antigen-1 (EBNA1) were selectively increased in individuals with multiple sclerosis compared with their unaffected siblings. We conclude that elevated IgG responses towards EBNA1 are associated with the development of multiple sclerosis.


Subject(s)
Antibodies, Viral/blood , Antigens, Viral/immunology , Herpesvirus 4, Human/immunology , Immunoglobulin G/blood , Multiple Sclerosis/immunology , Adult , Case-Control Studies , Cytomegalovirus/immunology , Epstein-Barr Virus Nuclear Antigens/immunology , Female , Herpesvirus 6, Human/immunology , Humans , Male , Measles virus/immunology , Middle Aged , Multiple Sclerosis/virology , Risk Assessment , Risk Factors , Siblings , Young Adult
4.
J Neuroimmunol ; 218(1-2): 107-11, 2010 Jan 25.
Article in English | MEDLINE | ID: mdl-19939466

ABSTRACT

Ubiquitous viruses have frequently been proposed as a cause or trigger of chronic immune-mediated diseases. Infections are reported to be temporally associated with clinical exacerbations in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We examined immunological parameters of herpesvirus infections in untreated patients with CIDP compared to demographically matched controls. Patients with CIDP were uniformly seropositive for EBV-specific IgG and the disease was associated with a moderately enhanced IgG reactivity to EBV-encoded antigens expressed during both B cell transformation and productive viral replication. Moreover, cellular EBV copy numbers were 3-fold increased in patients with CIDP. In contrast, humoral immune responses to other herpesviruses (HCMV, HSV) as well as virus-specific IgM responses were unchanged in CIDP. These data indicate that host-pathogen interactions during chronic EBV infection are dysregulated in treatment-naïve patients with CIDP.


Subject(s)
Epstein-Barr Virus Infections/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/immunology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/virology , Adolescent , Adult , Aged , Aged, 80 and over , Antigens, Viral/immunology , Child , Enzyme-Linked Immunosorbent Assay , Epstein-Barr Virus Infections/blood , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Middle Aged , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Young Adult
5.
Cell Death Differ ; 16(1): 79-86, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18636073

ABSTRACT

Autophagy is a homeostatic process that enables eukaryotic cells to deliver cytoplasmic constituents for lysosomal degradation, to recycle nutrients and to survive during starvation. In addition to these primordial functions, autophagy has emerged as a key mechanism in orchestrating innate and adaptive immune responses to intracellular pathogens. Autophagy restricts viral infections as well as replication of intracellular bacteria and parasites and delivers pathogenic determinants for TLR stimulation and for MHC class II presentation to the adaptive immune system. Apart from its role in defense against pathogens, autophagy-mediated presentation of self-antigens in the steady state could have a crucial role in the induction and maintenance of CD4(+) T-cell tolerance. This review describes the mechanisms by which the immune system utilizes autophagic degradation of cytoplasmic material to regulate adaptive immune responses.


Subject(s)
Antigen Presentation , Autoantigens/immunology , Autophagy/immunology , CD4-Positive T-Lymphocytes/immunology , Immune Tolerance , Animals , Bacteria/immunology , Bacterial Infections/immunology , Humans , Immunity, Cellular , Immunity, Innate , Lysosomes/immunology , Starvation/immunology , Virus Diseases/immunology , Viruses/immunology
7.
Cell Death Differ ; 12 Suppl 2: 1519-27, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16247499

ABSTRACT

MHC class II molecules are thought to present peptides derived from extracellular proteins to CD4+ T cells, which are important mediators of adaptive immunity to infections. In contrast, autophagy delivers constitutively cytosolic material for lysosomal degradation and has so far been recognized as an efficient mechanism of innate immunity against bacteria and viruses. Recent studies, however, link these two pathways and suggest that intracellular cytosolic and nuclear antigens are processed for MHC class II presentation after autophagy.


Subject(s)
Autophagy , Histocompatibility Antigens Class II/physiology , Immunologic Surveillance , ATP-Binding Cassette Transporters , Animals , Antigen Presentation , Biological Transport, Active , Histocompatibility Antigens Class I/physiology , Humans , Lysosomes/physiology , Proteasome Endopeptidase Complex/physiology
8.
Curr Top Microbiol Immunol ; 276: 55-76, 2003.
Article in English | MEDLINE | ID: mdl-12797443

ABSTRACT

The human gamma-herpesvirus, Epstein-Barr virus (EBV), has growth-transforming potential in vivo and in vitro. Despite this, most healthy carriers remain free of EBV-associated malignancies because of effective T cell-mediated immune control of the virus. A better understanding of these highly efficient control mechanisms is important in the development of new treatment strategies for EBV-associated malignancies. A rational approach to EBV immunotherapy requires answering two questions about the initiation of the protective EBV-specific immune response. The first question is, what is the antigen-presenting cell responsible for priming EBV specific immunity? Second, which viral antigen is central to protective EBV adaptive immunity seen in healthy carriers of the virus? We provide evidence in this review that dendritic cells rather than EBV-transformed B cells are responsible for orchestrating protective EBV immunity and that the EBV nuclear antigen 1 (EBNA1)-specific CD4+ T cell response probably plays a role in resistance against all types of EBV-associated malignancies in healthy carriers. This implies that EBNA1 targeting to dendritic cells should be a component of vaccine and immunotherapy development against EBV-associated malignancies.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Nuclear Antigens/immunology , Herpesvirus 4, Human/immunology , B-Lymphocytes/virology , Epstein-Barr Virus Nuclear Antigens/chemistry , Epstein-Barr Virus Nuclear Antigens/genetics , Humans
9.
J Immunol Methods ; 258(1-2): 111-26, 2001 Dec 01.
Article in English | MEDLINE | ID: mdl-11684128

ABSTRACT

CD4+ and CD8+ T cells are key components of immune response against tumors and viruses. Many techniques have been used to clone and expand these cells in vitro for purposes of immunotherapy. Here, we describe an improved method to obtain large quantities of tumor and virus-specific human CD4+ and CD8+ T-cell clones. T cells derived from peripheral blood mononuclear cells (PBMCs) of healthy donors were stimulated several times by peptide pulsed monocyte-derived mature dendritic cells (DCs) in the presence of exogenous cytokines. T cells specific for influenza or melanoma antigens were detected by IFN-gamma intracellular staining and were cloned by limiting dilution. Specific polyclonal T-cell populations were derived for all epitopes presented by mature DCs. Nine different populations were cloned and clones were raised from eight of them. Clonality was verified by HLA/peptide tetramer staining. With additional rounds of stimulation after the cloning procedure, it was possible to obtain from 10(9) to 10(12) of each clone. Furthermore, clones could be maintained in culture in the presence of IL-2 for at least 1 month without losing their antigen-specific reactivity (e.g. cytokine secretion, cytolytic activity and proliferation). Importantly, a majority of the CD8+ T-cell clones recognized endogenously processed antigens. This method is of value for the purposes of adoptive anti-virus or anti-tumor immunotherapy.


Subject(s)
Antigens, Neoplasm , Antigens, Viral , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Amino Acid Sequence , Antigen Presentation , Antigens, Neoplasm/genetics , Antigens, Viral/genetics , Clone Cells , HLA Antigens , Humans , Immunotherapy, Adoptive , Interferon-gamma/biosynthesis , Melanoma/genetics , Melanoma/immunology , Molecular Sequence Data , Orthomyxoviridae/genetics , Orthomyxoviridae/immunology , Receptors, Antigen, T-Cell, alpha-beta/genetics
10.
J Biol Chem ; 276(23): 20029-38, 2001 Jun 08.
Article in English | MEDLINE | ID: mdl-11274169

ABSTRACT

The expression of MMP13 (collagenase-3), a member of the matrix metalloproteinase family, is increased in vivo as well as in cultured osteosarcoma cell lines by parathyroid hormone (PTH), a major regulator of calcium homeostasis. Binding sites for AP-1 and Cbfa/Runt transcription factors in close proximity have been identified as cis-acting elements in the murine and rat mmp13 promoter required for PTH-induced expression. The cooperative function of these factors in response to PTH in osteoblastic cells suggests a direct interaction between AP-1 and Cbfa/Runt transcription factors. Here, we demonstrate interaction between c-Jun and c-Fos with Cbfa/Runt proteins. This interaction depends on the leucine zipper of c-Jun or c-Fos and the Runt domain of Cbfa/Runt proteins, respectively. Moreover, c-Fos interacts with the C-terminal part of Cbfa1 and Cbfa2, sharing a conserved transcriptional repression domain. In addition to the distal osteoblast-specific element 2 (OSE2) element in the murine and rat mmp13 promoter, we identified a new proximal OSE2 site overlapping with the TRE motif. Both interaction of Cbfa/Runt proteins with AP-1 and the presence of a functional proximal OSE2 site are required for enhanced transcriptional activity of the mmp13 promoter in transient transfected fibroblasts and in PTH-treated osteosarcoma cells.


Subject(s)
Collagenases/metabolism , Neoplasm Proteins , Osteoblasts/enzymology , Parathyroid Hormone/metabolism , Transcription Factor AP-1/metabolism , Transcription Factors/metabolism , Animals , Base Sequence , Cell Line , Core Binding Factor Alpha 1 Subunit , DNA Primers , Humans , Leucine Zippers , Matrix Metalloproteinase 13 , Mice , Protein Binding , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-jun/metabolism , Recombinant Proteins/metabolism , Tetradecanoylphorbol Acetate/pharmacology
11.
J Exp Med ; 193(3): 405-11, 2001 Feb 05.
Article in English | MEDLINE | ID: mdl-11157061

ABSTRACT

Dendritic cells (DCs) are not targets for infection by the transforming Epstein-Barr virus (EBV). To test if the adjuvant role of DCs could be harnessed against EBV latency genes by cross-presentation, DCs were allowed to process either autologous or human histocompatibility leukocyte antigen (HLA)-mismatched, transformed, B lymphocyte cell lines (LCLs) that had been subject to apoptotic or necrotic cell death. After phagocytosis of small numbers of either type of dead LCL, which lacked direct immune-stimulatory capacity, DCs could expand CD8(+) T cells capable of killing LCLs that were HLA matched to the DCs. Necrotic EBV-transformed, major histocompatibility complex (MHC) class I-negative LCLs, when presented by DCs, also could elicit responses to MHC class II-negative, EBV-transformed targets that were MHC class I matched to the DCs, confirming efficient cross-presentation of LCL antigens via MHC class I on the DC. Part of this EBV-specific CD8(+) T cell response, in both lytic and interferon gamma secretion assays, was specific for the EBV nuclear antigen (EBNA)3A and latent membrane protein (LMP)2 latency antigens that are known to be expressed at low levels in transformed cells. The induced CD8(+) T cells recognized targets at low doses, 1-10 nM, of peptide. Therefore, the capacity of DCs to cross-present antigens from dead cells extends to the expansion of high affinity T cells specific for viral latency antigens involved in cell transformation.


Subject(s)
Antigen Presentation/immunology , Dendritic Cells/immunology , Epstein-Barr Virus Nuclear Antigens/immunology , Herpesvirus 4, Human/immunology , Viral Matrix Proteins/immunology , Apoptosis/immunology , B-Lymphocytes , CD8-Positive T-Lymphocytes/immunology , Cell Line, Transformed , Cross Reactions , Humans , Necrosis , Phagocytosis/immunology , Virus Latency
12.
J Exp Med ; 193(2): 233-8, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11208863

ABSTRACT

Immunostimulatory properties of dendritic cells (DCs) are linked to their maturation state. Injection of mature DCs rapidly enhances antigen-specific CD4+ and CD8+ T cell immunity in humans. Here we describe the immune response to a single injection of immature DCs pulsed with influenza matrix peptide (MP) and keyhole limpet hemocyanin (KLH) in two healthy subjects. In contrast to prior findings using mature DCs, injection of immature DCs in both subjects led to the specific inhibition of MP-specific CD8+ T cell effector function in freshly isolated T cells and the appearance of MP-specific interleukin 10-producing cells. When pre- and postimmunization T cells were boosted in culture, there were greater numbers of MP-specific major histocompatibility complex tetramer-binding cells after immunization, but these had reduced interferon production and lacked killer activity. These data demonstrate the feasibility of antigen-specific inhibition of effector T cell function in vivo in humans and urge caution with the use of immature DCs when trying to enhance tumor or microbial immunity.


Subject(s)
Dendritic Cells/immunology , Dendritic Cells/transplantation , T-Lymphocytes/immunology , Adult , Cell Differentiation , Dendritic Cells/cytology , Hemocyanins/immunology , Humans , Immunization/methods , Immunologic Memory , In Vitro Techniques , Injections, Intradermal , Injections, Subcutaneous , Orthomyxoviridae/immunology , Transplantation, Autologous , Viral Matrix Proteins/immunology
13.
J Clin Invest ; 107(1): 121-30, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11134187

ABSTRACT

The Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1) maintains the viral episome in all host cells infected with EBV. Recently, EBNA1 was found to be the main EBV latency antigen for CD4+ T cells and could be recognized in cultures from all donors tested. We now identify a polarized Th1 phenotype and obtain evidence for its presence in vivo. When T cells were stimulated with dendritic cells infected with vaccinia vectors expressing EBNA1, 18 of 19 donors secreted IFN-gamma, whereas only two of 19 secreted IL-4. Magnetic selection was then used to isolate cells from fresh blood based on EBNA1-induced cytokine production. Specific IFN-gamma CD4+ cell lines were established from six of six donors and IL-4 lines from three of six. Only the Th1 lines specifically lysed targets expressing three different sources of EBNA1 protein. When the IgG isotype of EBNA1 plasma Ab's was tested, most specific Ab's were IgG1 and of a high titer, confirming a Th1 response to EBNA1 in vivo. Ab's to other microbial antigens generally were not skewed toward IgG1. Given emerging evidence that Th1 CD4+ T cells have several critical roles in host defense to viral infection and tumors, we propose that EBNA1-specific CD4+ Th1 cells contribute to resistance to EBV and EBV-associated malignancies.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Carrier State/immunology , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Nuclear Antigens/administration & dosage , Th1 Cells/immunology , Antibodies, Viral/blood , Cell Line , Humans , Immunoglobulin G/blood , Interferon-gamma/metabolism , Interleukin-4/metabolism
14.
Tissue Antigens ; 56(1): 10-8, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10958351

ABSTRACT

HLA class I molecules present endogenously processed peptide ligands for surveillance by the T-cell receptor. This potentially immunogenic surface of HLA and peptide is a consequence of the polymorphism found within the HLA molecule and its preference for ligand binding together with peptide conformation within the binding groove. To investigate the relation between the polymorphic differences between some closely related HLA alleles and their effect on peptide preference, transfectants were established, each containing one of four allelic variants of HLA-A*30. Peptides from all four transfectants were eluted, and both individual ligands and peptide pools were sequenced. The data shows two distinct peptide motifs which distinguish A*3001 from the other three known A*30 variants. Differences in preferences at minor positions within the peptide sequence were noted between A*3002, A*3003 and A*3004, providing additional evidence of the implications of sequence polymorphism to HLA function.


Subject(s)
Alleles , Amino Acid Motifs , HLA-A Antigens/metabolism , Peptides/chemistry , Peptides/metabolism , Amino Acid Sequence , B-Lymphocytes/chemistry , Binding Sites , HLA-A Antigens/chemistry , HLA-A Antigens/genetics , Humans , Models, Molecular , Polymorphism, Genetic , Transfection
15.
J Exp Med ; 191(11): 1965-74, 2000 Jun 05.
Article in English | MEDLINE | ID: mdl-10839811

ABSTRACT

Heat shock proteins (HSPs) like glycoprotein (gp)96 (glucose-regulated protein 94 [grp94]) are able to induce specific cytotoxic T lymphocyte (CTL) responses against cells from which they originate. Here, we demonstrate that for CTL activation by gp96-chaperoned peptides, specific receptor-mediated uptake of gp96 by antigen-presenting cells (APCs) is required. Moreover, we show that in both humans and mice, only professional APCs like dendritic cells (DCs), macrophages, and B cells, but not T cells, are able to bind gp96. The binding is saturable and can be inhibited using unlabeled gp96 molecules. Receptor binding by APCs leads to a rapid internalization of gp96, which colocalizes with endocytosed major histocompatibility complex (MHC) class I and class II molecules in endosomal compartments. Incubation of gp96 molecules isolated from cells expressing an adenovirus type 5 E1B epitope with the DC line D1 results in the activation of E1B-specific CTLs. This CTL activation can be specifically inhibited by the addition of irrelevant gp96 molecules not associated with E1B peptides. Our results demonstrate that only receptor-mediated endocytosis of gp96 molecules leads to MHC class I-restricted re-presentation of gp96-associated peptides and CTL activation; non-receptor-mediated, nonspecific endocytosis is not able to do so. Thus, we provide evidence on the mechanisms by which gp96 is participating in the cross-presentation of antigens from cellular origin.


Subject(s)
Antigen Presentation/immunology , Endocytosis/immunology , HSP70 Heat-Shock Proteins/immunology , Histocompatibility Antigens Class I/immunology , Membrane Proteins/immunology , Molecular Chaperones/immunology , Receptors, Cell Surface/immunology , Adenovirus E1B Proteins/immunology , Animals , Antigen-Presenting Cells/immunology , B-Lymphocytes/immunology , Dendritic Cells/immunology , H-2 Antigens/immunology , Histocompatibility Antigens Class II/immunology , Humans , Macrophages/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Tumor Cells, Cultured
16.
AIDS Res Hum Retroviruses ; 16(9): 893-905, 2000 Jun 10.
Article in English | MEDLINE | ID: mdl-10875615

ABSTRACT

HIV-specific CD4+ helper T cell responses, particularly to the envelope glycoproteins, are usually weak or absent in the majority of HIV-seropositive individuals. Since antibodies, by their capacity to alter antigen uptake and processing, are known to have modulatory effects on CD4+ T cell responses, we investigated the effect of antibodies produced by HIV-infected individuals on the CD4+ T cell response to HIV-1 gp120. Proliferative responses of gp120-specific CD4+ T cells were inhibited in the presence of either serum immunoglobulin from HIV-infected individuals or human monoclonal antibodies specific for the CD4-binding domain (CD4bd) of gp120. Human monoclonal antibodies to other gp120 epitopes did not have the same effect. The anti-CD4bd antibodies complexed with gp120 suppressed T cell lines specific for varying gp120 epitopes but did not affect T cell proliferation to non-HIV antigens. Moreover, inhibition by the anti-CD4bd/gp120 complexes was observed regardless of the types of antigen-presenting cells used to stimulate the T cells. These results indicate that the presence of anti-CD4bd antibodies complexed with gp120 can strongly suppress CD4+ helper T responses to gp120.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , HIV Antibodies/immunology , HIV Envelope Protein gp120/immunology , Lymphocyte Activation , Amino Acid Sequence , Antibodies, Monoclonal , Antigen-Antibody Complex , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/virology , Antigens, Bacterial , Cell Line , Epitopes/genetics , HIV Envelope Protein gp120/genetics , Humans , Mycobacterium tuberculosis/immunology
17.
J Exp Med ; 191(10): 1649-60, 2000 May 15.
Article in English | MEDLINE | ID: mdl-10811859

ABSTRACT

The Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1 is critical for the persistence of the viral episome in replicating EBV-transformed human B cells. Therefore, all EBV-induced tumors express this foreign antigen. However, EBNA1 is invisible to CD8(+) cytotoxic T lymphocytes because its Gly/Ala repeat domain prevents proteasome-dependent processing for presentation on major histocompatibility complex (MHC) class I. We now describe that CD4(+) T cells from healthy adults are primed to EBNA1. In fact, among latent EBV antigens that stimulate CD4(+) T cells, EBNA1 is preferentially recognized. We present evidence that the CD4(+) response may provide a protective role, including interferon gamma secretion and direct cytolysis after encounter of transformed B lymphocyte cell lines (B-LCLs). Dendritic cells (DCs) process EBNA1 from purified protein and from MHC class II-mismatched, EBNA1-expressing cells including B-LCLs. In contrast, B-LCLs and Burkitt's lymphoma lines likely present EBNA1 after endogenous processing, as their capacity to cross-present from exogenous sources is weak or undetectable. By limiting dilution, there is a tight correlation between the capacity of CD4(+) T cell lines to recognize autologous B-LCL-expressing EBNA1 and DCs that have captured EBNA1. Therefore, CD4(+) T cells can respond to the EBNA1 protein that is crucial for EBV persistence. We suggest that this immune response is initiated in vivo by DCs that present EBV-infected B cells, and that EBNA1-specific CD4(+) T cell immunity be enhanced to prevent and treat EBV-associated malignancies.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Epstein-Barr Virus Nuclear Antigens/immunology , Adult , Antigen Presentation , B-Lymphocytes/immunology , Cell Line , Dendritic Cells/immunology , Epitopes/chemistry , Epitopes/genetics , Epstein-Barr Virus Nuclear Antigens/chemistry , Epstein-Barr Virus Nuclear Antigens/genetics , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/immunology , Humans , In Vitro Techniques , Interferon-gamma/biosynthesis , Lymphocyte Activation , Protein Structure, Tertiary , Repetitive Sequences, Amino Acid
18.
J Immunol ; 163(12): 6665-70, 1999 Dec 15.
Article in English | MEDLINE | ID: mdl-10586062

ABSTRACT

The MHC class I protein HLA-B27 is strongly associated with susceptibility to spondyloarthropathies and can cause arthritis when expressed in rats and mice, implying a direct role in disease pathogenesis. A prominent hypothesis to explain this role suggests that the unique peptide binding specificity of HLA-B27 confers an ability to present arthritogenic peptides. The B pocket, a region of the peptide binding groove that is an important determinant of allele-specific peptide binding, is thought to be critical for arthritogenicity. However, this hypothesis remains unproven. We show that in addition to its role in peptide selection, the B pocket causes a portion of the pool of assembling HLA-B27 heavy chains in the endoplasmic reticulum to misfold, resulting in their degradation in the cytosol. The misfolding phenotype is corrected by replacing the HLA-B27 B pocket with one from HLA-A2. Our results suggest an alternative to the arthritogenic peptide hypothesis. Misfolding and its consequences, rather than allele-specific peptide presentation, may underlie the strong link between the HLA-B27 B pocket and susceptibility to spondyloarthropathies.


Subject(s)
Arthritis/immunology , HLA-B27 Antigen/metabolism , Peptide Fragments/metabolism , Protein Folding , Spondylitis/immunology , Amino Acid Substitution , Antigen Presentation , Arthritis/etiology , Arthritis/metabolism , Cytosol/immunology , Cytosol/metabolism , Disease Susceptibility , HLA-B27 Antigen/chemistry , HLA-B27 Antigen/physiology , Humans , Peptide Fragments/chemistry , Peptide Fragments/immunology , Peptide Fragments/physiology , Protein Binding/immunology , Spondylitis/etiology , Spondylitis/metabolism
19.
J Reprod Immunol ; 43(2): 139-55, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10479050

ABSTRACT

The expression of the nonclassical MHC class Ib molecule HLA-G is nearly exclusively restricted to the feto-maternal interface during pregnancy. There it probably serves the same physiological functions already known for classical MHC class I molecules; these include peptide presentation, natural killer cell (NK) inhibition and probably also T cell restriction. In this study a comparison between HLA-G and HLA-A2 as far as the amount and complexity of bound peptides is concerned revealed no significant differences. The peptide motif of HLA-G, as determined by analysis of naturally eluted peptides allows the construction of a peptide library that is efficient in binding to HLA-G and thereby confirms the rules of peptide binding to this nonclassical MHC class I molecule. In addition, we demonstrate that the inhibition of NK cells by HLA-G varies remarkably among the NK repertoires of different donors. The function of HLA-G as a survival factor in the development of the fetus during pregnancy is discussed in detail.


Subject(s)
Antigen Presentation/immunology , HLA Antigens/immunology , Histocompatibility Antigens Class I/immunology , Killer Cells, Natural/immunology , Peptides/immunology , Cell Line , HLA Antigens/genetics , HLA-A2 Antigen/genetics , HLA-A2 Antigen/immunology , HLA-G Antigens , Histocompatibility Antigens Class I/genetics , Humans
20.
Eur J Immunol ; 29(3): 1032-40, 1999 03.
Article in English | MEDLINE | ID: mdl-10092108

ABSTRACT

Ectopic expression of the proteoglycan, decorin, abrogates the growth of experimental C6 gliomas in the rat. Since gliomas release large amounts of transforming growth factor-beta (TGF-beta) and since decorin is a TGF-beta antagonist, decorin gene transfer-mediated abrogation of glioma growth in vivo may involve enhanced immunogenicity of the tumor cells. Here, we report that human glioma cells stimulate alloreactive immune responses when engineered to express decorin whereas parental glioma cells are non-immunogenic in vitro. The alloreactive immune response is mediated by CD8+ and CD4+ T cells as well as by NK cells. The immunosuppression exerted by parental or mock-transfected glioma cells is mediated by soluble factors and can in part be mimicked by exogenous TGF-beta. However, neutralizing anti-TGF-beta antibodies do not reverse glioma-mediated immunosuppression, suggesting that decorin abrogates glioma-induced immune cell inhibition by interfering with the activity of other, so far unidentified glioma-secreted mediators. We conclude that enhanced immunogenicity may mediate the antineoplastic effects of decorin gene therapy for malignant glioma but that factors other than TGF-beta may be responsible for glioma-induced immunosuppression.


Subject(s)
Proteoglycans/immunology , Transforming Growth Factor beta/immunology , Adenoviridae , Animals , Cell Line , Cytotoxicity, Immunologic , Decorin , Extracellular Matrix Proteins , Gene Expression Regulation , Gene Transfer Techniques , Genetic Engineering , Genetic Vectors , Glioma , Humans , Immune Tolerance , Immunophenotyping , Leukocytes, Mononuclear , Mice , Mink , Proteoglycans/genetics , Transfection , Tumor Cells, Cultured
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