Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding the process of inducing T cell activation has been hampered by the complex interactions between APC and inflammatory Th1 cells. To dissociate Ag-specific signaling through the TCR from costimulatory signaling, rTCR ligands (RTL) containing the alpha1 and beta1 domains of HLA-DR2b (DRA*0101:DRB1*1501) covalently linked with either the myelin basic protein peptide 85-99 (RTL303) or CABL-b3a2 (RTL311) peptides were constructed to provide a minimal ligand for peptide-specific TCRs. When incubated with peptide-specific Th1 cell clones in the absence of APC or costimulatory molecules, only the cognate RTL induced partial activation through the TCR. This partial activation included rapid TCR zeta-chain phosphorylation, calcium mobilization, and reduced extracellular signal-related kinase activity, as well as IL-10 production, but not proliferation or other obvious phenotypic changes. On restimulation with APC/peptide, the RTL-pretreated Th1 clones had reduced proliferation and secreted less IFN-gamma; IL-10 production persisted. These findings reveal for the first time the rudimentary signaling pattern delivered by initial engagement of the external TCR interface, which is further supplemented by coactivation molecules. Activation with RTLs provides a novel strategy for generating autoantigen-specific bystander suppression useful for treatment of complex autoimmune diseases.
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PMID:Rudimentary TCR signaling triggers default IL-10 secretion by human Th1 cells. 1159 63

We present the case of a 42-year-old female patient with the diagnoses of autoimmune hepatitis type I and autoimmune thyroiditis. Furthermore this patient had an unusual combination of coagulation disorders with homozygous Factor V Leiden mutation (APC resistance) and presence of antiphospholipid antibodies, leading to deep vein thromboses and miscarriages. Only few cases with the combination of autoimmune hepatitis and antiphospholipid antibodies have been described and almost all of them had become symptomatic with the antiphospholipid syndrome. As both autoimmune phenomenons furthermore share similar HLA-patterns, their coincidence is probably not as uncommon as the limited number of case reports suggests. Therefore attention in patients with autoimmune hepatitis should be focused on thrombophilia.
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PMID:Autoimmune hepatitis associated with coagulation disorders and immunethyreopathy. 1160 52

Three different HLA-DQ0602 restricted T-lymphocyte clones (clones 5, 44, and 48) specific for two different Herpes simplex virus type 2 (HSV-2) VP16 peptides were used in a series of proliferation assays with BLS-1 cell lines expressing mutated HLA-DQ0604 molecules as APC. Up to four residues in the peptide-binding region of DQ0604 were replaced by the respective DQ0602 residue. For all three clones, residue beta70 played a crucial role in TCR recognition; beta30 and beta57 were important, although beta86 was less significant. Clone 5 and 48, specific to the HSV-2 VP16 369--379 peptide, responded to the same mutated DQ0604 molecules. Both clones could be stimulated only when the antigen presenting DQ molecule contained the DQ0602-like Gly at position beta70. Stimulation of clone 44, which recognized a different HSV-2 VP16 epitope (VP16 40-50), was less restricted. Molecular homology modeling showed that the beta70Arg of DQ0604 partially covered the peptide around P5/P6. Interactions of beta70 with residues from the antigen-peptide and polymorphic residues at positions beta30 and beta57 can modulate this effect. Supported by molecular modeling data, we conclude that the distinct molecular topography of DQ0602 is not contributed by a single residue, but rather the interactions of various polymorphic DQ residues with particular antigenic peptides.
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PMID:Mutational analysis of critical residues determining antigen presentation and activation of HLA-DQ0602 restricted T-cell clones. 1187 36

The development of rapid, efficient, and safe methods for generating Ag-specific T cells is necessary for the clinical application of adoptive immunotherapy. We show that B cells stimulated with CD40 ligand and IL-4 (CD40-B cells) can be efficiently transduced with retroviral vectors encoding a model Ag, CMV tegument protein pp65 gene, and maintain high levels of costimulatory molecules after gene transfer. CTL lines specific for pp65 were readily generated in all four healthy CMV-seropositive donors by stimulating autologous CD8(+) T cells with these transduced CD40-B cells, both of which were derived from 10 ml peripheral blood. ELISPOT assays revealed that the CTL lines used multiple HLA alleles as restricting elements. Thus, CD40-B cells transduced retrovirally with Ag-encoding cDNA can be potent APC and facilitate to generate Ag-specific CTL in vitro.
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PMID:Efficient generation of antigen-specific cytotoxic T cells using retrovirally transduced CD40-activated B cells. 1216 46

Polymyositis (PM) is an autoimmune muscle disease characterized by oligoclonal T cell infiltrates mediating myocytotoxicity. Although antigenic triggers for this process remain undefined, clinically homogeneous subsets of PM patients are characterized by autoantibodies directed against nuclear and cytoplasmic Ags that include histidyl-tRNA synthetase (Jo-1). Available evidence suggests that formation of anti-Jo-1 autoantibodies is Ag-driven and therefore dependent on CD4(+) T cells that may also direct cytolytic CD8(+) T cells involved in myocyte destruction. To assess peripheral blood T cell responses to Jo-1, we first subcloned full-length human Jo-1 as well as novel fragments of Jo-1 into the maltose-binding protein expression vector pMALc2. Expressed proteins were then used in standard proliferation assays with either PBMC or autologous DCs as sources of APCs. Although PBMC-derived APCs and DCs both supported peripheral blood T cell proliferation when primed with full-length human Jo-1, only DCs promoted proliferative responses to a unique amino-terminal fragment of Jo-1. mAb blockade of different HLA Ags revealed that these responses were MHC class II dependent. Therefore, for the first time, these studies demonstrate anti-Jo-1 T cell responses in Jo-1 Ab-positive PM patients as well as in healthy control subjects. More importantly, this work underscores the critical importance of APC type in dictating T cell responses to a novel antigenic fragment of Jo-1.
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PMID:Critical requirement for professional APCs in eliciting T cell responses to novel fragments of histidyl-tRNA synthetase (Jo-1) in Jo-1 antibody-positive polymyositis. 1247 Nov 50

Small-molecular compounds with hydrogen bond (H-bond) donor function are able to trigger exchange reactions of MHC class II ligands. Here, we show that their effect is not limited to short peptides. Also encephalitogenic myelin basic protein (MBP) is transferred with great efficiency onto HLA-DR molecules when H-bond donor molecules such as parachlorphenol (pCP) are present. The effect was observed not only with soluble MHC class II but also with HLA-DR1 and HLA-DR2 molecules on the cell surface. The improved loading of APC translates directly into improved T cell activation. In the presence of pCP T cells reacted at significantly lower antigen concentrations, an effect observed with purified MBP protein as well as with crude spinal cord homogenate. The 'accidental' transfer of autoantigens such as MBP onto activated APC might trigger fatal autoimmune reactions and small molecules as catalysts of this process could represent risk factors, which had not been accounted for as yet.
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PMID:Small-molecular compounds enhance the loading of APC with encephalitogenic MBP protein. 1260 13

Type B T cells recognize peptide provided exogenously but are ignorant of the same epitope derived from intracellular processing. In this study, we demonstrate the existence of type B T cells to an abundant autologous peptide derived from processing of the I-A(k) beta-chain. T cell hybridomas raised against this peptide fail to recognize syngeneic APC despite abundant presentation of the naturally processed epitope but react in a dose-dependent manner to exogenous peptide. Moreover, these hybridomas respond to Abeta(k) peptide extracted from the surface of I-A(k)-expressing APC. This peptide was isolated from B cell lines where it was found in high abundance; it was also present in lines lacking HLA-DM, but in considerably lower amounts. Therefore, type B T cells exist in the naive repertoire to abundant autologous peptides. We discuss the implications of these findings to the potential biological role of type B T cells in immune responses and autoimmune pathology.
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PMID:APCs present A beta(k)-derived peptides that are autoantigenic to type B T cells. 1268 47

HLA-DM stabilizes peptide-receptive class II alphabeta dimers and facilitates the capture of high affinity peptides, thus influencing the peptide repertoire presented by class II molecules. Variations in DM levels may therefore have a profound effect on the antigenic focus of T cell-mediated immune responses. Specifically, DM expression may influence susceptibility and resistance to autoimmune diseases. In this study the role of DM in HLA-DR4-restricted presentation of an insulin-dependent diabetes mellitus autoantigen, glutamate decarboxylase (GAD), was tested. Presentation of immunodominant GAD epitope 273-285 was regulated by endogenous DM levels in human B lymphoblasts. T cell responses to exogenous GAD as well as an endogenous cytoplasmic form of this Ag were significantly diminished with increasing cellular expression of DM. Epitope editing by DM was observed only using Ag and not small synthetic peptides, suggesting that this process occurred within endosomes. Results with cytoplasmic GAD also indicated that peptides from this compartment intersect class II proteins in endocytic vesicles where DM editing was facilitated. Changes in DM levels within APC may therefore influence the presentation of autoantigens and the development of autoimmune disorders such as type I diabetes.
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PMID:Editing of an immunodominant epitope of glutamate decarboxylase by HLA-DM. 1284 54

We quantitated the amounts of peptides from hen egg-white lysozyme presented by I-A(k) molecules in APC lines. The large chemical gradient of presentation of the four hen egg-white lysozyme epitopes observed in cell lines expressing HLA-DM or H-2DM (referred to in this study as DM) was significantly diminished in the T2.A(k) line lacking DM. Differences in levels of presentation between wild-type and DM-deficient APC were observed for all four epitopes, but differences were most evident for the highest affinity epitope. As a result of these quantitative differences in display, presentation of all four epitopes to T cells was impaired in the line lacking DM. The binding affinity of the pool of naturally processed peptides from DM-expressing lines was higher than that from the DM-deficient line. Thus, using a direct biochemical approach in APC, we demonstrate that DM influences the selection of peptides bound to MHC class II by favoring high affinity peptides.
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PMID:Cutting edge: H-2DM is responsible for the large differences in presentation among peptides selected by I-Ak during antigen processing. 1292 60

CD4+ T cells play an important role in the induction and maintenance of an effective antiviral and antitumor immune response. However, standardized monitoring of antigen-specific CD4+ T cells has not been established at the single-cell level. We now present a sensitive, specific, and simple methodology in which purified memory CD4+ T cells are expanded from PBMC in a single cycle of antigen-driven stimulation and quantitatively assayed by interferon-gamma ELISPOT. Issues of nonspecific background in assays were resolved with the use of innovative target cells, autologous PHA-expanded CD4+ T cells (T-APC). Remarkably, T-APC could not only present peptide epitopes from model antigens NY-ESO-1 and influenza nucleoprotein, but could also process full-length antigen endogenously expressed from recombinant fowlpox vector. This approach makes it possible to monitor CD4+ T cells in large series of patients, regardless of HLA haplotype, against the full peptide repertoire of a given antigen.
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PMID:Monitoring CD4+ T cell responses against viral and tumor antigens using T cells as novel target APC. 1295 96


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