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)

We investigated changes in voltage-gated Na+ currents and effects of extracellular Na+ on proliferation in HLA-DR-restricted human CD4+ alphabeta T cells after stimulation with a non-self antigenic peptide, M12p54-68. In the absence of antigenic peptide, neither single (n = 80) nor APC-contacted (n = 71) T cells showed voltage-gated inward currents recording with whole-cell patch-clamp techniques, even with Ca2+ and Na+ ions present in the perfusion solution. However, with the same recording conditions, 31% (26 of 84) of APC-contacted T cells stimulated with the antigenic peptide showed voltage-dependent inward currents that were elicited from -60 mV. The inward currents were not inhibited in extracellular Ca2+-free conditions or in the presence of 1 mM NiCl2. However, they were completely inhibited in extracellular Na+-free conditions, which were made by replacing Na+ with iso-osmotic N-methyl-d -glucamine or choline. The Na+ currents were insensitive to tetrodotoxin, a classical blocker of Na+ channels, but were dose-dependently inhibited by amiloride, a potassium-sparing pyrazine diuretic. Furthermore, the Ag-specific proliferative response of T cells was completely inhibited in Na+-free Tyrode's solution and was suppressed by amiloride in a dose-dependent manner. Our findings suggest that activation of amiloride-sensitive and voltage-gated Na+ channels would be an important step to allow an adequate influx of Na+ and maintain a sustained high Ca2+ level during T cell activation.
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PMID:An amiloride-sensitive and voltage-dependent Na+ channel in an HLA-DR-restricted human T cell clone. 1086 Oct 38

We hypothesized that intradermal delivery of granulocyte-macrophage colony-stimulating factor (GM-CSF) would alter the number and differentiation state of local antigen-presenting cells and thereby alter immunization strength at that site in humans. GM-CSF or placebo was administered intradermally on consecutive days prior to contact sensitization at that site. In GM-CSF-treated skin, epidermal CD1a(+)S100(+) Langerhans cells were reduced in number and had altered morphology, while the number of dermal CD1a(+), HLA-DR(+), and S100(+) cells was increased. In the deep dermis CD68(+) macrophages were increased. Expression of the APC activation markers CD40 and ICAM-1 was also increased in the dermis. Subjects were sensitized to DNCB through GM-CSF- or placebo-pretreated skin and to DPCP through untreated skin. Subjects immunized through GM-CSF-treated sites exhibited 64% greater elicitation responses to DNCB than placebo-treated subjects. GM-CSF-treated subjects also showed 43% lower responses to DPCP than placebo-treated subjects. The difference between DNCB (local) and DPCP (distant) responses was significantly greater for GM-CSF-treated subjects than for placebo responses (n = 8, P < 0.05). Therefore, local immunization site pretreatment with intradermal GM-CSF enhances immunization efficiency at that site.
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PMID:Intradermal granulocyte-macrophage colony-stimulating factor alters cutaneous antigen-presenting cells and differentially affects local versus distant immunization in humans. 1087 25

Epstein-Barr virus (EBV) gene expression in tumor cells of posttransplant lymphoproliferative disorder (PTLD) patients resembles that of EBV transformed B-cell lines (LCL). EBV-specific cytotoxic T-lymphocytes can be generated by stimulating peripheral blood lymphocytes with autologous LCL. We describe a standardized method for the growth inactivation and cryopreservation of LCL for optimal T-cell stimulation and analyzed the function and phenotype of responding T-cells. LCL growth was completely blocked by mitomycin C treatment (McLCL) and McLCL could be cryopreserved while retaining excellent APC function. McLCL stimulated both CD4(+) and CD8(+) T-cells as measured by HLA-DR and CD25 expression using FACS analysis. EBV-specific CTL activity and T-cell proliferation were induced and immunocytochemical staining showed CD4(+) and (granzyme B positive) CD8(+) T-cells rosetting with McLCL. Granzymes A and B, IFN-gamma, and IL-6 were detected at significant levels in the supernatant. Thus, ex vivo T-cell activation with cryopreserved McLCL results in activation of both CD4(+) and CD8(+) T-cells producing a Th1-like cytokine profile, making this a suitable protocol for adoptive therapy of PTLD.
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PMID:Functional CD4(+) and CD8(+) T-cell responses induced by autologous mitomycin C treated Epstein-Barr virus transformed lymphoblastoid cell lines. 1127 16

We examined whether freshly isolated human bronchial cells (HBEC) and bronchial epithelial cell line/BEAS-2B cells expressed surface molecules required for APC function. These cells expressed CD40 and ICAM-1, but not B7-1, B7-2 or HLA-DR molecules. Treatment of these cells with IFN-gamma resulted in enhanced expression of CD40 and ICAM-1 as well as induction of HLA-DR expression. Th2 cytokines such as IL-4 and IL-5, proinflammatory cytokine of GM-CSF and nonspecific activator endotoxin had no effect on these phenotypic expressions. Functional examinations showed that allogeneic lymphocytes purified from peripheral blood strongly proliferated in response to BEAS-2B cells cultured with IFN-gamma, but only weakly compared with those without IFN-gamma. When allogeneic lymphocytes were purified to CD4+ cells, the proliferative response against BEAS-2B cells was abolished. Blockade of CD40-CD40L interaction by anti-CD40 antibody also inhibited the proliferation of lymphocytes to BEAS-2B cells, although this treatment showed a minimum effect on the response to allogeneic MNC. Thus, bronchial epithelial cells have the ability to present allogeneic antigens to T cells in both CD40- and IFN-gamma-dependent manners under the presence of third party cells that transduce co-stimulatory signals.
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PMID:CD40 and IFN-gamma dependent T cell activation by human bronchial epithelial cells. 1128 11

Human immunodeficiency virus (HIV)-1 Nef protein is an essential modulator of AIDS pathogenesis and we have previously demonstrated that rNef enters uninfected human monocytes and induces T cells bystander activation, up-regulating IL-15 production. Since dendritic cells (DCs) play a central role in HIV-1 primary infection we investigated whether rNef affects DCs phenotypic and functional maturation in order to define its role in the immunopathogenesis of AIDS. We found that rNef up-regulates the expression on immature DCs of surface molecules known to be critical for their APC function. These molecules include CD1a, HLA-DR, CD40, CD83, CXCR4, and to a lower extent CD80 and CD86. On the other hand, rNef down-regulates surface expression of HLA-ABC and mannose receptor. The functional consequence of rNef treatment of immature DCs is a decrease in their endocytic and phagocytic activities and an increase in cytokine (IL-1beta, IL-12, IL-15, TNF-alpha) and chemokine (MIP-1alpha, MIP-1beta, IL-8) production as well as in their stimulatory capacity. These results indicate that rNef induces a coordinate series of phenotypic and functional changes promoting DC differentiation and making them more competent APCs. Indeed, Nef induces CD4(+) T cell bystander activation by a novel mechanism involving DCs, thus promoting virus dissemination.
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PMID:HIV-1 Nef induces dendritic cell differentiation: a possible mechanism of uninfected CD4(+) T cell activation. 1196 93

CD123(bright) plasmacytoid cells (PC) and CD1c(+) peripheral blood myeloid dendritic cells (DC) are two human DC precursors that can be expanded in vivo by Fms-like tyrosine kinase 3 ligand (FL). It has been proposed that PC and myeloid CD1c(+) DC may represent two distinct lineages of DC. However, the phylogenetic affiliation of PC and its relationship with myeloid DC remain controversial. Here we show that CD123(bright)HLA-DR(+) PC from FL-treated healthy volunteers can be divided into mutually exclusive subsets that harbor either lymphoid or myeloid features. Lymphoid-like PC represent the majority of PC and include pTalpha-, CD3epsilon-, and CD7-expressing cells. They exhibit TCR-beta gene loci in germline configuration and show low allostimulatory capacity, but produce type I IFN upon virus infection and can be differentiated in vitro into potent APC. Myeloid-like PC represent a minor fraction of the total PC population. They exhibit a striking PC/myeloid DC intermediate phenotype (CD5(+)CD11c(low)CD45RA(low)CD45RO(-)CD101(+)), produce proinflammatory cytokines, and do not require in vitro maturation to act as potent APCs. We propose that, rather than forming a lineage, PC might represent a population of lymphoid cells undergoing an in vivo cell fate conversion from a lymphoid to a myeloid cell type.
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PMID:CD123bright plasmacytoid predendritic cells: progenitors undergoing cell fate conversion? 1207 31

Several HLA-DR alleles are genetically associated with rheumatoid arthritis. DRB1*0401 predominates in Northern Europe and has a characteristic (70)QKRAA motif. This sequence contacts bound peptides and the TCR. Further interactions have been suggested with additional proteins during Ag loading. We explored the much stronger processing/presentation of full-length recombinant human acetylcholine receptor alpha subunit to a specific T cell clone by APC from DRB1*0401+ than *0408+ donors. Using DR*04 transfectants, we show that this difference results largely from the single Lys71<-->Arg interchange (0401<-->0408), which scarcely affects epitope binding, rather than from any other associated polymorphism. Furthermore, we proved our recombinant polypeptides to contain the Escherichia coli 70-kDa heat shock protein molecule DnaK and its requirement for efficient processing and presentation of the epitope by DRB1*0401+ cells. According to a recent report, 70-kDa heat shock protein chaperones preferentially bind to the QKRAA, rather than the QRRAA, motif. Variations between the shared epitope motifs QKRAA and QRRAA are emphasized by underlining. We propose that such interactions enhance the intracellular epitope loading of *0401 molecules. They may thus broaden immune responses to pathogens and at least partially explain the distinct contributions of DRB1*0401 and other alleles to disease predisposition.
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PMID:Major differences in antigen-processing correlate with a single Arg71<-->Lys substitution in HLA-DR molecules predisposing to rheumatoid arthritis and with their selective interactions with 70-kDa heat shock protein chaperones. 1221 16

Rheumatoid arthritis is characterized by synovial joint infiltration of activated CD4(+) T cells and MHC class II(+) APC, and is linked to specific HLA-DR alleles. Candidate autoantigens in synovial fluid and cartilage include type II collagen (CII) and cartilage gp39 (HCgp39). Using preparations of native Ag and T cells derived from Ag-immunized DR4-transgenic mice, we determined that human ex vivo differentiated DR4(+) dendritic cells (DC) and macrophages (Mphi) can mediate MHC class II presentation of CII or HCgp39 epitopes. The form of the Ag (soluble, partially degraded, or particulate) delivered to the APC influenced its presentation by DC and Mphi. DC efficiently presented partially degraded, but not native CII alpha-chains, while Mphi presentation was most efficient after phagocytosis of bead-conjugated CII. Both DC and Mphi presented soluble HCgp39, and activated Mphi from some donors presented epitopes derived from endogenously synthesized HCgp39. When synovial fluid from rheumatoid arthritis patients was used as a source of Ag, DC presentation of HCgp39 and CII epitopes was efficient, indicating that synovial fluid contains soluble forms of CII and HCgp39 amenable to internalization, processing, and presentation. These data support the hypothesis that CII and HCgp39 are autoantigens and that their class II-mediated presentation by DC and Mphi to T cells in vivo has a critical role in the pathogenesis of human rheumatoid arthritis.
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PMID:Differential MHC class II-mediated presentation of rheumatoid arthritis autoantigens by human dendritic cells and macrophages. 1244 76

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

Following trauma, increased inflammatory monokine activation and depressed APC function can occur simultaneously. These contradictory monocyte (Mphi) dysfunctions could result if postinjury Mphi differentiation preferentially favored inflammatory macrophage (Mac) differentiation over development into the most potent APC, dendritic cells (DC). In this report, Mphi of trauma patients with a depressed MLR induction capacity are, for the first time, shown to be unable to differentiate in vitro to immature CD1a(+) DC under the influence of GM-CSF and IL-4. Trauma patient Mphi that retained MLR-inducing capacity had a nonsignificant reduction in DC differentiation capacity. Only patient Mphi populations with depressed differentiation to immature DC (iDC) demonstrated depressed IL-12 and IL-15 production and a continued reduced MLR induction capacity. Neither increased IL-10 production nor decreased CD11c(+) DC precursor numbers correlated with depressed Mphi-to-DC differentiation. Instead, these patients' APC-dysfunctional Mphi populations had increased expression of inflammatory Mac phenotypes (CD64(+), CD86(low), HLA-DR(low)) and up-regulated secretion of M-CSF. M-CSF combined with IL-6 inhibits Mphi-to-iDC differentiation and promotes Mphi-to-Mac differentiation by down-regulating GM-CSFR expression and increasing DC apoptosis. Both depressed GM-CSFR expression and increased Mphi iDC apoptosis, as well as increased expression of CD126 (IL-6R) and CD115 (M-CSFR), were detected in APC-defective patient Mphi. In vitro addition of anti-M-CSF enhanced the IL-4 plus GM-CSF-induced Mphi-to-DC differentiation of these patients. This suggests that, in trauma patients, enhanced Mphi-to-Mac differentiation with concomitant inhibited iDC development is partially due to increased circulating Mphi sensitivity to and production of M-CSF and contributes to postinjury immunoaberrations.
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PMID:Failure of monocytes of trauma patients to convert to immature dendritic cells is related to preferential macrophage-colony-stimulating factor-driven macrophage differentiation. 1279 69


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