Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06126 (CD1a)
 2,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

UVB irradiation of the skin causes immunosuppression and Ag-specific tolerance in which Langerhans cells (LC) are involved. We tested the effect of UVB on LC that had migrated out of cultured epidermal sheets derived from the skin that was irradiated ex vivo (200, 400, 800, or 1600 J/m2). Two separate subpopulations of LC were distinguished: large-sized LC with high HLA-DR expression, and HLA-DR-low, small LC. UVB stimulated the maturation of the former LC subset as demonstrated by enhanced up-regulation of CD80, CD86, CD54, CD40, and CD83 and reduced CD1a expression in comparison with unirradiated controls. In contrast, the latter LC exhibited little or no up-regulation of these molecules except for high CD1a expression and high binding of annexin V, indicating that they were apoptotic, although their CD95 expression was relatively low. Stimulation of enriched LC with CD40 ligand-transfected cells and IFN-gamma revealed that the release of IL-1beta, IL-6, IL-8, and TNF-alpha was enhanced by UVB. In comparison with HLA-DR-low LC, HLA-DR-high LC were the principal IL-8 producers as demonstrated by intracellular cytokine staining, and they retained more accessory function. There was no detectable secretion of IL-12 p70, and IL-18 production was neither affected by any stimulus nor by UVB. These results suggest a dual action of UVB on LC when irradiated in situ: 1) immunosuppression by preventing maturation and inducing apoptotic cell death in part of LC, and 2) immunopotentiation by enhancing the up-regulation of costimulatory molecules and the production of proinflammatory cytokines in another part.
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PMID:Differential modulation of human epidermal Langerhans cell maturation by ultraviolet B radiation. 1055 39

The intestinal epithelium is anatomically positioned to serve as the critical interface between the lumen and the mucosal immune system. In addition to MHC class I and II antigens, intestinal epithelia constitutively express the nonclassical MHC molecule CD1d, a transmembrane molecule with a short cytoplasmic tail expressed as a beta(2)-microglobulin-associated 48-kDa glycoprotein and novel beta(2)-microglobulin-independent 37-kDa nonglycosylated protein on intestinal epithelia. At present, it is not known whether extracellular ligands can signal intestinal epithelial CD1d. To define signaling of CD1d cytoplasmic tail, retrovirus-mediated gene transfer was used to generate stable cell lines expressing wild-type CD1d or a chimeric molecule (extracellular CD1d and cytoplasmic CD1a), and surface CD1d was triggered by antibody crosslinking. Although wild-type CD1d was readily activated (tyrosine phosphorylation), no demonstrable signal was evident in cell lines expressing the chimeric molecule. Subsequent studies revealed that anti-CD1d crosslinking specifically induces epithelial IL-10 mRNA and protein and is blocked by the tyrosine kinase inhibitor genistein. Further studies addressing epithelial-derived IL-10 revealed that anti-CD1d crosslinking attenuates IFN-gamma signaling and that such attenuation is reversed by addition of functionally inhibitory IL-10 antibodies. These results define signaling through surface CD1d, and, importantly, they demonstrate that this pathway may serve to dampen epithelial proinflammatory signals.
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PMID:Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling. 1057 Jan 77

Imiquimod (R-837) and its more potent derivative (R-848) are imidazoquinolines that have adjuvant activity in cultured human mononuclear cells. Its mechanism of action on epidermal antigen-presenting cells is not known. The purpose of the present investigation was to determine whether imiquimod and R-848 affect human epidermal Langerhans' cells' (LC) in vitro maturation. Pulse incubations (6-16 h) of cultured unfractionated epidermal cells or highly enriched LC suspensions with either imiquimod or R-848 (0. 05-5.0 microg/ml of culture medium) reproducibly enhanced their ability to induce T-cell proliferation in a primary mixed lymphocyte reaction. There was a 30 to 300% increase in T-lymphocyte proliferation induced by either imiquimod- or R-848-treated LC when compared to control, untreated LC. IFN-gamma secretion by T-lymphocytes stimulated by imiquimod- or R-848-treated LC was increased compared to control, untreated LC. After a 6-h incubation, phenotypic analysis of control-, imiquimod-, or R-848-treated LC indicated that such antigen-presenting cells were in an "intermediate" state of maturation (CD1a(+), HLA-DR, DP, DQ(bright+), CD40(low+), CD86(high+), and CD80(low+)). RNase protection assays demonstrated that either imiquimod or R-848 treatments increased steady-state transcripts encoding for IL-12 p40, IL-1beta, TNF-alpha, and IL-1 receptor antagonist by LC. These data indicate that imiquimod and R-848 dissociate the functional maturation (cytokine-mediated) and phenotypic maturation of epidermal LC. These data warrant further exploration for the use of imidazoquinoline-treated LC or other DC subsets for processing and presentation of viral peptides to Th-lymphocytes as a novel vaccine strategy to induce protective antiviral responses.
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PMID:The imidazoquinolines, imiquimod and R-848, induce functional, but not phenotypic, maturation of human epidermal Langerhans' cells. 1060 86

The combination of interferon-alpha (IFN-alpha) plus interleukin (IL-2) has been accepted in the treatment of metastatic renal cell carcinoma (MRCC), whereas vaccines based on IL-12 or dendritic cells (DCs) are still being investigated. Here the authors analyzed 1) the feasibility to generate functional monocyte-derived DCs (MDDCs) from patients treated with biological response modifiers (BRMs) who have MRCC, 2) the phenotypic modulations of these MDDCs during BRM treatment. Eight and 13 MRCC patients received IL-2 plus IFN-alpha or IL-12 immunotherapy, respectively. The adherent fraction of mononuclear cells from patients' blood drawn before, during, and after immunotherapy was incubated in clinically approved culture medium supplemented with 5% autologous serum, rhu granulocyte macrophage colony-stimulating factor, and rhuIL-4 for a week. At day 7 or 8 of culture, floating cells were examined in flow cytometric and functional assays (alloreactivity, proliferation assays in the presence of tetanus toxoid or tumor peptides, IL-12 secretion). In all patients except two, MDDCs could be generated but at a lower rate compared with healthy volunteers. Morphologic and phenotypical analyses revealed immature DCs with low levels of CD1a or CD83 expression throughout therapy with BRMs. Capacities in mixed leukocyte reactions were similar to those of healthy volunteers and stable during immunotherapy, whereas presentation of major histocompatibility complex class II tetanus toxoid peptide complexes was slightly enhanced during and after IL-12 therapy. IL-12 expression levels under IFN-gamma and CD40L stimulation were significantly lower in MDDC cultures from patients with MRCC compared with healthy volunteers. Overall, peripheral blood mononuclear cells from a cohort of 21 patients with metastatic disease who were treated with BRMs maintained their ability to differentiate into functional MDDCs with no selective quantitative or qualitative advantage.
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PMID:Generation of monocyte-derived dendritic cells from patients with renal cell cancer: modulation of their functional properties after therapy with biological response modifiers (IFN-alpha plus IL-2 and IL-12). 1083 66

Dendritic cell (DC) precursors and immature DC reside in epithelium where they encounter pathogens and cytokines, which stimulate their differentiation. We hypothesized that type-I interferons (IFN-alpha and -beta), cytokines that are produced early in the innate immune response against viruses and some bacteria, may influence DC differentiation and function. To examine this possibility, we used an in vitro model of DC differentiation in which initial culture of human CD14(+) monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 generates immature DC, and subsequent culture with tumor necrosis factor (TNF)-alpha drives the final development into mature DC. We found in this model that IFN-alpha/beta, added from the initiation of the culture on, significantly reduced the survival and altered the morphology and differentiation of DC. TNF-alpha-dependent maturation of IFN-beta-treated immature DC led to cells with reduced expression of CD1a, CD40, CD54, and CD80 when compared with mature DC controls. IFN-alpha/beta-treated DC further had a reduced capacity to induce naive Th-cell proliferation through allostimulation or anti-CD3 monoclonal antibody stimulation. In addition, IFN-alpha/beta-treated DC secreted less IL-12 upon stimulation with Staphylococcus aureus Cowan strain or with CD4(+) T cells, and this decrease correlated directly with their inability to support CD4(+) T-cell secretion of IFN-gamma, even though T-cell lymphotoxin production was unaffected. These findings indicate that type-I IFNs can influence the generation of acquired immune responses by modifying T-helper cell differentiation through the regulation of DC differentiation and function.
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PMID:Interferon-alpha and -beta inhibit the in vitro differentiation of immunocompetent human dendritic cells from CD14(+) precursors. 1089 53

We describe a phenotypically and functionally novel monocyte-derived dendritic cell (DC) subset, designated mDC2, that lacks IL-12 synthesis, produces high levels of IL-10, and directs differentiation of Th0/Th2 cells. Like conventional monocyte-derived DC, designated mDC1, mDC2 expressed high levels of CD11c, CD40, CD80, CD86, and MHC class II molecules. However, in contrast to mDC1, mDC2 lacked expression of CD1a, suggesting an association between cytokine production profile and CD1a expression in DC. mDC2 could be matured into CD83+ DC cells in the presence of anti-CD40 mAbs and LPS plus IFN-gamma, but they remained CD1a- and lacked IL-12 production even upon maturation. The lack of IL-12 and CD1a expression by mDC2 did not affect their APC capacity, because mDC2 stimulated MLR to a similar degree as mDC1. However, while mDC1 strongly favored Th1 differentiation, mDC2 directed differentiation of Th0/Th2 cells when cocultured with purified human peripheral blood T cells, further indicating functional differences between mDC1 and mDC2. Interestingly, the transfection efficiency of mDC2 with plasmid DNA vectors was significantly higher than that of mDC1, and therefore mDC2 may provide improved means to manipulate Ag-specific T cell responses after transfection ex vivo. Taken together, these data indicate that peripheral blood monocytes have the capacity to differentiate into DC subsets with different cytokine production profiles, which is associated with altered capacity to direct Th cell differentiation.
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PMID:Monocyte-derived CD1a+ and CD1a- dendritic cell subsets differ in their cytokine production profiles, susceptibilities to transfection, and capacities to direct Th cell differentiation. 1103 59

Although significant progress has been made in understanding immune reconstitution in peripheral blood following highly active antiretroviral therapy (HAART), less is known about immune changes in lymphoid tissue. Here, the expression of cytokine proteins (interferon gamma [IFN-gamma], interleukin [IL]-2, IL-4, IL-10, IL-1alpha, and IL-1beta) and surface antigens (CD4, CD8, CD1a, CD68) as well as cellular proviral HIV-1 DNA were determined in sequential tonsil biopsies before and at 4, 12, and 48 to 56 weeks posttherapy by quantitative in situ image analysis and fluorescent in situ 5;-nuclease assay (FISNA). Despite plasma virus suppression, a fraction of tonsil cells harbored pro-viral DNA for up to 1 year. A fourfold to eightfold increase in CD8+ T cells in tissue compared with seronegative controls and an increased frequency of CD1a+ dendritic cells prior to HAART reached control levels at week 56. The frequency of IFN-gamma expressing cells was 10-to 15-fold higher than controls before therapy and was comparable with findings in seronegative controls by week 56. Elevated baseline expression of IL-1alpha and IL-1beta was reduced by week 4 but IL-1alpha levels remained elevated in 1 of 3 patients at week 56. These findings suggest that with effective viral suppression the immune system in tissue may return to a more resting state.
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PMID:Normalization of immune activation in lymphoid tissue following highly active antiretroviral therapy. 1110 45

Based on the relative expression of CD11c and CD1a, we previously identified subsets of dendritic cells (DCs) or DC precursors in human peripheral blood. A CD1a(+)/CD11c(+) population (CD11c(+) DCs), also called myeloid DCs, is an immediate precursor of Langerhans cells, whereas a CD1a(-)/CD11c(-) population (CD11c(-) DCs), sometimes called lymphoid DCs but better known as plasmacytoid DCs, is composed of type I IFN (IFN-alpha beta)-producing cells. Here, we investigate the effects of IFN-alpha beta and IFN-gamma as well as other cytokines on CD11c(+) and CD11c(-) DC subsets, directly isolated from the peripheral blood, instead of in vitro-generated DCs. IFN-gamma and IFN-alpha, rather than GM-CSF, were the most potent cytokines for enhancing the maturation of CD11c(+) DCs. Incubation of CD11c(+) DCs with IFN-gamma also resulted in increased IL-12 production, and this IL-12 allowed DCs to increase Th1 responses by alloreactive T cells. In contrast, IFN-alpha did not induce IL-12 but, rather, augmented IL-10 production. IFN-alpha-primed matured CD11c(+) DCs induced IL-10-producing regulatory T cells; however, this process was independent of the DC-derived IL-10. On the other hand, IFN-alpha by itself neither matured CD11c(-) DCs nor altered the polarization of responding T cells, although this cytokine was a potent survival factor for CD11c(-) DCs. Unlike IFN-alpha, IL-3 was a potent survival factor and induced the maturation of CD11c(-) DCs. The IL-3-primed CD11c(-) DCs activated T cells to produce IL-10, IFN-gamma, and IL-4. Thus, CD11c(+) and CD11c(-) DC subsets play distinct roles in the cytokine network, especially their responses to IFNs.
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PMID:Differential regulation of human blood dendritic cell subsets by IFNs. 1120 45

Suppression of interleukin 12 (IL-12) production by dendritic cells (DCs) has been hypothesized to be a principal mechanism underlying the biological action of interferon (IFN)-beta used for treatment of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system with possible autoimmune origin. How IFN-beta interacts with DCs to inhibit IL-12 production remains unclear. In this study, we found that DCs derived from human blood monocytes, upon culture in the presence of IFN-beta with granulocyte-macrophage colony- stimulating factor (GM-CSF) and IL-4, differentiated into a population expressing CD14- CD1a- HLA-DR+. This population expressed CD123 (IL-3Ralpha). IFN-beta dose-dependently increased IL-3Ralpha+ DCs and decreased CD1a+ DCs. After 7 days' culture with IFN-beta at a concentration of 10 000 U/ml, more than 40% of DCs expressed IL-3Ralpha. IFN-beta, together with GM-CSF and IL-4, also induced maturation of IL-3Ralpha-expressing cells, as reflected by upregulation of HLA-DR and of the costimulatory molecules CD40, CD80 and CD86. In contrast to control DCs, IFN-beta-treated DCs produced predominantly IL-10 but only low levels of IL-12p40. Correspondingly, IFN-beta-treated DCs strongly suppressed IFN-gamma production but enhanced IL-10 production by allogeneic blood mononuclear cells. Our data suggest that IFN-beta in vitro can induce the development of DC2, which provide a permissive environment for Th2 differentiation. This finding represents a novel mechanism for action of IFN-beta in MS.
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PMID:Interferon-beta induces the development of type 2 dendritic cells. 1124 4

Skin lesions of dermatophytosis are thought to be a result of a T cell-dependent inflammatory response that is mediated by various cytokines. We examined whether IFN-gamma-positive cells (as expression of Th1 response) were present in the skin lesions of dermatophytosis in situ by immunohistochemical techniques. Mixtures of CD4-positive T cells and CD8-positive T cells were found to be present in the dermal infiltrates of the lesions. Considerable numbers of CD1a-positive cells were detected in the upper dermis and epidermis. A marked accumulation of CD68-positive cells was found in the upper dermis. IFN-gamma-positive cells were present in the upper dermis of the lesions. The pattern of IFN-gamma staining appeared to be intracellular in mononuclear lymphoid cells. The staining was considered to be highly specific because it could be completely blocked by preabsorption with recombinant IFN-gamma. Our data support the hypothesis that the skin lesions of dermatophytosis may be associated with a Th1 response. Th1 response, which is characterized by IFN-gamma release, is thought to be involved in the host defense against dermatophytes and to reflect cutaneous reaction in dermatophytosis.
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PMID:Immunohistochemical detection of interferon-gamma-producing cells in dermatophytosis. 1127 3


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