Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An initial event in T cell activation is the specific adherence of T cells via their T cell receptor to the MHC peptide complex. We have studied this adherence by incubating T cells with preformed HLA DR4Dw4 peptide complexes attached to a solid support. Adherence of sodium 51Cr-labeled T cell clones specific for the influenza hemagglutinin peptide, HA 307-319, was maximal after 15 min and was specific for the HLA DR4Dw4-HA 307-319 complex. The binding was temperature dependent and could be blocked with azide or protein kinase C inhibitors, indicating that for adherence the T cells need to be metabolically active and have a functioning protein kinase C pathway. The adherence could be blocked with CD4- or CD3-reactive murine mAb, suggesting that the TCR and CD4 molecules work in concert to induce strong adherence to the HLA DR4Dw4-HA 307-319 complex. A subsequent event in T cell activation is proliferation, which is thought to need additional proteins such as IL-1 or other adhesion molecules. MHC peptide complexes coated on microtiter plates also induced proliferation in the human T cell clones. Removal of any monocytes by treatment of human T cell clones with anti-CD14 in conjunction with C, followed by purification over a nylon wool column, did not abrogate proliferation. After prolonged culture of the T cell clones in plates coated with peptide-pulsed HLA DR4Dw4 in the presence of IL-2, the T cell clones continued to proliferate in response to peptide. These results suggest that human T cell clones do not require a second signal from a monocyte or other APC to proliferate.
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PMID:Purified HLA class II peptide complexes can induce adherence and activation of peptide-specific human T cell clones. 153 49

Recent studies have shown that infusion of the anticoagulant protein, activated protein C (APC), can ameliorate many of the systemic effects of endotoxemia in experimental animals, although the mechanisms in this action are unknown. We investigated the effects of APC on the responses of blood monocytes, alveolar macrophages, and cells of the monocyte line, THP-1, to stimulation in vitro by LPS, IFN-gamma, or PMA. Mononuclear phagocyte (MO) activation was associated with rapid production of TNF-alpha, down-regulation of the glycophosphatidylinositol-linked protein CD14 (the key MO receptor for complexes of LPS and LPS-binding protein responsible for intracellular signaling), and down-regulation of the related LPS-binding proteins CD11b and CD18. Addition of APC, but not the zymogen, PC, or active site-blocked APC, inhibited selected MO responses involving the CD14-dependent LPS-induced pathway of MO activation, or activation induced by IFN-gamma or PMA. Thus, APC inhibited the production of TNF-alpha and prevented down-regulation of membrane CD11b, CD14, and CD18, but had no effect on up-regulation of MHC class II, ICAM-1, or IL-2R, down-regulation of MO expression of another glycophosphatidylinositol-linked protein, CD59, or production of reactive oxygen intermediates. These data show that APC inhibits host cytokine production but maintains MO responses associated with adhesion, phagocytosis, and killing of Gram-negative bacteria, such that use of APC may be a logical and potent adjunctive therapy in select inflammatory diseases involving MO activation and damaging host cytokine overproduction.
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PMID:Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-gamma, or phorbol ester. 752

Dendritic cells (DC) are the major APC capable of stimulating resting T cells in human peripheral blood (PB). Recent evidence suggested that various subsets of DC and monocytes might circulate in human PB, but their exact phenotype and function had not been delineated. We have previously characterized a population of human PB DC precursors that express the myeloid marker CD33, but not the monocyte marker CD14. To identify and characterize further functional myeloid APC subsets, triple color FACS analysis and sorting was used. A CD33dimCD14dimCD16+ monocyte subset, with similar APC function but less efficient accessory function than CD14bright monocytes, was isolated. In addition to the CD33+CD14dimCD16- DC precursors, a smaller population (0.1 to 0.2% of PBMC) of CD33brightCD14dimCD16- cells with potent APC function was identified. This DC population expressed greater amounts of MHC class II, adhesion, and accessory molecules, and demonstrated a greater costimulatory capacity when freshly isolated than CD33dimCD14dim DC precursors, and therefore had the characteristics of mature, possibly tissue-derived DC. When freshly isolated, however, these DC did not express B7, and up-regulation of accessory function occurred after in vitro differentiation. These data demonstrate multiple circulating myeloid accessory and APC subsets in human PB. Phenotypic and functional differences suggest that they are at different stages of differentiation, and have specialized roles in Ag presentation in vivo. Furthermore, full functional DC differentiation, associated with B7 expression and the capacity to activate T cells maximally, is likely to occur only in specific physiologic circumstances.
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PMID:Human peripheral blood dendritic cell subsets. Isolation and characterization of precursor and mature antigen-presenting cells. 752 13

Dendritic cells (DC) are potent APC that can be purified from cultured peripheral blood non-T cells. Because no specific cell surface marker has been found, the lineage of DC remains obscure. The purpose of these studies was to determine the circulating blood cells that could give rise to functional human DC. DC were enriched when purified by standard techniques from non-T cells that were treated with L-leucyl-L-leucine methyl ester, known to be toxic to monocytes and cytolytic cells. To determine whether monocytes or B cells could give rise to DC, fresh non-T cells were sorted into CD14+ monocytes, CD19+ B cells, and CD14- and CD19- cells. Although there was some enrichment for APC function by cultured nonadherent CD14- or CD19- cells, a marked enrichment for cells with dendritic morphology and potent APC function was found in the population that was sorted by the absence of expression of CD14, CD19, CD3, and CD16. More than 90% of the CD14-CD19-CD16-CD3- sorted cells, and of control DC, expressed the myeloid markers CD13 and CD33. Therefore, fresh non-T cells were sorted based on the expression of these myeloid markers. In comparison with CD33-CD14- B cells, some of the CD33+ cells expressed CD14 dimly. However, they were easily distinguished from monocytes, which intensely expressed CD14. CD33+CD14dim cells developed dendritic processes and were more potent APC than control DC, CD33+CD14+, or CD33-CD14- cells. Although freshly isolated CD33+CD14dim DC expressed a number of cell surface molecules also expressed by CD14+ monocytes, they demonstrated lower levels of lysosomal enzymes and a lack of FcR-mediated phagocytosis in comparison with monocytes. Differentiation of morphology and phenotype of CD33+CD14dim cells occurred within 6 to 36 h in culture. However, the CD33+CD14dim cells could effectively function as APC without prolonged preincubation to develop dendritic morphology. These data indicate that human blood DC arise from precursors that express the myeloid lineage markers CD13 and CD33, but are functionally distinct from classic CD14+ monocytes.
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PMID:Isolation and characterization of human peripheral blood dendritic cells. 767 23

The relative ability of unmanipulated monocytes, B cells, and dendritic cells (DC) from peripheral blood to stimulate an allogeneic MLR has not been clearly established. We studied the allostimulatory ability of these cell types from minimally manipulated PBMC populations to exclude the induction of stimulatory properties by the complex isolation procedures commonly used to isolate blood DC. Highly purified cell populations were obtained from volunteer donors by immunolabeling PBMC with mAb directed against known lineage-associated markers and separating the positive and negative population on a FACS. These cells were used as stimulators in an allogeneic MLR. The major allostimulatory activity resides in the CD14, CD11b, and CD19 negative fractions. A mixture of antibodies to T, B, NK, monocyte, and FcRIII positive cells was then used to isolate a minor cell population that contained a markedly superstimulatory population of (CD3, CD14, CD16, CD19, and CD57) negative cells. We demonstrate that this activity is constitutive, and is not an artifact of the adherence and in vitro culture steps used in conventional DC purification procedures. We also show by rigorous depletion of the T cell responders that endogenous HLA class II positive cells in the responder population have little role in presenting processed allogeneic antigens during the primary MLR. Monocytes and B cells are stimulators of the allogeneic MLR, but are considerably less potent on a cell for cell basis than the putative DC population. Finally, because human blood and tonsil DC lack detectable CD43 by immunoperoxidase staining, in contrast to monocytes and activated B cells, we examined the ability of CD43 negative and positive cells to stimulate an allogeneic MLR. Similar allostimulatory activity for the human MLR was shown to reside in both the CD43 positive and negative fractions, suggesting that there may be some heterogeneity in the APC population.
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PMID:Allostimulatory cells in fresh human blood: heterogeneity in antigen-presenting cell populations. 769 38

The association of paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) raises the yet unresolved questions as to whether these two disorders are different forms of the same disease. We compared two groups of patients with respect to cytogenetic features, glycosylphosphatidylinositol (GPI)-linked protein expression, protein C/protein S/thrombomodulin/antithrombin III activity, and PIG-A gene expression. The first group consisted of eight patients with PNH (defined as positive Ham and sucrose tests at diagnosis), and the second, 37 patients with AA. Twelve patients with AA later developed a PNH clone. Monoclonal antibodies used to study GPI-linked protein expression (CD14 [on monocytes], CD16 [on neutrophils], CD48 [on lymphocytes and monocytes], CD67 [on neutrophils and eosinophils], and, more recently, CD55, CD58, and CD59 [on erythrocytes]) were also tested on a cohort of 20 normal subjects and five patients with constitutional AA. Ham and sucrose tests were performed on the same day as flow-cytometric analysis. Six of 12 patients with AA, who secondarily developed a PNH clone, had clinical symptoms, while all eight patients with PNH had pancytopenia and/or thrombosis and/or hemolytic anemia. Cytogenetic features were normal in all but two patients. Proteins C and S, thrombomodulin, and antithrombin III levels were within the normal range in patients with PNH and in those with AA (with or without a PNH clone). In patients with PNH, CD16 and CD67 expression were deficient in 78% to 98% of the cells and CD14 in 76% to 100%. By comparison, a GPI-linked defect was detected in 13 patients with AA, affecting a mean of 32% and 33% of CD16/CD67 and CD14 cell populations, respectively. Two of three tested patients with PNH and 1 of 12 patients with AA had a defect in the CD48 lymphocyte population. In a follow-up study of our patient cohort, we used the GPI-linked molecules on granulocytes and monocytes investigated earlier and added the study of CD55, CD58, and CD59 on erythrocytes. Two patients with PNH and 14 with AA were studied for 6 to 13 months after the initial study. Among patients with AA, four in whom no GPI-anchoring defect was detected in the first study had no defect in follow-up studies of all blood-cell subsets (including erythrocytes). Analysis of granulocytes, monocytes, and erythrocytes was performed in 7 of 13 AA patients in whom affected monocytes and granulocytes were previously detected. A GPI-anchoring defect was detected on erythrocytes in five of six.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link. 785 65

We found that human monocytes differentiate into macrophages (Mp) by GM-CSF and M-CSF. The Mp induced by GM-CSF and M-CSF are different in their morphology, cell surface antigen expression and functions. In the course of that study, we found that IL-4 modulate the differentiation of monocytes induced by GM-CSF and M-CSF. IL-4 alone did not induce the proliferation and differentiation of monocytes. IL-4, however, inhibited the proliferative response of monocytes to GM-CSF. When monocytes were incubated with GM-CSF and IL-4 simultaneously, the cells recovered were non-adherent, non-phagocytic, and did not form rosette with EA. The cells were also negative in nonspecific esterase and showed an appearance of dendritic cells (DC). The DC-like cells expressed CD1, DR, DQ and CD11c, but not CD14, CD71 and 710F. The cells showed strong APC activity in alogeneic and autologous mixed lymphocyte reaction (MLR). When monocytes were incubated with M-CSF and IL-4, TRAP positive multinucleated giant cells appeared. Taken together, these results suggest that IL-4 is a principal factor that control the differential development of human monocytes into DC and multinucleated giant cells.
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PMID:[Differentiation and function of human monocytes]. 787 93

Dendritic cells (DC) have been isolated from blood, lymphoid tissue, and other tissues, as potential members of a hemopoietic lineage of specialist APC for naive T lymphocyte activation. To define human bone marrow (BM) DC we have attempted to identify allostimulatory cells with DC-like characteristics among human BM mononuclear cells (BMMC) by FACS cell sorting and immunophenotyping, monitoring the APC function of different cell lineages in the human primary MLR. We show that fresh human BM stimulates allogeneic T lymphocytes with an activity equal to or greater than that of peripheral blood. As with DC from other tissue sources, the most potent stimulatory activity was found in the low density BMMC, and these cells, like peripheral blood, stimulated a maximal allogeneic MLR response at days 5 to 6. FACS purification of the allostimulatory population in fresh human BMMC was undertaken by using a wide range of mAb directed against lineage-associated molecules of mature and immature lymphoid, erythroid, and myeloid cells. The most potent constitutive BMMC stimulatory activity was located in the CD3-, CD11b-, CD14-, CD15-, CD16-, CD19-, CD57-, and glycophorin A- population. A mixture of antibodies to these Ag was used to isolate a "mix-negative" BMMC population, which contained the most highly potent MLR-stimulatory cells. Further cytologic and immunophenotypic analysis of this population revealed an enriched population of HLA-DP+, HLA-DQ+, HLA-DR+, and CD45+ cells, with morphologic similarities to the human tonsil and blood DC. These cells were CD4- and CD1a- and were weakly CD33+ (but CD15-), suggesting a possible early myeloid origin distinct from both the committed granulocytic and monocytic lineages. In addition, they lacked both CD10 and CD20, making a lymphoid origin unlikely. Further identification of these putative DC precursors will allow analysis of the early phases of DC hemopoiesis, whereas the characterization of the MLR-stimulatory cells in human BM will be of major importance in the understanding of BM transplant failure and graft-vs-host disease.
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PMID:Identification of potent mixed leukocyte reaction-stimulatory cells in human bone marrow. Putative differentiation stage of human blood dendritic cells. 845 72

Microglial cells are resident cells of the CNS and are implicated as regulators and effectors of immune responses which occur within this compartment. The precise role of parenchymal microglia remains speculative because distinctions between these cells, perivascular "microglia," and blood-derived monocytes/macrophages are not well defined. The current study describes the phenotype and function of microglia immediately upon isolation from the non-inflamed adult human CNS and the phenotypic changes which occur in these cells when maintained in tissue culture. We find that the characteristic phenotype of immediately ex vivo parenchymal microglia (CD11c+/CD45low/CD14) corresponds to that found in situ in the "normal" human brain. The phenotype differs from that of perivascular "microglia" in situ and PBDM (both CD45hi/CD14++). The immediately ex vivo microglia express B7-2 and HLA class II molecules and can support alloantigen-induced proliferation by CD4+ T cells freshly isolated from peripheral blood. Following in vitro culture, the cells are characterized by a bipolar morphology, continued lower levels of CD45 expression compared to PBDM, and slight upregulation of B7-1 and HLA-DR antigen expression. CD14 becomes expressed at high levels on the cells, suggesting that CD14 can serve as an apparent marker of microglia activation which is not based on changes in morphology or APC capacity. Further, treatment of the cells with IFN-gamma and LPS causes further upregulation of HLA-DR and clear expression of B7-1 molecules on the surface. The capacity to characterize phenotypic and functional properties of microglia before and after activation provides an opportunity to determine means to manipulate the immune regulatory and effector properties of this cell type.
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PMID:Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia. 889 87

We have investigated the effects of oxidized low density lipoproteins (oxidized LDL) on the expression of TM by THP-1 monocytic cells. TM antigen levels and its cofactor activity for thrombin-dependent protein C activation were increased by oxidized LDL and accompanied by an increase in TM mRNA levels. Incubation of THP-1 cells with 300 microg/ml oxidized LDL for 24 h resulted in an 80% increase of cellular TM antigen levels. Native LDL and acetylated LDL did not affect the TM expression by these cells. The resultant aqueous phase after extraction of oxidized LDL by chloroform/methanol increased the TM antigen levels as well as oxidized LDL. Phorbol 12-myristate 13-acetate (PMA) also increased the TM antigen level 2.1 times the control and was accompanied by the adhesion of cells to plastic dishes and increasing macrophage cell surface antigen CD14 levels. In contrast, oxidized LDL did not induce differentiation to the macrophage. The present results indicate that oxidized LDL increases cellular TM antigen without cellular differentiation and that up-regulation of TM by oxidized LDL in monocytes may have some implication in atherosclerosis.
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PMID:Effect of oxidized low density lipoprotein on thrombomodulin expression by THP-1 cells. 936 89


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