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

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains results in a chronic, immune-mediated demyelinating disease similar to human multiple sclerosis. Here, we examined the role of astrocytes as an APC population in TMEV-induced demyelination and assessed the potential consequences of T cell activation following Ag presentation. IFN-gamma-pretreated astrocytes were able to process and present all the predominant T cell epitopes of TMEV to virus-specific T cell hybridomas, clones, as well as bulk T cells. Despite low levels of proliferation of T cells due to prostaglandins produced by astrocytes, such Ag presentation by activated astrocytes induced the production of IFN-gamma, a representative proinflammatory cytokine, in TMEV-specific Th cell clones derived from the CNS of virus-infected mice. Furthermore, these Th cell clones mediate lysis of the astrocytes in vitro in a Fas-dependent mechanism. TUNEL staining of CNS tissue demonstrates the presence of apoptotic GFAP+ cells in the white matter of TMEV-infected mice. These results strongly suggest that astrocytes could play an important role in the pathogenesis of TMEV-induced demyelination by activating T cells, subsequently leading to T cell-mediated apoptosis of astrocytes and thereby compromising the blood-brain barrier.
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PMID:Potential role of CD4+ T cell-mediated apoptosis of activated astrocytes in Theiler's virus-induced demyelination. 1035 70

Receptors that display negative signalling functions on lymphocytes and other cells of the reticuloendothelial system now number about 30. These negative receptors are transmembrane glycoproteins activated by phosphorylation of a tyrosine residue in immunoreceptor tyrosine-based inhibitory motifs that bind various phosphatases to induce dominant negative signals. Since these receptors are armed by the action of activating receptors and inhibit signalling by activating receptors, we have termed them coinhibitory receptors and the negative outcome is coinhibition. Coinhibitory receptors and some inhibitory mediators include FcgammaRIIB, CTLA-4, CD5, CD22, p58/70/140 KIR, gp49B1/gp91, PIRB1-5, LAIR-1, NKB1, Ly49 A/C/E/F/G, NKG2-A/B APC-R, CD66, CD72, PD-1, SHPS-1, SIRP-alpha1, ILT1-5, MIR7, 10, hMIR(HM18), hMIR(HM9), LIR1-3,5,8, Fas (CD95), TGFbeta-R, TNF-R1, IFNgamma-R (alpha and beta chains), mast cell function Ag, H2-M, HLA-DM, CD1, CD1-d, CD46, c-cbl, Pyk2/FADK2, P130 Ca rel prot, PGDF-R, LIF, LIF-R, CIS, SOCS13 and 5, and others are being defined regularly. This long list suggests that coinhibitors are needed not only for self-nonself discrimination, but also for control of ongoing responses to foreign antigens so that infectious agents are ideally dealt with by an appropriate level of immune responses to nonself and an appropriate amount of immunopathology and sickness behaviour.
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PMID:Why so many coinhibitory receptors? 1040 45

MHC class II molecules have a crucial role in thymic selection and in generating Ag-specific T cell responses. There is extensive evidence for second messenger generation via MHC class II molecules, which can lead to apoptosis of B lymphocytes. We have examined HLA class II-mediated apoptosis in both normal and tumoral human B lymphocytes. Phosphatidylserine exposure and DNA fragmentation were observed in B cells within 24 h of stimulation via HLA class II. In marked comparison with Fas, the cell-permeable and irreversible caspase inhibitors zVAD-fmk and DEVD-fmk failed to inhibit HLA-DR-mediated apoptosis. No direct activation of caspase 3 was detected, and cleavage of pro-caspase 3 was not observed. Cleavage of poly(ADP-ribose) polymerase was detected via Fas but not via HLA class II. Although phosphatidylinositol-3-kinase has been implicated in HLA class I-mediated apoptosis, neither wortmannin nor LY294002 affected HLA class II-mediated apoptosis. CD95-sensitive cells were used to reveal that death occurred independently of CD95-CD95 ligand interactions. Overall, these data reveal a pathway of HLA-DR-mediated apoptosis that neither requires nor involves caspases. Moreover, it is phosphatidylinositol-3-kinase independent and Fas/CD95 independent. This pathway of HLA class II-mediated apoptosis could have an important role in the regulation of APC populations or in the control of malignant B lymphocyte proliferations.
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PMID:A caspase-independent pathway of MHC class II antigen-mediated apoptosis of human B lymphocytes. 1051 Mar 46

Immunoregulation of lymphocytes and macrophages in the peripheral immune system is achieved in part by activation-induced cell death. Members of the TNF receptor family including Fas (CD95) are involved in the regulation of activation-induced cell death. To determine whether activation-induced cell death plays a role in regulation of dendritic cells (DCs), we examined interactions between Ag-presenting murine DCs and Ag-specific Th1 CD4+ T cells. Whereas mature bone marrow- or spleen-derived DCs expressed high levels of Fas, these DCs were relatively insensitive to Fas-mediated killing by the agonist mAb, Jo-2, as well as authentic Fas ligand expressed on the CD4+ T cell line, A.E7. The insensitivity to Fas-mediated apoptosis was not affected by priming with IFN-gamma and/or TNF-alpha or by blocking the DC survival signals TNF-related activation-induced cytokine and CD40L. However, apoptosis could be induced with C2-ceramide, suggesting that signals proximal to the generation of ceramide might mediate resistance to Fas. Analysis of protein expression of several anti-apoptotic mediators revealed that expression of the intracellular inhibitor of apoptosis Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein was significantly higher in Fas-resistant DCs than in Fas-sensitive macrophages, suggesting a possible role for Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein in DC resistance to Fas-mediated apoptosis. Our results demonstrate that murine DCs differ significantly from other APC populations in susceptibility to Fas-mediated apoptosis during cognate presentation of Ag. Because DCs are most notable for initiation of an immune response, resistance to apoptosis may contribute to this function.
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PMID:Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway. 1055 53

In vivo administration of APC expressing Fas ligand (Fas-L(+) dendritic cells (DCs)) has shown promise in dampening allergic reactions and transplant rejection. Since the effect in these studies was mainly on CD4 lymphocytes, our goal was to evaluate the ability of such killer DCs to eliminate antiviral CD8 lymphocytes and in this way ameliorate viral immunopathology or, conversely, impede viral clearance. Intravenous administration of Fas-L(+) DCs resulted in a 50% reduction of lytic CD8 precursors following intracerebral infection with lymphocytic choriomeningitis virus (LCMV), and accordingly, immunopathology and survival of LCMV meningitis were improved, whereas viral clearance remained unaffected. In transfer studies the effect of the Fas-L(+) DCs was only quantifiable on experienced, not naive, CD8 lymphocytes. Importantly, loading of Fas-L(+) DCs with viral Ag before therapy was not necessary to achieve this effect, indicating that non-LCMV-infected Fas-L(+) DCs acquired viral Ag during acute LCMV infection in vivo. Our studies delineate important aspects for the clinical use of Fas-L(+) DCs in vivo. One should expect that they acquire viral Ags and suppress antiviral CD8 responses to some degree when given while an acute infection is ongoing. In terms of safety it is encouraging that resolution of the infection, at least in the case of LCMV, is not inhibited.
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PMID:Reduction of antiviral CD8 lymphocytes in vivo with dendritic cells expressing Fas ligand-increased survival of viral (lymphocytic choriomeningitis virus) central nervous system infection. 1239 Nov 97

Several in vitro and animal studies have been performed to modulate the interaction of APCs and T cells by Fas (CD95/Apo-1) signaling to delete activated T cells in an Ag-specific manner. However, due to the difficulties in vector generation and low transduction frequencies, similar studies with primary human APC are still lacking. To evaluate whether Fas ligand (FasL/CD95L) expressing killer APC could be generated from primary human APC, monocyte-derived dendritic cells (DC) were transduced using the inducible Cre/Loxp adenovirus vector system. Combined transduction of DC by AdLoxpFasL and AxCANCre, but not single transduction with these vectors, resulted in dose- and time-dependent expression of FasL in >70% of mature DC (mDC), whereas <20% of immature DC (iDC) expressed FasL. In addition, transduction by AdLoxpFasL and AxCANCre induced apoptosis in >80% of iDC, whereas FasL-expressing mDC were protected from FasL/Fas (CD95/Apo-1)-mediated apoptosis despite coexpression of Fas. FasL-expressing mDC eliminated Fas(+) Jurkat T cells as well as activated primary T cells by apoptosis, whereas nonactivated primary T cells were not deleted. Induction of apoptosis in Fas(+) target cells required expression of FasL in DC and cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. Induction of apoptosis in Fas(+) target cells required expression of FasL in DC, cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. The present results demonstrate that FasL-expressing killer APC can be generated from human monocyte-derived mDC using adenoviral gene transfer. Our results support the strategy to use killer APCs as immunomodulatory cells for the treatment of autoimmune disease and allograft rejection.
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PMID:Mature but not immature Fas ligand (CD95L)-transduced human monocyte-derived dendritic cells are protected from Fas-mediated apoptosis and can be used as killer APC. 1275 15

Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly.
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PMID:Colon cancer: genomics and apoptotic events. 1525 76

CTLA-4.Fas ligand (CTLA-4.FasL), a paradigmatic 'trans signal converter protein (TSCP)', can attach to APC (via CTLA-4 binding to B7) and direct intercellular inhibitory signals to responding T cells (via FasL binding to Fas receptor), converting an activating APC-to-T cell signal into an inhibitory one. Our previous studies established that CTLA-4.FasL inhibits human primary mixed lymphocyte reactions (MLR) and induces alloantigen-specific hyporesponsiveness ex vivo. The present study extends this to an in vivo context. Using splenocytes from MHC-mismatched C57BL/6 and Balb/c mice, we demonstrated that his(6)CTLA-4.FasL, effectively inhibits murine MLR. Moving in vivo, we demonstrated that subcutaneously administered his(6)CTLA-4.FasL modulates the in vivo response of infused allogeneic splenocytes. his(6)CTLA-4.FasL reduces the number of cells in each cell division, and increases the percentage of dead cells in each division. These findings are consistent with an antigen-induced cell death of the alloreactive cells, and bolsters recombinant TCSP promise as a therapeutic for transplantation diseases.
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PMID:CTLA-4.FasL inhibits allogeneic responses in vivo. 1682 66

Recent evidence from several groups indicates that IL-17-producing Th17 cells, rather than, as once was thought, IFN-gamma-producing Th1 cells, can represent the key effector cells in the induction/development of several autoimmune and allergic disorders. Although Th17 cells exhibit certain phenotypic and developmental differences from Th1 cells, the extent of the differences between these two T cell subsets is still not fully understood. We found that the expression profile of cell surface molecules on Th17 cells has more similarities to that of Th1 cells than Th2 cells. However, although certain Th1-lineage markers [i.e., IL-18 receptor alpha, CXCR3, and T cell Ig domain, mucin-like domain-3 (TIM-3)], but not Th2-lineage markers (i.e., T1/ST2, TIM-1, and TIM-2), were expressed on Th17 cells, the intensity of expression was different between Th17 and Th1 cells. Moreover, the expression of CTLA-1, ICOS, programmed death ligand 1, CD153, Fas, and TNF-related activation-induced cytokine was greater on Th17 cells than on Th1 cells. We found that IL-23 or IL-17 can suppress Th1 cell differentiation in the presence of exogenous IL-12 in vitro. We also confirmed that IL-12 or IFN-gamma can negatively regulate Th17 cell differentiation. However, these cytokines could not modulate such effects on T cell differentiation in the absence of APC.
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PMID:Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17. 1730 64

Microorganisms with pathogen-associated molecular patterns (PAMP) activate B cells directly by binding to TLR and also indirectly by inducing APC to release cytokines such as BAFF that promote B cell survival. We found that murine B cells activated concomitantly with LPS (TLR-4 ligand) and BAFF are protected from spontaneous apoptosis, but are more susceptible to Fas/CD95-mediated cell death. This increased susceptibility to Fas-induced apoptosis is associated with a dramatic coordinated up-regulation of Fas/CD95 and IRF-4 expression through a mechanism mediated, at least in part, by inhibition of the MEK/ERK pathway. Up-regulation of Fas/CD95 by BAFF is restricted to B cells activated through TLR-4, but not through TLR-9, BCR or CD40. TLR ligands differ in the BAFF family receptors (R) they induce on B cells: BAFF-R is increased by the TLR4 ligand, LPS, but not by the TLR9 ligand, CpG-containing oligodeoxynucleotides, which, in contrast, strongly up-regulates transmembrane activator and CAML interactor (TACI). This suggests the up-regulation of Fas by BAFF is mediated by BAFF-R and not by TACI. Consistently, APRIL, which binds to TACI and B cell maturation antigen but not BAFF-R, did not enhance Fas expression on LPS-activated B cells. Increased susceptibility to Fas-mediated killing of B cells activated with LPS and BAFF may be a fail-safe mechanism to avoid overexpansion of nonspecific or autoreactive B cells.
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PMID:BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas-mediated cell death. 1735 8


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