Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

There is controversy regarding the ability of short term (2 to 3 days) cultured epidermal Langerhans cells (cLC) to process and present intact protein Ag to primed T cells. Some studies have shown that cLC are potent APC for both haptens and intact protein Ag, whereas in others cLC have been unable to process and present intact protein Ag. In an attempt to resolve this controversy, we tested the ability of Langerhans cells from several strains of mice to process and present intact protein Ag to T cell clones and T cell hybridomas. We found that both cLC and freshly prepared Langerhans cells from various Iak mice, including BALB.k mice, process and present intact protein antigens (i.e., hen egg lysozyme, cytochrome c, and OVA) to T cells. These functions are retained in cLC cultured for 7 days. In contrast, cLC from Iad mice do not process intact protein Ag, such as hen egg lysozyme and myoglobin, although they can present relevant peptides to specific T cells and are potent stimulators of allogeneic responses. Furthermore, cLC from (Iak x Iad)F1 mice process and present intact protein Ag to Iak-restricted T cells, but not to Iad-restricted T cells. Although cLC that processed and presented intact protein Ag to T cells exhibited enhanced class II MHC expression, they were, on a per cell basis, somewhat less efficient than were fresh Langerhans cells. Finally, we found that if Iad Langerhans cells are pulsed with intact protein Ag and then cultured for 3 days, they are then fully capable of inducing Ag- and MHC-specific T cell proliferation.
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PMID:The ability of cultured Langerhans cells to process and present protein antigens is MHC-dependent. 184 34

Two lines of evidence in the current study indicate that antigen processing is a major factor, in addition to MHC binding and T cell repertoire, that determines Ir gene responsiveness and epitope immunodominance. First, immunization with synthetic peptides of myoglobin sequences revealed new reactivities that had not appeared after priming with native myoglobin. For example, B10.S mice (H-2S) immune to equine myoglobin predominantly responded to peptide 102-118, whereas there was little, if any, response to this peptide in B10.BR (H-2k) mice immunized with native equine myoglobin. However, after immunization with the 102-118 peptide, both strains responded to the peptide. After in vitro restimulation, B10.BR T cells responded as well as B10.S T cells. Similarly, some individual 102-118-specific T cell clones from mice of both haplotypes showed similar dose responses and fine specificity patterns. Thus, low responsiveness to this site is due neither to a hole in the repertoire nor to a failure to bind to the appropriate MHC molecule. An alternative explanation was suggested by the observation that, whereas B10.S T cells from peptide 102-118-immune mice responded almost as well to whole myoglobin as to the peptide, the B10.BR T cells from peptide immune mice, while responding well to peptide, were poorly stimulated by whole myoglobin. Thus, the product of natural processing of equine myoglobin probably has hindering structures in the regions flanking the core epitope 102-118 that interfere with presentation by I-Ak but not I-AS. The second line of evidence that processing of native myoglobin may influence the apparent specificity of the T cell response was obtained using the I-Ad-restricted sperm whale myoglobin 102-118-specific clone 9.27. This clone discriminated readily between whole sperm whale myoglobin and equine myoglobin, but it did not distinguish between peptides corresponding to 102-118 of the sperm whale and equine sequences. This distinction between equine peptide and native equine myoglobin could be overcome by artificial "processing" of equine myoglobin with cyanogen bromide. In both sets of experiments, F1 APCs that present the same epitope well to T cells of another haplotype failed to overcome the defect, which was therefore not due to the availability of different processed cleavage fragments in APC of different haplotypes, as would be expected if there were MHC-linked processing. Thus, the differential responses to peptides versus native molecule for both I-Ad- and I-Ak-restricted clones appeared to depend on the restricting molecule used.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Influences of antigen processing on the expression of the T cell repertoire. Evidence for MHC-specific hindering structures on the products of processing. 245 73

Although studies of the association of antigen with APC have been complicated by antigen-processing requirements, recent studies have suggested that immunologically relevant antigen should be present on the APC surface. Nevertheless, blocking of antigen presentation with antibody to the antigen has not been demonstrable in most systems. To study this problem we developed a system using avidin to block presentation of amino-terminal biotinylated synthetic peptide 132-146 of sperm whale myoglobin (B132) to a murine T cell clone specific for this site in association with I-Ed. greater than 95% specific inhibition was observed with doses of B132 equipotent to unmodified peptide. Specific blocking could be observed: (a) after pulsing APC with antigen, washing, and incubating for a chase period of 8-16 h before addition of avidin and T cells to assure adequate time for intracellular trafficking and maximal display of antigen on the cell surface, or (b) when monensin is present during the antigen pulse to inhibit such traffic. Therefore, the inhibition appeared to be occurring at the cell surface unless dissociation and reassociation were constantly occurring. To distinguish these, B10.GD APC (I-Ed-negative) were pulsed with antigen and cocultured with B10.D2 APC (I-Ed-positive). No detectable antigen presentation resulted. Thus, minimal dissociation and reassociation between antigen and APC occurs and, consequently, blocking by extracellular solution-phase binding of avidin to antigen is unlikely. Taken together, these data suggest that the blocking is occurring at the cell surface. Thus, under physiologic conditions, immunologically relevant antigen necessary for T cell activation appears to be present on the APC surface and is freely accessible to macromolecules the size of avidin. These findings hold specific implications for models of antigen presentation for T cell recognition.
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PMID:Immunologically relevant peptide antigen exists on the presenting cell in a manner accessible to macromolecules in solution. 349 May 31

T cell activation is widely believed to depend on interleukin 1 (IL 1) provided by antigen (Ag)-presenting cells (APC). Because IL 1 is not a constitutive product of APC, we examined the features of its production during the interaction of murine T cell clones and APC. We observed that IL 1 was detectable in supernatants of most myoglobin-specific T cell clones grown with APC and Ag. Two of these T cell clones induced exceptionally high levels of IL 1 in their supernatants, and these same clones demonstrated the unusual restriction to I-Ek, which is a low responder type for sperm whale myoglobin. One of these clones was characterized additionally as to the mechanism of IL 1 induction. This clone rapidly stimulated IL 1 production in the APC population (detectable at 4 hr of co-culture) or in macrophages (M phi) or a M phi-like cell line. IL 1 induction was Ag dependent and H-2 restricted. Induction was radioresistant, both on the part of the T cell and of the IL 1 producer. The IL 1-induction process was attributable to a lymphokine produced by the T cell clone. This lymphokine was distinct from IFN-gamma, TNF and CSF-1 and may account for a principal mechanism of T----APC signalling. The induced IL 1 was the same in size, co-mitogenicity, and pyrogenicity as lipopolysaccharide-induced IL 1.
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PMID:IL 1 induction by murine T cell clones: detection of an IL 1-inducing lymphokine. 349 59

Mixed isotype MHC class II molecules (E alpha dA beta d) occur at extremely low levels on the surface of normal mouse B cells and macrophages, as determined by surface staining with an E alpha dA beta d-specific hamster mAb, H71-258.41. The surface levels of mixed isotype on the B cell lymphoma line A20 are approximately 1 to 2% that of surface I-A, whereas the levels of these molecules on normal mouse B cells were estimated to be at least two to four times less than those on A20. Nevertheless, other investigators have recently reported that immunization of normal H-2d mice with the sperm whale myoglobin peptide 110-121 (SWM(110-121)) elicits T cells, predominantly, V beta 8.2+, that recognize the peptide only in context of E alpha A beta. We have characterized a large number of SWM(110-121)-specific T cell hybridomas from several strains of H-2d haplotype mice. All of the V beta 8.2+ 110-121-specific hybridomas were found to be restricted by E alpha dA beta d, whereas, of the V beta 8.2- 110-121-specific group, approximately half recognized the peptide through E alpha dA beta d whereas the remainder were restricted by either I-Ad or I-Ed. mAb inhibition experiments revealed that 14-4-4S (E alpha-specific) could block presentation by mixed isotype completely, while MK-D6 (A beta d-specific) and H71-258.41 (E alpha dA beta d-specific) only inhibited presentation when the concentration of peptide was limiting. Although A20 expresses very low levels of mixed isotype, 10 to 100 nmol of the peptide produced a detectable response, illustrating the remarkable efficiency in presenting this peptide through E alpha dA beta d. The ability of normal mouse APC to use this restriction element despite its extremely low expression has important implications for the activation of T cells by low levels of peptide-MHC complexes.
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PMID:Expression and function of mixed isotype MHC class II molecules in normal mice. 825 92

The hypothesis that reduction of disulfide bonds and exposure to low pH may be sufficient to allow intact proteins to bind class II MHC was addressed in this study. Functional assays were used to determine minimal conditions sufficient to bypass the requirement for Ag processing. Fixed APC, pulsed with HEL at pH 5 in the presence of a reducing agent, were observed to stimulate I-Ed-restricted T cell hybridomas. Activity required both low pH and reducing agent. Fixed APC also stimulated cytochrome c-specific T cells after exposure to Ag at pH 5 but not pH 7. No reducing agent was required. Peptide was considerably more potent in these assays than intact cytochrome c. By contrast, highly purified cytochrome c was equal in potency with a peptide in competition binding assays using purified I-Ek. The protein did not bind I-Ad or I-Ak. This suggested that cytochrome c can efficiently bind I-Ek at low pH without the requirement for proteolytic cleavage. The capacity of HEL to bind purified I-Ed was strictly dependent on the presence of reducing agent. The reducing agent alone had no effect. A small panel of proteins was screened for class II binding at low pH in competition assays. Horse myoglobin and human hemoglobin were particularly potent in their capacity to inhibit binding of biotin-labeled peptide to purified class II. Unlabeled peptide inhibited binding of labeled peptide to I-Ad at pH 5 and pH 7. By contrast, intact horse myoglobin was active only at pH 5. This result suggested that low pH may enhance the binding of horse myoglobin to I-Ad through effects on the structure of both proteins. Our observations support the hypothesis that low pH and disulfide reduction can be sufficient to allow partially unfolded or structurally destabilized proteins to bind class II MHC.
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PMID:Acidification and disulfide reduction can be sufficient to allow intact proteins to bind class II MHC. 838 84

(B6 X A)F1 mice were immunized with sperm whale myoglobin, and T cell clones and hybridomas were generated. Hybridoma 74a.e9 was specific for the sperm whale myoglobin 67-79 peptide and could be partially activated by a peptide analogue, equine myoglobin with a natural 74G substitution. Using this hybridoma in T cell activation assays, we studied the effects of varying the avidity of the TCR for its ligand, the concentration of MHC:peptide complex on the APC, and the density of TCR on the surface. Varying ligand concentration on the surface of the APC, the TCR avidity, or the density of TCR on the T cell were equally important parameters in driving T cell activation. The mouse myoglobin (74T) analogue, however, acted as an antagonist to the T cell response. Its effectiveness was also partially determined by its ability to bind to MHC. By independently altering each of these variables and following T cell activation, we describe the interrelationships among these three components (MHC:peptide:TCR) that control the activation of the T cell.
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PMID:Quantitative analysis of T cell activation: role of TCR/ligand density and TCR affinity. 860 91

A model of gram-negative lethal endotoxin shock, involving continuous peritoneal infusion of lipopolysaccharide (LPS), has been applied to wild-type (WT) mice and mice with a severe deficiency of endothelial protein C receptor (EPCR(delta/delta)). The survival of EPCR(delta/delta) mice was significantly diminished as compared to WT mice after administration of LPS via this route. Heart rates and central blood pressures also were significantly more depressed in EPCR(delta/delta) mice, indicating that the receptor-based protein C (PC) pathway functions in regulation of hemodynamic properties in the mouse. Further, heart muscle damage was more severe in EPCR(delta/delta) mice as compared to WT mice after endotoxin administration, as revealed by the more elevated plasma myoglobin levels in EPCR(delta/delta) mice and by microscopic examination of stained heart sections. Neutrophil infiltration was more pronounced in heart tissue of EPCR(delta/delta) mice, perhaps in response to the greatly increased expression level of the chemokine, MIP-2, which also significantly more up-regulated in the LPS-treated EPCR(delta/delta) mouse cohort. In conclusion, a severe deficiency of EPCR adversely affects survival of mice subjected to continuous infusion of endotoxin, via contributions of more responsive hemodynamic and cardiac alterations, thus suggesting that, among its other functions, the PC-based receptor system has a cardioprotective role after acute inflammatory challenge.
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PMID:A cardioprotective role for the endothelial protein C receptor in lipopolysaccharide-induced endotoxemia in the mouse. 1552 12

A prototype of a fiber-optic, multi-analyte, immunobiosensing system was developed to simultaneously quantify disease-representing biomarkers in blood plasma. This system was for simultaneous quantification of two different groups of multi-biomarkers related to cardiovascular diseases (CVD): anticoagulants (protein C, protein S, antithrombin III, and plasminogen) for deficiency diagnosis; and cardiac markers (B-type natriuretic peptide, cardiac troponin I, myoglobin, and C-reactive protein) for coronary heart disease diagnosis. As an initial effort towards the development of a disposable and easy-to-use sensing cartridge as a rapid diagnostic tool for CVD related diseases, a prototype of a flow control system was also developed to automatically perform simultaneous four-analyte quantification. Currently, the system is capable of quantifying the multiple anticoagulants in their clinically significant sensing ranges within 5 minutes, at an average signal-to-noise (S/N) ratio of 25. A simultaneous assay of the four cardiac markers can be performed within 10 min, at an average S/N ratio of 20. When this highly portable multi-analyte sensing system is completed and successfully tested for CVD patient's plasma, it can provide rapid (<10 min) and reliable diagnostic and prognostic information at a patient's bedside.
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PMID:Fluorophore-mediated, fiber-optic, multi-analyte, immunosensing system for rapid diagnosis and prognosis of cardiovascular diseases. 1667 86

Using a combination of H2 nuclear magnetic resonance (NMR) methods, we study internal rotational dynamics of the perdeuterated protein C-phycocyanin (CPC) in dry and hydrated states over broad temperature and dynamic ranges with high angular resolution. Separating H2 NMR signals from methyl deuterons, we show that basically all backbone deuterons exhibit highly restricted motion occurring on time scales faster than microseconds. The amplitude of this motion increases when a hydration shell exists, while it decreases upon cooling and vanishes near 175 K. We conclude that the vanishing of the highly restricted motion marks a dynamical transition, which is independent of the time window and of a fundamental importance. This conclusion is supported by results from experimental and computational studies of the proteins myoglobin and elastin. In particular, we argue based on findings in molecular dynamics simulations that the behavior of the highly restricted motion of proteins at the dynamical transition resembles that of a characteristic secondary relaxation of liquids at the glass transition, namely the nearly constant loss. Furthermore, H2 NMR studies on perdeuterated CPC reveal that, in addition to highly restricted motion, small fractions of backbone segments exhibit weakly restricted dynamics when temperature and hydration are sufficiently high.
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PMID:Vanishing amplitude of backbone dynamics causes a true protein dynamical transition: 2H NMR studies on perdeuterated C-phycocyanin. 2473 Aug 77


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