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:3.2.1.17 (lysozyme)
21,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During antigen presentation, a close association between CD4 and the T cell receptor (TCR) occurs as a result of interacting with the same major histocompatibility complex class II molecule. The potential consequences of such an intimate interaction on TCR specificity was addressed using CD4 loss variants of four different murine T cell hybridomas specific for the immunodominant hen egg lysozyme (HEL) peptide 46-61. While all the CD4+ and CD4- variants tested possessed comparable surface expression of TCR, CD3, CD2 and LFA-1, and responded similarly to immobilized anti-TCR and anti-CD3 monoclonal antibodies, they differed dramatically in their responses to either the naturally processed HEL antigen, synthetic peptide 46-61 or staphylococcal enterotoxin superantigens. While one hybridoma was comparatively unaffected by the loss of CD4, another lost its responsiveness to antigen and peptide completely while retaining reactivity to SE. In contrast, two other hybridomas still responded to antigen but lost reactivity to synthetic peptide and SE. These data could not be readily explained on the basis of affinity or signal transduction requirements alone, and thus suggest that the intimate association of CD4 with the TCR may result in a subtle modulation of its fine specificity for some but not all T cells.
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PMID:Does CD4 help to maintain the fidelity of T cell receptor specificity? 162 97

An in vitro model was used to investigate the potential for different structural forms of endogenous antigen to be processed and presented by major histocompatibility complex class II molecules. For this purpose the class II-restricted presentation of an immunodominant epitope of hen egg lysozyme [HEL-(46-61)] was studied in class II-positive B-lymphoma cells (M12.C3) transfected with genes encoding HEL molecules either (i) secreted in high (hi) or low (lo) amounts as soluble antigen [sHEL(hi/lo)], (ii) localized within the endoplasmic reticulum (ER)/salvage compartment (ER-HEL), or (iii) anchored on the cell surface as an integral membrane protein (mHEL). The corresponding sHEL, ER-HEL, and mHEL gene products were expressed as predicted except that HEL determinants accumulated in the culture supernatant as well as on the cell membrane of mHEL-transfected cells. Class II-positive cells endogenously expressing all three forms of HEL antigen constitutively presented the immunodominant HEL-(46-61) determinant with differential efficiency (mHEL, sHEL greater than ERHEL) to a class II-restricted T hybridoma. A second T hybridoma recognized endogenous HEL-(46-61) determinants constitutively presented on sHEL(hi) and mHEL transfectants but not on sHEL(lo) or ERHEL transfectants. The formation of HEL-(46-61)/I-Ak complexes in the ERHEL and sHEL(lo) transfectants was therefore limiting. Mixing experiments with different antigen-presenting cells indicated that the HEL-(46-61) determinant was derived from endogenous antigen rather than by reuptake of shed or secreted HEL determinants. We conclude that MHC class II molecules can present some antigenic determinants derived from endogenous proteins that are sequestered in the ER/salvage compartment as well as distally transported in the form of secretory or membrane antigens.
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PMID:Class II-restricted presentation of an endogenously derived immunodominant T-cell determinant of hen egg lysozyme. 170 37

Antigen processing involves endocytosis, proteolysis and denaturation of antigens to generate peptides that bind to major histocompatibility complex class II molecules (Ia) in a complex recognized by CD4+ T cells. Ia and antigen are internalized and processed intracellularly, but the exact subcellular site of antigen degradation and formation of the Ia-peptide complex remains unclear. The present studies utilized low-temperature incubation in an attempt to functionally block certain steps in the processing of the antigen hen egg white lysozyme (HEL) by peritoneal exudate cells (PEC) and TA3 B lymphoma cells. Ia endocytosis and uptake of HEL by PEC persisted at 18 degrees C, albeit at somewhat slower rates, but delivery of ligands to lysosomes was blocked. Under these conditions HEL catabolism and antigen processing were effectively blocked, although enough catabolism and antigen processing were effectively blocked, although enough HEL was internalized at 18 degrees C to provide effective presentation during a subsequent incubation at 37 degrees C. In TA3 cells transferrin endocytosis and recycling were notably slowed at 18 degrees C, and iron uptake from transferrin by TA3 cells was completely blocked, indicating that certain specifically endosomal functions were inhibited at 18 degrees C. Thus, intracellular steps in antigen processing were blocked at 18 degrees C, corresponding to deficits in endosomal processing and targeting. These results demonstrate that antigen endocytosis and certain temperature-sensitive endosomal and lysosomal processes are essential for antigen processing.
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PMID:Low-temperature inhibition of antigen processing and iron uptake from transferrin: deficits in endosome functions at 18 degrees C. 196 38

We investigated parameters that affect the efficiency with which antigenic epitopes from Salmonella typhimurium are processed for presentation to T lymphocytes. As a model system, the hen egg white lysozyme 52-61 [HEL(52-61)] epitope, which binds the murine major histocompatibility complex class II (MHC-II) molecule I-Ak, was expressed in soluble fusion proteins in S. typhimurium. Murine peritoneal macrophages mediated phagocytic processing of viable S. typhimurium expressing fusion proteins of the HEL epitope for presentation via I-Ak regardless of the bacterial compartment in which the epitope was contained (i.e., surface exposed, facing the periplasmic space, or in the cytoplasm). Minor differences in processing efficiency observed with different epitope compartmentalizations could be overcome by altering the relative expression level, indicating that epitope abundance is an important factor for efficient processing of epitopes from S. typhimurium. This processing pathway required phagocytosis of bacteria followed by passage through an acidic compartment, suggesting a pathway involving phagolysosomal degradation of the bacteria to liberate epitopes that bind MHC-II. HEL(52-61) was processed more efficiently from heat-killed S. typhimurium than from viable bacteria, and in addition, the HEL epitope was processed more efficiently from a rough lipopolysaccharide (LPS) strain than from its isogenic smooth LPS counterpart, most likely because of enhanced phagocytosis of the rough LPS strain. These data suggest that the efficiency of epitope processing from S. typhimurium for presentation via MHC-II is affected by bacterial viability, epitope abundance, and LPS phenotype, factors which may be important to consider in development of recombinant S. typhimurium vaccine strains.
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PMID:Parameters that influence the efficiency of processing antigenic epitopes expressed in Salmonella typhimurium. 752 93

The effect of abundance and compartmentalization of antigenic epitopes expressed in Escherichia coli on phagocytic processing was studied by expressing fusion proteins containing the epitope from positions 52 to 61 of hen egg white lysozyme [HEL(52-61)], which binds the I-Ak murine major histocompatibility complex class II (MHC-II) molecule or the epitope from positions 257 to 264 of chicken egg ovalbumin [OVA(257-264]), which binds the Kb murine MHC-I molecule. Epitopes expressed as fusion proteins in the outer membrane protein LamB allowed exposure of the epitopes either at the bacterial surface, in the periplasmic space, or in the cytoplasm. Regardless of epitope compartmentalization within the bacterium, MHC-II-restricted or MHC-I-restricted presentation to T hybridoma cells occurred after macrophages phagocytosed bacteria producing the HEL(52-61) epitope or the OVA(257-264) epitope, respectively. Increased epitope abundance within a given microbial compartment resulted in increased processing and presentation to epitope-specific T hybridoma cells. Minor differences in the efficiency of epitope processing between the constructs was observed, and the HEL or OVA epitope exposed in the periplasmic space was processed most efficiently compared with the surface- or cytoplasm-localized epitopes. These differences could be overcome by increasing the amount of epitope per bacterium as little as two to five times. The minor differences in processing efficiency may be due to differing protein contexts of the epitope as well as differing epitope compartmentalizations within the bacteria. Thus, production of abundant epitope is the important parameter influencing processing of epitopes expressed in E. coli to induce T-cell responses rather than targeting of an epitope to a specific bacterial compartment.
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PMID:Compartmentalization of defined epitopes expressed in Escherichia coli has only a minor influence on efficiency of phagocytic processing for presentation by class I and class II major histocompatibility complex molecules to T cells. 769 56

We have analyzed the relative contribution of dendritic cells (DC) and B cells in the presentation of peptide-class II complexes in an inflammatory situation in vivo. Draining lymph node cells from mice immunized subcutaneously with hen egg-white lysozyme (HEL) in adjuvant display HEL peptide-major histocompatibility complex class II complexes able to stimulate, in the absence of any further antigen addition, specific T hybridoma cells. The antigen-presenting capacity of three different antigen-presenting cell (APC) populations recruited in lymph nodes, DC (N418+, class II+, B220-, low buoyant density), large B cells (B220+, low buoyant density), and small B cells (B220+, high buoyant density), was analyzed. After immunization with HEL in adjuvant, DC are the only lymph node APC population expressing detectable HEL peptide-class II complexes. These results indicate that lymph node DC and not B cells are the APC initiating the immune response in vivo after administration of antigen in adjuvant.
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PMID:Dendritic cells but not B cells present antigenic complexes to class II-restricted T cells after administration of protein in adjuvant. 864 79

Graft-versus-host disease (GVHD) is a T-cell-mediated disease of transplanted donor T cells recognizing host alloantigens. Data presented in this report show, to our knowledge, for the first time that a synthetic copolymer of the amino acids L-Glu, L-Lys, L-Ala, and L-Tyr (molecular ratio, 1.9:6.0:4.7:1.0; Mr, 6000-8500) [corrected], termed GLAT, with promiscuous binding to multiple major histocompatibility complex class II alleles is capable of preventing lethal GVHD in the B10.D2 --> BALB/c model (both H-2d) across minor histocompatibility barriers. Administration of GLAT over a limited time after transplant significantly reduced the incidence, onset, and severity of disease. GLAT also improved long-term survival from lethal GVHD: 14/25 (56%) of experimental mice survived > 140 days after transplant compared to 2/26 of saline-treated or to 1/10 of hen egg lysozyme-treated control mice (P < 0.01). Long-term survivors were documented to be fully chimeric by PCR analysis of a polymorphic microsatellite region in the interleukin 1beta gene. In vitro, GLAT inhibited the mixed lymphocyte culture in a dose-dependent fashion across a variety of major barriers tested. Furthermore, GLAT inhibited the response of nylon wool-enriched T cells to syngeneic antigen-presenting cells presenting minor histocompatibility antigens. Prepulsing of the antigen-presenting cells with GLAT reduced the proliferative response, suggesting that GLAT inhibits antigen presentation.
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PMID:A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo. 864 29

Gallium arsenide (GaAs) is an intermetallic compound used in the electronics industry as a semiconductor. Acute exposure of animals to GaAs suppresses various immune functions. We investigated the effects of GaAs on immunocompetency with emphasis on macrophages. Mice were given 12.5 to 200 mg/kg GaAs i.p., and immune parameters were examined 1 or 5 days later. Chemically exposed mice did not display alteration in spienic cellular composition. Despite this, primary in vitro humoral response to sheep red blood cells by GaAs-exposed mice was inhibited in a dose-dependent manner. The ability of 5-day vehicle- or 200 mg/kg GaAs-exposed splenic macrophages to induce interleukin-2 production by antigen-specific CD4+ helper T cell hybridomas stimulated with soluble protein antigens was assessed. GaAs-exposed macrophages were less competent in eliciting T cell responses to pigeon cytochrome c and pork insulin than vehicle-exposed cells. However, GaAs-exposed macrophages activated hen egg lysozyme- and chicken ovalbumin-specific T cells as efficiently as vehicle control cells. Also, suppressed processing of cytochrome c was not observed after a 1-day exposure. Chemical exposure did not alter the expression of major histocompatibility complex class II molecules on the macrophages or their activation of T cells by peptides, which do not require processing. Therefore, GaAs causes a time- and antigen-dependent defect in antigen processing that is essential for CD4+ T cell stimulation by splenic macrophages.
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PMID:Gallium arsenide selectively suppresses antigen processing by splenic macrophages for CD4+ T cell activation. 881 8

We have previously identified an intracellular compartment involved in the association between processed lysozyme and IAk major histocompatibility complex class II molecules (called the lysozyme-loading compartment (LLC)). Here, we show that the LLC polypeptide composition analyzed by two-dimensional gel electrophoresis shares similarities with that of early endosomes, but not with that of late endosomes. The transferrin receptor, a well known marker for both early and recycling endosomes, colocalizes with IAk molecules in LLC. Moreover, both transferrin and fluid-phase markers have access to LLC after 15 min of internalization. In the presence of concanamycin B, SDS-stable dimer formation and transport of class II molecules out of LLC are impaired. In contrast, nocodazole treatment has no effect. These results suggest that LLC is a specialized compartment of the recycling pathway involved in lysozyme loading and in the targeting of lysozyme-major histocompatibility class II complexes toward the cell surface.
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PMID:Characterization of a lysozyme-major histocompatibility complex class II molecule-loading compartment as a specialized recycling endosome in murine B lymphocytes. 891 Mar 13

Previously, we reported that Chinese hamster ovary (CHO) cells transfected with murine mouse major histocompatibility complex class II genes, exhibit a unique antigen (Ag) processing defect whereby these cells are impaired in processing only Ag with disulfide bonds. Here, we examined various aspects of the intracellular reducing environment in the CHO cells to understand the underlying mechanism causing the defect. A cell hybrid generated by the fusion of CHO cells and L cell fibroblasts was used for comparison due to their competency in processing Ag. The transport pathway of cysteine within the CHO cells appeared normal. However, these cells had a significantly lower level of glutathione, a major physiological reducing thiol, compared to the cell hybrid. Treatment of the CHO cells with N-acetyl-L-cysteine did not augment their glutathione content nor their ability to process Ag. When the cell hybrid was treated with L-buthionine-(S,R)-sulfoximine (BSO), which significantly decreased their glutathione level, the hybrid poorly processed hen egg lysozyme (HEL) and ovalbumin, which have disulfide bonds. In contrast, BSO treatment did not affect the capacity of the hybrid to process pigeon cytochrome c and carboxymethylated HEL, which lack disulfide bonds. Therefore, low intracellular glutathione levels in antigen-presenting cells correlated with defective processing of Ag with disulfide bonds, indicating that this thiol may be a critical factor in regulating productive Ag processing.
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PMID:Defective antigen processing correlates with a low level of intracellular glutathione. 897 98


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