Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.17 (lysozyme)
 21,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B-cell tolerance to soluble protein self antigens such as hen egg lysozyme (HEL) is mediated by clonal anergy. Anergic B cells fail to mount antibody responses even in the presence of carrier-primed T cells, suggesting an inability to activate or respond to T helper cells. To investigate the nature of this defect, B cells from tolerant HEL/anti-HEL double-transgenic mice were incubated with a membrane preparation from activated T-cell clones expressing the CD40 ligand. These membranes, together with interleukin 4 and 5 deliver the downstream antigen-independent CD40-dependent B-cell-activating signals required for productive T-B collaboration. Anergic B cells responded to this stimulus by proliferating and secreting antibody at levels comparable to or better than control B cells. Furthermore, anergic B cells presented HEL acquired in vivo and could present the unrelated antigen, conalbumin, targeted for processing via surface IgD. In contrast, the low immunoglobulin receptor levels on anergic B cells were associated with reduced de novo presentation of HEL and a failure to upregulate costimulatory ligands for CD28. These defects in immunoglobulin-receptor-mediated functions could be overcome in vivo, suggesting a number of mechanisms for induction of autoantibody responses.
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PMID:Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions. 751 4

Genomic clones for the human CD95 (Fas/APO-1) and CD40 genes have been isolated and 2.3 kb of the CD95 and 0.8 kb of the CD40 gene 5'-flanking regions sequenced. Comparisons of the human CD95 gene with the human CD40 and the murine CD40 and TNFR-II genes showed a low degree of sequence similarity. However, dot matrix analyses revealed conservation of two stretches between human CD95 (-387 to -362 and -288 to 261 in CD95) and murine TNFR-II genes. Additionally, TCCTCC motifs are present within 400 bp up-stream of the ATG of all genes examined. Repeated interferon-beta (IFN-beta) silencer B motifs and a lysozyme silencer 1 motif have been found in the CD95 gene at approximately -1,600 and -1,100, respectively. Sequence comparison of the 5'-flanking regions of the murine and human CD40 genes revealed the presence of a conserved AP-4 site and two SP-1 sites. CD95, CD40, and TNFR-II genes all lack classical TATA and CAAT boxes. However, a strongly increased frequency of CpG dinucleotides was found. Primer extension analysis revealed multiple transcriptional start sites in the CD95 gene, where the usage of individual start sites appeared to be cell type-specific. Functional analysis, using reporter constructs and transient transfections, identified a silencer activity residing between nucleotide positions -1,781 and -1007 and a strong enhancer region between -1,007 and -425 in the human CD95 gene. The region between -425 and -1 retained a basal promoter activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a silencer, enhancer, and basal promoter region in the human CD95 (Fas/APO-1) gene. 757 79

The specificity of antibody (Ab) responses depends on focusing helper T (Th) lymphocyte signals to suitable B lymphocytes capable of binding foreign antigens (Ags), and away from nonspecific or self-reactive B cells. To investigate the molecular mechanisms that prevent the activation of self-reactive B lymphocytes, the activation requirements of B cells specific for the Ag hen egg lysozyme (HEL) obtained from immunoglobulin (Ig)-transgenic mice were compared with those of functionally tolerant B cells isolated from Ig-transgenic mice which also express soluble HEL. To eliminate the need for surface (s)Ig-mediated Ag uptake and presentation and allow the effects of sIg signaling to be studied in isolation, we assessed the ability of allogeneic T cells from bm12 strain mice to provide in vivo help to C57BL/6 strain-transgenic B cells. Interestingly, non-tolerant Ig-transgenic B cells required both allogeneic Th cells and binding of soluble HEL for efficient activation and Ab production. By contrast, tolerant self-reactive B cells from Ig/HEL double transgenic mice responded poorly to the same combination of allogeneic T cells and soluble HEL. The tolerant B cells were nevertheless normally responsive to stimulation with interleukin 4 and anti-CD40 Abs in vitro, suggesting that they retained the capacity to respond to mediators of T cell help. However, the tolerant B cells exhibited a proximal block in the sIg signaling pathway which prevented activation of receptor-associated tyrosine kinases in response to the binding of soluble HEL. The functional significance of this sIg signaling defect was confirmed by using a more potent membrane-bound form of HEL capable of triggering sIg signaling in tolerant B cells, which markedly restored their ability to collaborate with allogeneic Th cells and produce Ab. These findings indicate that Ag-specific B cells require two signals for mounting a T cell-dependent Ab response and identify regulation of sIg signaling as a mechanism for controlling self-reactive B cells.
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PMID:Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. 829 58

Dendritic cells (DC) are the most potent APCs within the immune system. We show here that highly purified CD14(bright) peripheral blood monocytes supplemented with granulocyte-monocyte (GM)-CSF plus IL-4 develop with high efficacy (>95% of input cells) into DC. They neo-expressed CD1a, CD1b, CD1c, CD80, and CD5; they massively up-regulated CD40 (109-fold) and HLA-DQ and DP (125- and 87-fold); and significantly (>5-fold) up-regulated HLA-DR, CD4, CD11b, CD11c, CD43, CD45, CD45R0, CD54, CD58, and CD59. CD14, CD15s, CD64, and CDw65 molecules were down-regulated to background levels, and no major changes were observed for HLA class I, CD11a, CD32, CD33, CD48, CD50, CD86, CDw92, CD93, or CD97. Monocytes cultured in parallel with GM-CSF plus TNF-alpha were more heterogeneous in expression densities but otherwise similar in their surface molecule repertoire. They clearly differed, however, in their accessory cell capacity. Only GM-CSF plus IL-4-cultured cells were found to be potent stimulators in allogeneic and autologous MLR and they presented tetanus toxoid 100- to 1000-fold more efficiently than other cell populations tested. Furthermore, only cytokine-treated monocytes formed clusters with resting T cells. At variance from all these similarities between in vitro-generated monocyte-derived DC and in vivo-developing DC, the DC populations generated by us contained significant amounts of myeloperoxidase and also expressed lysozyme. At least in this respect they, thus, differ from "classical" DC types.
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PMID:Molecular and functional characteristics of dendritic cells generated from highly purified CD14+ peripheral blood monocytes. 889 15

Susceptibility to Fas-mediated apoptosis in nontolerant B cells is regulated in a receptor-specific fashion. To explore the regulation of Fas killing in tolerant, autoreactive B cells, mice doubly transgenic for hen egg lysozyme (HEL)-specific B cell receptors and soluble HEL were examined. Engagement of CD40 led to enhanced Fas expression and acquisition of sensitivity to Fas-mediated apoptosis in tolerant B cells, similar to that observed in nontolerant, receptor transgenic B cells. Engagement of surface immunoglobulin by specific (HEL) antigen failed to induce Fas resistance in tolerant B cells, in contrast to its effect on nontolerant B cells; however, cross-linking of biotinylated HEL with streptavidin induced similar levels of Fas resistance in tolerant and nontolerant B cells, which approximated the degree of Fas resistance produced by anti-Ig. Unlike surface Ig (sIg) engagement, physiological engagement of IL-4 receptors produced similar levels of Fas resistance in tolerant and nontolerant B cells. Thus, tolerant B cells differ from nontolerant B cells in the diminished capacity of surface immunoglobulin engagement to produce Fas resistance; however, tolerant B cells can be induced to become resistant to Fas-mediated apoptosis by IL-4 or by higher order cross-linking of sIg receptors.
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PMID:Tolerant B lymphocytes acquire resistance to Fas-mediated apoptosis after treatment with interleukin 4 but not after treatment with specific antigen unless a surface immunoglobulin threshold is exceeded. 950 Jul 87

Many antigens encountered by the immune system are included in complex structures such as bacteria or parasites. We previously developed an in vivo model to study the immunogenicity of particulate antigens, based on covalent linkage of proteins or peptides to 1 microm latex particles and showed that these antigens cannot be presented to MHC class II-restricted specific T cells by B cells. However, they induce strong CD4+ T cell responses when injected to mice without adjuvant. The present study demonstrates that four out of the five proteins tested did not stimulate antibody synthesis when linked to 1 microm microparticles, although a strong IgG production was induced by the same proteins administered in soluble form with adjuvant. In contrast, lysozyme and two synthetic peptides containing B and T cell viral epitopes induced strong and long-lasting specific antibody responses when linked to 1 micrometer synthetic beads. The isotypic pattern of antibodies induced by particulate lysozyme was similar to that induced by the soluble protein in alum. Studies using CD4+ T cell-depleted mice revealed that the induction of antibodies by particulate lysozyme strictly required Th cell activity. Moreover, the T-B cell cooperation involved in B cell activation by antigens linked to beads required CD40-CD40 ligand interaction. Thus, these particulate antigens provide a useful tool to study the mechanisms of induction of antibody response against complex bacterial or parasitic antigens. Moreover, they may represent attractive candidates to elaborate efficient new vaccines using short synthetic peptides.
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PMID:Activation of B cells by 1 microm particulate lysozyme or peptides: a Th-dependent pathway requiring CD40-CD40 ligand interaction. 972 97

Ag-mediated changes in B lymphocyte migration are important for normal immune function, yet the mechanisms by which these changes occur are poorly defined. Because chemokines direct many lymphocyte movements, molecules that regulate signaling by G protein-coupled chemokine receptors are likely to participate in Ag receptor-induced changes in cell migration. In this study, we have investigated the expression pattern and activity in murine B cells of members of the regulators of G protein signaling (RGS) family of molecules. We present the sequence of mouse RGS1 and describe a novel short isoform of RGS3 that we term RGS3s. Following in vivo activation by Ag, B cells rapidly up-regulate expression of RGS1 and RGS2 while simultaneously decreasing expression of RGS3 and RGS14. Anergic hen egg lysozyme autoantigen-binding B cells are also shown to have slightly elevated RGS1 and RGS2 expression. CD40 signaling, by contrast, fails to cause rapid up-regulation of RGS1 or RGS2. Using a transient transfection approach in a mature B cell line, 2PK3, we demonstrate that RGS1 and RGS3s are effective inhibitors of chemotaxis toward the lymphoid tissue chemokines stromal cell-derived factor-1, B lymphocyte chemoattractant, and EBV-induced molecule 1 ligand chemokine, whereas RGS2 has a minimal effect on migration to these chemokines. Together these findings support the conclusion that Ag-mediated changes in RGS molecule expression are part of the mechanism by which Ag receptor signaling regulates B cell migration within lymphoid tissues. The findings also suggest important roles for additional G protein-mediated events in B cell activation and tolerance.
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PMID:RGS molecule expression in murine B lymphocytes and ability to down-regulate chemotaxis to lymphoid chemokines. 1077 78

B cells and dendritic cells (DC) internalize and degrade exogenous Ags and present them as peptides bound to MHC class II molecules for scrutiny by CD4(+) T cells. Here we use an Ab specific for a processed form of the model Ag, hen egg lysozyme (HEL), to demonstrate that this protein is not efficiently presented by lymph node DC following s.c. immunization. HEL presentation by the DC can be dramatically enhanced upon coinjection of a microbial adjuvant, which appears to act by enhancing peptide loading onto MHC class II. CD40 cross-linking or the presence of a high frequency of T cells specific for HEL can similarly improve presentation by DC in vivo. For any of these activating stimuli, CD8alpha(+) DC consistently display the highest proportion of HEL-loaded MHC class II molecules. These data indicate that exogenous Ags can be displayed to T cells in lymphoid tissues by a large cohort of resident DC whose presentation is regulated by innate and adaptive stimuli. Our data further reveal the existence of a feedback mechanism that augments Ag presentation during cognate APC-T cell interactions.
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PMID:Microbial and T cell-derived stimuli regulate antigen presentation by dendritic cells in vivo. 1104 31

Murine bone marrow cultured with GM-CSF produced dendritic cells (DCs) expressing MHC class II (MHC-II) but little CD40, CD80, or CD86. Oligodeoxynucleotides (ODN) containing CpG motifs enhanced DC maturation, increased MHC-II expression, and induced high levels of CD40, CD80, and CD86. When added with Ag to DCs for 24 h, CpG ODN enhanced Ag processing, and the half-life of peptide:MHC-II complexes was increased. However, Ag processing was only transiently enhanced, and exposure of DCs to CpG ODN for 48 h blocked processing of hen egg lysozyme (HEL) to HEL(48-61):I-A(k) complexes. Processing of this epitope required newly synthesized MHC-II and was blocked by brefeldin A (BFA), suggesting that reduced MHC-II synthesis could explain decreased processing. Real-time quantitative PCR confirmed that CpG ODN decreased I-A(beta)(k) mRNA in DCs. In contrast, RNase(42-56):I-A(k) complexes were generated via a different processing mechanism that involved recycling MHC-II and was partially resistant to BFA. Processing of RNase(42-56):I-A(k) persisted, although at reduced levels, after CpG-induced maturation of DCs, and this residual processing by mature DCs was completely resistant to BFA. Changes in endocytosis, which was transiently enhanced and subsequently suppressed by CpG ODN, may affect Ag processing by both nascent and recycling MHC-II mechanisms. In summary, CpG ODN induce DC maturation, transiently increase Ag processing, and increase the half-life of peptide-MHC-II complexes to sustain subsequent presentation. Processing mechanisms that require nascent MHC-II are subsequently lost, but those that use recycling MHC-II persist even in fully mature DCs.
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PMID:CpG DNA induces maturation of dendritic cells with distinct effects on nascent and recycling MHC-II antigen-processing mechanisms. 1112 Aug 13

We have recently reported the lateral and rotational diffusion parameters for I-A(k) molecules expressing various cytoplasmic truncations (Int. Immunol. 12 (2000) 1319). We now describe the membrane dynamics of I-A(k) with various mutations in the presumed contact region between alphabeta-heterodimers in an (alphabeta)2 dimer of dimers structure. Such mutations are known to strongly affect the antigen presentation ability of these molecules (Int. Immunol. 10 (1998) 1237-1249) but cause relatively small changes in the molecular dynamics of I-A(k). Lateral diffusion coefficients of I-A(k) wild-type molecules and mutants obtained via fringe fluorescence photobleaching recovery (FPR) ranged from 1.1 to 2.3x10(-10)cm2/s at room temperature while fractional mobilities averaged 75+/-6%. For all cell types examined, treatment with either hen egg lysozyme 46-61 peptide or db-cAMP reduced the I-A(k) mobile fraction by about 10% relative to untreated cells, suggesting that these treatments may increase lateral confinement of class II in lipid rafts or cytoskeletal interactions of the molecules. Wild-type I-A(k) and mutants capable of normal or partial antigen presentation exhibited, as a group, slightly longer rotational correlation times (RCT) at 4 degrees C than did mutants inactive in antigen presentation, 14+/-4 versus 10+/-1 micros, respectively. Moreover, peptide, cAMP and anti-CD40 mAb treatment all increased rotational correlation times for fully- and partially-functional I-A(k) but not for non-functional molecules. For example, 16 h peptide treatment yielded average RCTs of 28+/-12 and 10+/-1 micros for the groups of functional and non-functional molecules, respectively. Such modulation of the dynamics of functional class II molecules is consistent with these treatments' stabilization of class II or induction of new gene expression. Measurements of fluorescence resonant energy transfer between I-A(k), though complicated by cellular autofluorescence, averaged 6+/-7% over 15 cells or treatments, a result consistent with the presence of a small fraction of I-A(k) as a dimer of dimers species. In summary, our results suggest subtle changes in the molecular motions of class II molecules correlate with a significant impact on class II function. Molecules active in antigen presentation exhibit more restricted motion in the membrane, and thus presumably more extensive intermolecular interactions, than non-functional molecules. Further, treatments, such as db-cAMP and anti-CD40, which rescue antigen presentation by partially defective mutants, appear to increase such interactions, several types of which have already been reported for class II. A more detailed understanding of these phenomena will require both more sensitive biophysical tools and a more refined model of the role of class II intermolecular interactions in antigen presentation.
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PMID:Molecular dynamics of point mutated I-A(k) molecules expressed on lymphocytes. 1141 Feb 53


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