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)

A bound conformation of the antigenic decapeptide hen egg lysozyme HEL[52-61] associated to the mouse MHC class II (MHC II) I-Ak was modeled by homology with the three-dimensional structure of hemagglutinin HA[306-318]-HLA-DR1 complex. HEL peptide Tyr53 could not be aligned with the HA peptide Tyr308 because this resulted in a buried Tyr53 side chain within the I-Ak peptide-binding groove and this conflicted with this side chain being recognized by T cells. Therefore, Asp52 of HEL was fixed as the P1 anchor and aligned on Tyr308 of HA. After molecular dynamics, the modeled complex was stable even in the absence of any constraint. The peptide backbone adopted a polyproline II-like conformation with canonical hydrogen bonding between the peptide backbone and MHC II molecule. Asp52, IIe55, Gin57 and Ser60 were predicted to be deeply buried into P1, P4, P6 and P9 MHC II pockets, and Tyr53, Leu56, Asn59 and Arg61 as TCR contacting residues. The modeling of 15 complexes associating I-Ak with peptides derived from HEL[52-61] by single amino acid substitution proved stable with conserved hydrogen bonds and side chain orientation compatible with their recognition by two T cell hybridomas. Moreover, comparison with the recently solved crystal structure of the related HEL[50-62]-I-Ak complex revealed striking similarities.
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PMID:Molecular modeling of hen egg lysozyme HEL[52-61] peptide binding to I-Ak MHC class II molecule. 988 96

The current studies were carried out to examine the basis for the differences in the antigenic peptides generated from exogenous and endogenous forms of hen egg white lysozyme (HEL). The role of different intracellular compartments in the generation and binding of HEL peptides derived from two endogenous forms of HEL, either secreted (sHEL) or retained in the endoplasmic reticulum (ER, KDELHEL), presented by MHC class II molecules was examined and compared to exogenous HEL. Initially it was found that antigen-presenting cells bearing both intracellular forms of HEL generated and presented a number of IAk-restricted HEL epitopes to T cell hybridomas, although sHEL was processed more efficiently than KDEL-HEL. There were differences, however, for some determinants between endogenous and exogenous HEL. At equivalent antigen-presenting efficiencies, endogenous HEL-bearing cells displayed a lower surface density of IAk-bound HEL-52-61-related peptides than cells pulsed with exogenous HEL, as detected by a specific monoclonal antibody. Neither endogenous HEL degradation nor peptide binding to MHC class II molecules occurred in the ER. Processing of sHEL and KDELHEL appears to take place either in a post-trans-Golgi network acidic compartment or in the cytosol, whereas peptide binding to MHC class II molecules occurs in endocytic compartments. Furthermore, the peptides generated were derived from an endogenous source rather than from secreted and re-endocytosed HEL. Thus, processing of endogenous HEL is from a different pool than exogenous HEL and occurs in different compartments.
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PMID:Endogenous and exogenous forms of the same antigen are processed from different pools to bind MHC class II molecules in endocytic compartments. 993 93

The 3A9 transgenic mouse line carries the rearranged TCR genes from a T cell hybridoma that recognizes hen egg lysozyme peptide 46-61 in the context of MHC class II Ak molecules. As expected, positive selection of immature 3A9 thymocytes to become mature CD4+ 8- T cells was efficient on the "selecting" CBA (H-2k) genetic background but not on the "non-selecting" C57BL/6 (H-2b) background. Surprisingly, positive selection was also inefficient on the CBA x C57BL/6 F1 background (H-2kb). We present evidence that expression of A(beta)b molecules on thymus epithelium (in conjunction with A(alpha)b or A(alpha)k molecules) inhibits the positive selection of 3A9 thymocytes mediated by A(alpha)k:A(beta)k complexes, in a process evocative of peptide antagonism of mature T cells.
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PMID:Inhibition of thymocyte positive selection by natural MHC: peptide ligands. 1006 54

The intracellular sites in which Ags delivered by the B cell receptor (BCR) are degraded and loaded onto class II molecules remain poorly defined. To address this issue, we generated wild-type and invariant chain (Ii)-deficient H-2k mice bearing BCR specific for hen egg lysozyme. Our results show that, 1) unlike Ags taken up from the fluid phase, Ii is required for presentation of hen egg lysozyme internalized through the BCR in a manner independent of the peptide analyzed; 2) BCR ligation induces intracellular accumulation of MHC class II molecules only in Ii-positive B cells; and 3) these class II molecules reach intracellular compartments where BCR targets exogenous Ag. No differences in expression of adhesion and costimulatory molecules or in the presentation of soluble peptides were detectable between Ii-positive and -negative B cells. Therefore, the BCR delivers its ligand to compartments containing MHC class II-Ii complexes and bypasses the Ii-independent presentation pathway. The linked roles of Ag internalization and B cell activation of the BCR leads to potent Ii-dependent presentation in splenic B cells.
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PMID:Engagement of B cell receptor regulates the invariant chain-dependent MHC class II presentation pathway. 1007 88

Exogenous Ags taken up from the fluid phase can be presented by both newly synthesized and recycling MHC class II molecules. However, the presentation of Ags internalized through the B cell receptor (BCR) has not been characterized with respect to whether the class II molecules with which they become associated are newly synthesized or recycling. We show that the presentation of Ag taken up by the BCR requires protein synthesis in splenic B cells and in B lymphoma cells. Using B cells transfected with full-length I-Ak molecules or molecules truncated in cytoplasmic domains of their alpha- or beta-chains, we further show that when an Ag is internalized by the BCR, the cytoplasmic tails of class II molecules differentially control the presentation of antigenic peptides to specific T cells depending upon the importance of proteolytic processing in the production of that peptide. Integrity of the cytoplasmic tail of the I-Ak beta-chain is required for the presentation of the hen egg lysozyme determinant (46-61) following BCR internalization, but that dependence is not seen for the (34-45) determinant derived from the same protein. The tail of the beta-chain is also of importance for the dissociation of invariant chain fragments from class II molecules. Our results demonstrate that Ags internalized through the BCR are targeted to compartments containing newly synthesized class II molecules and that the tails of class II beta-chains control the loading of determinants produced after extensive Ag processing.
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PMID:Presentation of antigens internalized through the B cell receptor requires newly synthesized MHC class II molecules. 1009 96

The establishment of CD4(+) T cell tolerance requires that self-reactive thymocytes are negatively selected during thymic development. A threshold of antigen concentration appears to exist for both MHC class I- and class II-mediated negative selection, below which clonal deletion of a self-reactive transgenic TCR does not occur. Similarly, both the specificity and thymic concentration of MHC molecules affect the efficiency with which autoreactive thymocytes are deleted. However, this threshold for MHC class II concentration has not been well established. Here, we show that this threshold must be extraordinarily low. We have used the human lysozyme promoter to re-express an A(beta)(b) cDNA on macrophages and other phagocytic myelomonocytic cells of class II-deficient A(beta)(b) -/- mice. Surface expression of I-A(b) could be detected on mature peritoneal macrophages and, minimally, on thymic dendritic cells; however, this level of expression was not sufficient for antigen-specific T cell activation. Nevertheless, when backcrossed onto an autoreactive K14 background, this minimal level of class II was sufficient to induce negative selection of a polyclonal self-reactive population. We conclude that provision of extremely low levels of class II to thymic dendritic cells confers on them the ability to mediate clonal deletion of autoreactive T cells.
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PMID:A minimal level of MHC class II expression is sufficient to abrogate autoreactivity. 1042 87

The Ag processing and structural requirements involved in the generation of a major T cell epitope from the hen egg-white lysozyme protein (HEL74-88), containing two cysteine residues at positions 76 and 80, were investigated. Several T cell hybridomas derived from both low responder (I-Ab) and high responder (I-Ak) mice recognize this region. These hybridomas are strongly responsive to native HEL, but unresponsive to the reduced and carboxymethylated protein. Air-oxidized HEL74-88 peptide was unable to bind I-Ak molecules and failed to stimulate T cells in the absence of intracellular Ag processing. Further functional competition assays showed that alkylation of cysteine residues with bulky methyl groups interferes with the contacts for the MHC class II molecules (I-Ak) of high responder mice and the I-Ab-restricted TCR of low responder mice. Serine substitutions of the cysteine residues of HEL74-88 either enhanced or abrogated T cell stimulation by the peptides without significant alterations in the class II binding. These results suggest that the cysteine residues of peptides must be free from disulfide bonding for efficient stimulation of T cells and yet frequently used modifications of cysteine residues may not be suitable for peptide-based vaccine development.
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PMID:Processing and reactivity of T cell epitopes containing two cysteine residues from hen egg-white lysozyme (HEL74-90). 1065 24

During their final differentiation or maturation, dendritic cells (DCs) redistribute their major histocompatibility complex (MHC) class II products from intracellular compartments to the plasma membrane. Using cells arrested in the immature state, we now find that DCs also regulate the initial intracellular formation of immunogenic MHC class II-peptide complexes. Immature DCs internalize the protein antigen, hen egg lysozyme (HEL), into late endosomes and lysosomes rich in MHC class II molecules. There, despite extensive colocalization of HEL protein and MHC class II products, MHC class II-peptide complexes do not form unless the DCs are exposed to inflammatory mediators such as tumor necrosis factor alpha, CD40 ligand, or lipoplolysaccharide. The control of T cell receptor (TCR) ligand formation was observed using the C4H3 monoclonal antibody to detect MHC class II-HEL peptide complexes by flow cytometry and confocal microscopy, and with HEL-specific 3A9 transgenic T cells to detect downregulation of the TCR upon MHC-peptide encounter. Even the binding of preprocessed HEL peptide to MHC class II is blocked in immature DCs, including the formation of C4H3 epitope in MHC class II compartments, suggesting an arrest to antigen presentation at the peptide-loading step, rather than an enhanced degradation of MHC class II-peptide complexes at the cell surface, as described in previous work. Therefore, the capacity of late endosomes and lysosomes to produce MHC class II-peptide complexes can be strictly controlled during DC differentiation, helping to coordinate antigen acquisition and inflammatory stimuli with formation of TCR ligands. The increased ability of maturing DCs to load MHC class II molecules with antigenic cargo contributes to the >100-fold enhancement of the subsequent primary immune response observed when immature and mature DCs are compared as immune adjuvants in culture and in mice.
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PMID:The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. 1072 55

The presence of potentially autoreactive T cells is a necessary, but not sufficient, condition for the development of autoimmune disease. However, the relationship between T cell response and susceptibility to disease is not straightforward. In this report, we use experimental allergic encephalomyelitis as a model to demonstrate that subtle alterations of the T cell response to an encephalitogenic epitope are sufficient to cause a dramatic decrease in disease susceptibility. Transgenic expression of a fusion protein of hen egg lysozyme and an encephalitogenic peptide of myelin basic protein (MBP) residues 84-105, coexpressed with MHC class II, causes profound tolerance to hen egg lysozyme, while maintaining a near normal response to MBP. Detailed analysis of the T cell repertoire of transgenic animals using a panel of T cell hybridomas revealed a highly selective loss of one minor component of the response to the MBP84-104 region. Despite this, transgenic animals were highly resistant to experimental allergic encephalomyelitis induction with the MBP peptide, indicating that minor changes to the T cell repertoire may result in major alterations in disease susceptibility. Possible reasons for this are discussed.
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PMID:Subtle effects on myelin basic protein-specific T cell responses can lead to a major reduction in disease susceptibility in experimental allergic encephalomyelitis. 1086 Oct 37

We have determined the crystal structure of I-Ag7, an integral component in murine type I diabetes development. Several features distinguish I-Ag7 from other non-autoimmune-associated MHC class II molecules, including novel peptide and heterodimer pairing interactions. The binding groove of I-Ag7 is unusual at both terminal ends, with a potentially solvent-exposed channel at the base of the P1 pocket and a widened entrance to the P9 pocket. Peptide binding studies with variants of the hen egg lysozyme I-Ag7 epitope HEL(11-25) support a comprehensive structure-based I-Ag7 binding motif. Residues critical for T cell recognition were investigated with a panel of HEL(11-25)-restricted clones, which uncovered P1 anchor-dependent structural variations. These results establish a framework for future experiments directed at understanding the role of I-Ag7 in autoimmunity.
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PMID:Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice. 1089 69


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