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)

Antigen processing determines the production of peptides from antigens, including allergens, and their binding to class II major histocompatibility complex (MHC-II) molecules, which stimulate T-cell responses. Our studies have addressed the cell biology and biochemistry of the MHC-II antigen processing pathway using subcellular fractionation of macrophages on Percoll density gradients, coupled with other techniques. We have isolated a high density, late endocytic antigen processing compartment, with lysosomal properties, that contains a high level of MHC-II molecules, as assessed by several techniques. Moreover, the direct formation of peptide MHC-II complexes was demonstrated within this compartment, using a T hybridoma assay for peptide MHC-II complexes present in subcellular fractions of macrophages previously exposed to the model antigen, hen's egg-white lysozyme. These observations support an important role for this compartment in the class II major histocompatibility complex antigen processing pathway.
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PMID:Antigen processing: approaches for dissecting subcellular mechanisms that form the basis for T-cell responses modulating allergic reactions. 887 Oct 49

Induction of T cell responses to an antigenic peptide that is known to bind a major histocompatibility complex molecule is a function of either the T cell receptor (TCR) repertoire or regulatory influences by CD8 or CD4 regulatory T cells. We have tested the hypothesis that a lack of 10 TCR V beta gene segments in V beta a mice may result in an incomplete repertoire of regulatory T cells involved in maintaining peripheral tolerance. Such a hole in the repertoire of regulatory cells could result in expression of T cell responses to antigenic determinants that normally remain undetected in mice with a wild-type repertoire of TCR V beta gene segments. We show here that H-2d mice respond to the peptide 74-96 of hen egg-white lysozyme (HEL) when they are of V beta a haplotype at their TCR locus. The wild-type (V beta b) H-2d mice with their complete set of 20 TCR V beta gene segments fail to respond to HEL 74-96. The 74-96-specific T cell responsiveness was revealed in the wild-type (V beta b) mice when they were treated in vivo with anti-CD8 antibody, implicating the existence of regulatory cells that prevent expression of T cell responses specific for peptide 74-96. This is a demonstration that holes in the regulatory T cell repertoire can, in certain circumstances, become beneficial to the host, for example, in susceptibility against pathogens.
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PMID:A truncated T cell receptor repertoire reveals underlying immunogenicity of an antigenic determinant. 906 21

The class II major histocompatibility complex molecule I-A(g7) is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its beta chain. To identify the requirements for peptide binding to I-A(g7) and thereby potentially pathogenic T cell epitopes, we analyzed a known I-A(g7)-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9-27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-A(g7) M12-Y20/K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-A(g7) deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-A(g7)-restricted T cell epitopes or eluted from I-A(g7). Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.
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PMID:A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice. 909 75

Covalent conjugates of hen egg lysozyme (HEL) and anti-major histocompatibility complex (MHC) class II monoclonal antibodies (mAb) were used to immunize mice intranasally. Three weeks after intranasal (IN) priming, mice responded rapidly to IN challenge with a mixture of HEL and cholera toxin (CT), by producing large titres of anti-HEL IgA and IgG1 antibody in serum, and IgA antibody in nasal secretions. No secondary response to HEL plus CT occurred in mice that received no priming or mice primed with HEL alone. The secondary serum IgG antibody response was dominated by the IgG1 subclass. HEL combined with CT adjuvant worked much better than HEL alone in producing the secondary response. Control conjugates, containing an IgG isotype-matched mAb without specificity for mouse tissues, provided poor priming. Mice expressing MHC class II molecules, to which the anti-MHC II mAb could not bind, produced a weak antibody response compared with those that expressed the appropriate. MHC class II molecule. Our results demonstrate that immunotargeting to MHC class II molecules via the IN route allows priming of the local IgA and circulating IgG antibody, and indicate that this technique is a feasible approach for delivery of subunit vaccines in the upper respiratory tract.
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PMID:Intranasal antigen targeting to MHC class II molecules primes local IgA and serum IgG antibody responses in mice. 915 36

Intravenous (i.v.) injection of high amounts of soluble proteins often results in the induction of antigen-specific tolerance or deviation to helper rather than inflammatory T cell immunity. It has been proposed that this outcome may be due to antigen presentation to T cells by a large cohort of poorly costimulatory or IL-12-deficient resting B cells lacking specific immunoglobulin receptors for the protein. However, previous studies using T cell activation in vitro to assess antigen display have failed to support this idea, showing evidence of specific peptide-major histocompatibility complex (MHC) class II ligand only on purified dendritic cells (DC) or antigen-specific B cells isolated from protein injected mice. Here we reexamine this question using a recently derived monoclonal antibody specific for the T cell receptor (TCR) ligand formed by the association of the 46-61 determinant of hen egg lysozyme (HEL) and the mouse MHC class II molecule I-Ak. In striking contrast to conclusions drawn from indirect T cell activation studies, this direct method of TCR ligand analysis shows that i.v. administration of HEL protein results in nearly all B cells in lymphoid tissues having substantial levels of HEL 46-61-Ak complexes on their surface. DC readily isolated from spleen also display this TCR ligand on their surface. Although the absolute number of displayed ligands is greater on such DC, the relative specific ligand expression compared to total MHC class II levels is similar or greater on B cells. These results demonstrate that in the absence of activating stimuli, both lymphoid DC and antigen-unspecific B cells present to a similar extent class II-associated peptides derived from soluble proteins in extracellular fluid. The numerical advantage of the TCR ligand-bearing B cells may permit them to interact first or more often with naive antigen-specific T cells, contributing to the induction of high-dose T cell tolerance or immune deviation.
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PMID:Antigen-unspecific B cells and lymphoid dendritic cells both show extensive surface expression of processed antigen-major histocompatibility complex class II complexes after soluble protein exposure in vivo or in vitro. 927 83

The contribution of T-cell-receptor beta-chain diversity to the T-cell antigen-specific repertoire was investigated using single-chain T-cell-receptor transgenic mice. Animals that express the rearranged beta-chain gene from a T hybridoma with specificity for a hen egg lysozyme peptide, designated HEL (85-96) were analysed for their ability to respond to a panel of diverse antigens. Transgenic mice exhibited a significantly elevated response to HEL (85-96) which was shown to be due to an increased frequency of HEL (85-96)-specific T-cell progenitors. This increased frequency of specific progenitors resulted in the ability of transgenic mice to respond to the peptide in the absence of antigen priming. Conversely, transgenic mice failed to respond to any other antigen tested. Furthermore, this apparent deficiency was associated with a significant decrease in the frequency of antigen-specific T-cell progenitors in transgenic mice. Surprisingly, the ability to launch an alloresponse was unaffected by the exclusive expression of the transgene-derived beta-chain. These results indicate that beta-chain diversity is crucial for the ability of the T-cell population to elicit a rapid and robust response to the profusion of different antigen/major histocompatibility complex (MHC) ligands potentially encountered by an individual. Furthermore, these results suggest a lesser role for beta-chain diversity in contributing to allorecognition, and support a model in which the direct recognition of peptide-mediated conformational MHC forms is the major contributor to the alloreactive response exhibited by the majority of T cells.
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PMID:Elimination of T-cell-receptor beta-chain diversity in transgenic mice restricts antigen-specific but not alloreactive responses. 930 26

Several unanswered questions in T cell immunobiology relating to intracellular processing or in vivo antigen presentation could be approached if convenient, specific, and sensitive reagents were available for detecting the peptide-major histocompatibility complex (MHC) class I or class II ligands recognized by alphabeta T cell receptors. For this reason, we have developed a method using homogeneously loaded peptide-MHC class II complexes to generate and select specific mAb reactive with these structures using hen egg lysozyme (HEL) and I-Ak as a model system. mAbs specific for either HEL-(46-61)-Ak or HEL-(116-129)-Ak have been isolated. They cross-react with a small subset of I-Ak molecules loaded with self peptides but can nonetheless be used for flow cytometry, immunoprecipitation, Western blotting, and intracellular immunofluorescence to detect specific HEL peptide-MHC class II complexes formed by either peptide exposure or natural processing of native HEL. An example of the utility of these reagents is provided herein by using one of the anti-HEL-(46-61)-Ak specific mAbs to visualize intracellular compartments where I-Ak is loaded with HEL-derived peptides early after antigen administration. Other uses, especially for in vivo tracking of specific ligand-bearing antigen-presenting cells, are discussed.
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PMID:Production, specificity, and functionality of monoclonal antibodies to specific peptide-major histocompatibility complex class II complexes formed by processing of exogenous protein. 939 Nov 17

The inflammatory cells of eleven dogs with canine granulomatous meningoencephalitis were characterized immunohistochemically. Macrophages were identified by antibodies directed against lysozyme and the DH82 antigen (expressed by cells of a malignant histiocytosis). T cells were demonstrated by CD3, CD43, and CD45R antigen, and B cells by immunoglobulin G and immunoglobulin M expression. Furthermore, staining for the major histocompatibility complex (MHC) class II antigen was evaluated. Diseased animals ranged from 1 to 9 years of age. Small and medium-sized breeds were affected predominantly. Lesions were widespread and localized mainly in the brain stem, less frequently in the cerebrum or cerebellum. Alterations were represented by perivascular cuffs, parenchymal granulomas, and leptomeningeal infiltrates. Lymphocytes and macrophages comprised the dominant cell populations; their percentage varied substantially between different animals and between sections from the same individual. Immunohistochemically, the bulk of lymphocytes were CD3 antigen-positive T cells, while only a few cells were CD43 and CD45R antigen-positive or were classified as B cells. The majority of macrophages expressed both lysozyme and DH82 antigen; however, some were positive for only one antigen. MHC class II antigen-expression, observed only within and in close proximity to the lesions, was found on all inflammatory cells, pericytes/endothelial cells, and microglia. Results were negative for canine distemper virus antigen and nucleoprotein mRNA, rabies virus antigen, fungi, bacteria, and protozoal agents. This immunomorphologic study reveals that inflammatory lesions in canine granulomatous meningoencephalitis consist of a heterogeneous population of MHC class II antigen-positive macrophages and predominantly CD3 antigen-positive lymphocytes. The data suggest a T cell-mediated delayed-type hypersensitivity of an organ-specific autoimmune disease as a possible pathogenic mechanism for this unique canine brain lesion.
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PMID:Immunohistochemical characterization of inflammatory cells in brains of dogs with granulomatous meningoencephalitis. 954 34

Forty five cases of canine cutaneous histiocytoma (CCH) were examined by immunohistology for expression and distribution of major histocompatibility complex (MHC) class II antigen in neoplastic cells. In addition, expression of lysozyme and calprotectin (leucocyte protein L1) in neoplastic cells was investigated. Furthermore, B and T lymphocytes were demonstrated by antibodies against the CD3 antigen, IgG, and IgM. Neoplastic cells showed two staining patterns for MHC class II antigen: focal juxtanuclear cytoplasmic staining and/or rim-like staining along the cell periphery. In 24 cases, a predominant or exclusive focal juxtanuclear cytoplasmic MHC class II antigen reaction in neoplastic cells, and the presence of few diffusely distributed infiltrating CD3 antigen-positive T lymphocytes were observed. Tumors with numerous neoplastic cells exhibiting staining for MHC class II antigen along the cell periphery (n = 21) showed increased inflammatory alterations, represented by disseminated and nodular infiltrations of mainly CD3 antigen-positive T cells. B cells, plasma cells, exudate macrophages, and neutrophils were rarely seen disseminated between neoplastic cells whereas their number increased within focal inflammatory infiltrates. The focal cytoplasmic reaction for MHC class II antigen in neoplastic cells might represent newly synthesized MHC class II molecules stored in vesicles, whereas staining of the cell periphery might occur due to accumulation of MHC class II molecules along the plasma membrane. The increasing expression of MHC class II molecules on the cell surface might be the decisive factor for onset and progression of tumor regression. However, the exact mechanism of priming and activation of T cells by neoplastic cells and the nature of the presented antigen are not yet known.
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PMID:Expression of major histocompatibility complex class II antigen in neoplastic cells of canine cutaneous histiocytoma. 961 64

IDDM results from the destruction of pancreatic beta-cells by autoreactive T-cells that appear to avoid deletion early in development, possibly due to improper interaction with antigen-presenting cells (APCs) resident in the thymus or periphery. In the nonobese diabetic (NOD) mouse, there exists a defect in APC function characterized by its failure to fully mature upon stimulation. The NOD mouse thus provides an excellent model for the investigation of APC dysfunction and development and how these relate to the incidence of autoimmune diabetes. We initiated studies of APC function in the NOD mouse with respect to antigen processing and presentation, using a well-characterized antigen hen egg lysozyme (HEL) and comparing it with the closely related, major histocompatibility complex (MHC) (I-Ag7) identical, diabetes-resistant mouse strain NOR. Proliferation assays comparing NOD and NOR HEL-specific T-cells demonstrated that the T-cell proliferation response of the NOD mouse to both native and denatured forms of the antigen is lower than that of NOR. When crisscross proliferation experiments were conducted using purified T-cells and irradiated spleen cells as APCs from both strains, the results demonstrated that the defect in proliferation resided in the APC compartment of activation. The levels of intracellular glutathione (GSH) were compared in splenic macrophages from NOD and NOR mice; it was found that on antigenic stimulation, NOR macrophages produced significantly more intracellular GSH than did NOD macrophages, even under hyperglycemic (50 mmol/l glucose) conditions. The lower amount of GSH seen in the NOD may result in less efficient processing of antigen, and subsequently, lower levels of T-cell activation.
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PMID:Splenic macrophages from the NOD mouse are defective in the ability to present antigen. 970 19


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