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)

In a serological laboratory with a routine service for determining autoantibodies to human neutrophils, antibodies giving a selective or preferential reaction with the nucleus or perinuclear area of neutrophils are not uncommon. The aim of this study was to look for clinical correlates with the presence of such neutrophil-reactive autoantibodies. The specificity of such antibodies for nuclear or cytoplasmic antigens was studied in 65 consecutive sera displaying nuclear/perinuclear reactivity at a titre of at least 80 using the indirect immunofluorescence technique (IIF) on ethanol-fixed leucocytes. The sera were also investigated by IIF on formalin-acetone fixed leucocytes and on HEp-2 cells. ELISA techniques were used to measure antibodies to azurophil granule constituents (ANCA), purified myeloperoxidase (MPO-ANCA), and lactoferrin (LF-ANCA). Furthermore a qualitative spot immunoassay was used for the detection of antibodies to alpha, beta, and gamma fractions, and the nuclear fraction of neutrophils, purified proteinase 3 (PR3), MPO, enolase, lysozyme, elastase, lactoferrin, and cathepsin G. The diagnoses linked to such GS-ANA/pANCA positivity were arthritides, vasculitides, inflammatory bowel disease and chronic hepatic conditions. MPO was the main antigen recognized in the vasculitis group, but apart from that, rather limited antigen reactivity was demonstrable by these techniques, lysozyme being the most frequently recognized autoantigen in patients with arthritides. Human lymphocytes served as a suitable control substrate when distinguishing between GS-ANA/pANCA and ANA, whereas HEp-2 cells usually could not be used if both classes of antibodies were present in a sample. Furthermore, formalin-acetone fixation is not recommended for routine use.
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PMID:Clinical correlates and substrate specificities of antibodies exhibiting neutrophil nuclear reactivity--a methodological study. 749 88

The recessive mouse mutations lpr and gld create deficiencies in an interacting pair of cell surface molecules, CD95 (Fas/APO-1) and Fas-ligand (FasL), respectively, resulting in autoantibody production resembling human systemic lupus erythematosus. The mechanisms of self-tolerance affected by deficiency in either molecule are not established, but CD95 deficiency both in B cells and in CD4+ T cells recognizing major histocompatibility complex (MHC) class II molecules is required for autoimmunity in lpr mice. Here we track the outcome of in vivo interactions between B cells and CD4+ T cells that recognize a transgene-encoded autoantigen, hen egg lysozyme (HEL), using cells from mice transgenic for immunoglobulin and T-cell receptor (TCR) genes. B cells that had not previously encountered HEL autoantigen (naive cells) were triggered into proliferation and antibody production upon interaction with antigen and HEL-specific CD4+ T cells. By contrast, B cells that had been chronically exposed to HEL during their development and carried desensitized surface immunoglobulin (sIg) antigen receptors (anergic cells) did not produce antibody but instead were eliminated in the presence of HEL-specific CD4+ T cells. CD95-deficient anergic B cells, however, were not eliminated by CD4+ T cells and were triggered to proliferate. These findings identify a novel regulatory step for eliminating autoreactive B cells that seems unique in its dependence on CD95.
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PMID:CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. 760 71

Mice homozygous for the lymphoproliferation (lpr) mutation, which disrupts expression of the Fas cell surface molecule, develop an autoimmune syndrome with a spectrum of autoantibodies resembling human SLE. It is not known how the loss of Fas leads to autoantibody production. To study the fate of autoreactive B cells in lpr/lpr mice, C57BL/6 (B6) strain transgenic mice expressing hen egg lysozyme (HEL) as a model autoantigen in soluble or membrane-bound forms and carrying HEL-specific Ig (Ig) transgenes were mated onto the congenic B6-lpr/lpr background. Despite the absence of Fas, elimination of self-reactive lpr/lpr B cells recognizing membrane-bound autoantigen occurred as efficiently as in autoreactive B cells bearing the wild-type (+/+) Fas gene. Functional inactivation of autoreactive B cells binding soluble HEL also occurred normally in most young lpr/lpr animals. Nevertheless, breakdown of B cell tolerance to soluble lysozyme occurred in one of eight young lpr/lpr animals and in four of seven old animals with lymphadenopathy. Interestingly, the presence of the rearranged Ig transgenes markedly delayed the onset of lymphadenopathy. These results demonstrate that Fas is not an essential molecule in the biochemical pathways mediating autoreactive B cell elimination or inactivation. The breakdown of tolerance observed in a considerable fraction of older animals nevertheless confirms that autoantibody production in this model of SLE involves a defect in active censoring of autoreactive B cells. The possible basis for that defect is discussed.
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PMID:Effects of the lpr mutation on elimination and inactivation of self-reactive B cells. 807 85

Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2-dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Th1 cytokines (interleukin[IL]-2 and interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Th1-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Th1 to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1 mediated autoimmune diseases.
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PMID:Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity. 866 87

Elimination of self-reactive B cells must be balanced against the need for B-cell diversity for antibody responses to pathogens. To analyse factors that determine the extent of B-cell negative selection, we crossed CD45-deficient mice with mice carrying immunoglobulin transgenes specific for hen egg lysozyme (HEL). CD45 positively regulates antigen-receptor signalling and CD45-deficient HEL-specific B cells gave diminished signalling in response to HEL. Significantly, few mature CD45-/- B cells accumulated, despite normal immature B-cell production. Circulating HEL autoantigen mediates negative selection of mature CD45+/+ HEL-binding B cells but, in striking contrast, the autoantigen positively selected CD45-/- HEL-binding B cells, promoting their accumulation as long-lived IgD(hi) cells. These findings are consistent with a signal-threshold model for B-cell selection and demonstrate that changes in antigen receptor signalling can cause high-affinity self-reactive B cells to be actively retained instead of eliminated, thus revealing a potential mechanism for inherited susceptibility to autoimmune disease.
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PMID:Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. 869 71

The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.
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PMID:CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. 938 90

Graves' Disease results from the production of autoantibodies against receptors for thyroid stimulating hormone (TSH) on thyroid epithelial cells, and represents the prototype for numerous autoimmune diseases caused by autoantibodies that bind to organ-specific cell membrane antigens. To study how humoral tolerance is normally maintained to organ-specific membrane antigens, transgenic mice were generated selectively expressing membrane-bound hen egg lysozyme (mHEL) on the thyroid epithelium. In contrast to the deletion of autoreactive B cells triggered by systemic mHEL (Hartley, S.B., J. Crosbie, R. Brink, A.B. Kantor, A. Basten, and C.C. Goodnow. 1991. Nature. 353:765-769), selective expression of mHEL autoantigen on thyroid cells did not trigger elimination or inactivation of circulating HEL-reactive B cells. These results provide evidence that tolerance is not actively acquired to organ-specific antigens in the preimmune B cell repertoire, underscoring the importance of maintaining tolerance to such antigens by other mechanisms. The role of an intact endothelial barrier in sequestering organ-specific antigens from circulating preimmune B cells is discussed.
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PMID:Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells. 939 69

In mice with a diverse B cell repertoire, hen egg lysozyme (HEL) autoantigen-binding B cells are excluded from follicles and eliminated in 3 days. To explore the roles of competitor B cells and of T cells in this mechanism of self-tolerance, HEL-specific B cells were transferred into mice containing HEL and deficient in endogenous B cells (muMT), T cells (TCR-/-), or B and T cells (RAG1-/-). Previous studies suggested a dual requirement for B cell receptor (BCR) engagement and competition in HEL autoantigen-binding B cell elimination, but interpretation of these experiments has been confounded by the possible failure to independently regulate autoantigen concentration and competitor B cell frequency. In experiments in this study, we have fixed one variable, HEL concentration, while varying the second, the presence or absence of other B cells. By this approach, we find that follicular exclusion and rapid elimination of autoreactive B cells require BCR engagement plus competition with other B cells, rather than BCR engagement alone. We also find, by transfers into T cell-deficient mice, that T cells are not required for this peripheral tolerance mechanism. Unexpectedly, in mice lacking both T cells and competitor B cells (RAG1-/-), transferred HEL-binding cells survive less well than in mice just lacking competitor B cells. These results suggest T cells can enhance autoreactive B cell survival. Enhanced survival of autoreactive B cells, due to the presence of T cells and the lack of competitor B cells, might contribute to the elevated frequency of autoimmunity in B cell-deficient individuals.
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PMID:Follicular exclusion and rapid elimination of hen egg lysozyme autoantigen-binding B cells are dependent on competitor B cells, but not on T cells. 988 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

This study addresses the issue of the effect of immunomodulating therapies in the target organ-the central nervous system (CNS)-in the case of multiple sclerosis. Copolymer 1 (Cop 1, Copaxone, glatiramer acetate), an approved drug for the treatment of multiple sclerosis, is a potent inducer of Th2 regulatory cells in both mice and humans. Highly reactive Cop 1-specific T cell lines that secrete IL-4, IL-5, IL-6, IL-10, and transforming growth factor-beta in response to Cop 1 and crossreact with myelin basic protein (MBP) at the level of Th2 cytokine secretion were established from both brains and spinal cords of Cop 1-treated mice. In contrast, no reactivity to the control antigen lysozyme could be obtained in lymphocytes isolated from CNS of mice injected with lysozyme. Adoptively transferred labeled Cop 1-specific suppressor cells were found in brain sections 7 and 10 days after their injection to the periphery, whereas lysozyme-specific cells were absent in the CNS. Hence, Cop 1-induced Th2 cells cross the blood-brain barrier and accumulate in the CNS, where they can be stimulated in situ by MBP and thereby exert therapeutic effects in the diseased organ. This therapeutic effect was manifested, in brains of experimental autoimmune encephalomyelitis-induced mice, by a decrease in the inflammatory cytokine interferon-gamma and by secretion of the anti-inflammatory cytokine IL-10 in response to the autoantigen MBP.
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PMID:Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. 1102 47


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