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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pyrogenic toxin (PT) family is composed of the staphylococcal enterotoxins (SE), the toxic shock syndrome toxin, and the streptococcal pyrogenic exotoxins (SPE). Whereas considerable effort has focused on characterization of PTs due to their unique biological properties, our understanding of the evolution of this gene family is incomplete. Phylogenetic relationships for members of the PT family were estimated by examining the previously reported nucleotide sequences of the genes encoding SPEA, SPEC, SEA, SEB, SEC1, SEC2, SEC3, SED, and SEE. Additionally, we present and analyze sequence data on seven previously unreported sec genes. Within the PT family, sequence divergence was partitioned in a hierarchical fashion such that mean sequence divergence ranged from 1.179 among all 16 toxin genes, 0.443 among those restricted to Staphylococcus, and 0.028 among the genes encoding 10 variants of Type C SE. Results of this study are interpreted as suggesting that the PT family consists of two large clades. One clade consists of the staphylococcal toxins SEA, SEE, and SED, being closely related to the streptococcal toxin SPEC, whereas the other clade depicts close relationships of the staphylococcal toxins SEC and SEB with the streptococcal toxin SPEA.
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PMID:Molecular evolution of the staphylococcal and streptococcal pyrogenic toxin gene family. 804 78

Macrophages from C2D transgenic mice deficient in the expression of major histocompatibility complex (MHC) class II proteins were used to identify binding sites for superantigens distinct from the MHC class II molecule. Iodinated staphylococcal enterotoxins A and B (SEA and SEB) and exfoliative toxins A and B (ETA and ETB) bound to C2D macrophages in a concentration-dependent and competitive manner. All four toxins increased F-actin concentration within 30 s of their addition to C2D macrophages, indicating that signal transduction occurred in response to toxin in the absence of class II MHC. Furthermore, ETA, ETB, SEA, and, to a lesser extent, SEB induced C2D macrophages to produce interleukin 6. Several molecular species on C2D macrophages with molecular masses of 140, 97, 61, 52, 43, and 37 kDa bound SEA in immunoprecipitation experiments. These data indicate the presence of novel, functionally active toxin binding sites on murine macrophages distinct from MHC class II molecules.
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PMID:Binding and activation of major histocompatibility complex class II-deficient macrophages by staphylococcal exotoxins. 806 7

Bacterial and retroviral superantigens (SAGs) interact with major histocompatibility complex (MHC) class II molecules and stimulate T cells upon binding to the V beta portion of the T cell receptor. Whereas both types of molecules exert similar effects on T cells, they have very different primary structures. Amino acids critical for the binding of bacterial toxins to class II molecules have been identified but little is known of the molecular interactions between class II and retroviral SAGs. To determine whether both types of superantigens interact with the same regions of MHC class II molecules, we have generated mutant HLA-DR molecules which have lost the capacity to bind three bacterial toxins (Staphylococcus aureus enterotoxin A [SEA], S. aureus enterotoxin B [SEB], and toxic shock syndrome toxin 1 [TSST-1]). Cells expressing these mutated class II molecules efficiently presented two retroviral SAGs (Mtv-9 and Mtv-7) to T cells while they were unable to present the bacterial SAGs. These results demonstrate that the binding sites for both types of SAGs can be dissociated.
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PMID:Binding sites for bacterial and endogenous retroviral superantigens can be dissociated on major histocompatibility complex class II molecules. 811 71

The in vitro response of unprimed rat T cells to retroviral and bacterial superantigens (SAg) was analyzed with TCR V beta 8.2-, 8.5-, 10-, and 16-specific mAbs. Specific stimulation of V beta 8.2 and 8.5 CD4 cells was observed in the response to Mls1a, the retroviral SAg encoded by integrated provirus Mtv-7 (Mtv-7 SAg), which was presented by mouse B cells or mouse fibroblasts transfected with DR1 genes and the Mtv-7 SAg. Additionally, a strong response of V beta 16 CD4 cells to an as yet unidentified mouse SAg was found. Only some of the bacterial SAg known to stimulate mouse and human T cells also activated rat lymph node cells. SEA, SEE, and TSST-1 stimulated rat T cells well; SEB, SEC1, and SED did not. This defect was apparently a result of weak binding to rat MHC class II molecules because presentation by human MHC class II molecules restored T cell activation. Under these conditions, SEB stimulated V beta 8.2+ and 8.5+ CD4 and CD8 cells from Lewis rats. A comparison of several rat strains revealed an unresponsiveness to SEB or Mtv-7 SAg for V beta 8.2 cells from F344 and DA rats. Determination of the nucleotide sequences of the Tcrb-V8.2 of these strains revealed differences between SAg-responsive and SAg-unresponsive Tcrb-V8.2 in seven amino acids, four of them located in the putative SAg contact site. The significance of these findings for the evolution of TCR-SAg interactions is discussed.
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PMID:Control of the rat T cell response to retroviral and bacterial superantigens by class II MHC products and Tcrb-V8.2 alleles. 815 53

Overlapping peptides corresponding to the entire Nef (HIVBRU) sequence were tested for their relative abilities to block binding of staphylococcal enterotoxins (SEs) to Raji cells. An internal sequence, Nef(123-160), blocked binding of two highly homologous SEs, SEA and SEE, while it was less effective against SEB and SEC1. Nef(123-160) bound directly class II DR antigens, as assessed by specific antibodies, and its binding was significantly inhibited by SEE, and also by SEA to a lesser degree. Purified Nef inhibited specific binding of SEA to Raji cells in a dose-dependent manner. Nef induced IL 2 production and proliferation by human mononuclear cells. Definitive expansion of specific V beta T cell populations was not observed, possibly due to lesser mitogenic activity of Nef relative to SEs. Thus, Nef may have mitogenic activity similar to that of superantigens.
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PMID:Identification of an HIV-1 Nef peptide that binds to HLA class II antigens. 817 82

The biological effects of staphylococcal enterotoxins (SE), potentiated by bacterial lipopolysaccharide (LPS), were studied with mice. Control animals survived the maximum dose of either SE or LPS, while mice receiving both agents died. SEA was 43-fold more potent than SEB and 20-fold more potent than SEC1. The mechanism of toxicity was further examined with transgenic mice deficient in major histocompatibility complex class I or II expression. Class II-deficient mice were resistant to SEA or SEB. However, class I-deficient animals were less susceptible to SEA (30% lethality) than wild-type mice (93% lethality). In vitro stimulation of T cells from the three mouse phenotypes by SEA correlated well with toxicity. T cells from transgenic or wild-type mice were similarly responsive to SEA when presented by irradiated, wild-type mononuclear cells. These data confirmed that the toxicity of SE was mainly exerted through a mechanism dependent on the expression of major histocompatibility complex class II molecules. Toxicity was also linked to stimulated cytokine release. Levels in serum of tumor necrosis factor alpha, interleukin-6, and gamma interferon peaked 2 to 4 h after the potentiating dose of LPS but returned to normal within 10 h. Concentrations of interleukin-1 alpha were also maximal after 2 h but remained above the background for up to 22 h. Relative to the levels in mice given only SEA or LPS, the levels in serum of tumor necrosis factor alpha, interleukin-6, and gamma interferon increased 5-, 10-, and 15-fold, respectively, after injections of SEA plus LPS. There was only an additive effect of SEA and LPS on interleukin-1 alpha concentrations.
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PMID:Toxicity of staphylococcal enterotoxins potentiated by lipopolysaccharide: major histocompatibility complex class II molecule dependency and cytokine release. 822 6

Bacterial superantigens have two immunologically important features. They bind MHC class II molecules and stimulate T cells bearing certain V beta TCR phenotypes. Superantigens such as SEA, SEB, and TSST bind to each of the three HLA class II isotypes (DR, DQ, and DP). Allotypic variation seems to play an important role in superantigen binding to class II molecules, but the functional implications of these differences remain largely unknown. In the present investigation, we studied the effects of SEA, SEB, and TSST on allostimulation of HLA-DR-, DQ-, and DP-allospecific T-cell clones. To avoid direct stimulation of T-cell responses by the superantigens, SEA and/or SEB nonresponsive T-cell clones were selected. We show that SEA strongly inhibited DQ- and DP-specific T-cell responses. In contrast, SEB and TSST had only weak inhibitory effects. DR-specific T-cell responses were unaffected or only weakly inhibited by the superantigens tested. The inhibition appeared not to be due to induction of cytotoxicity or suppression of either T cells or EBV-LCLs by SEA. In conclusion, the bacterial superantigen SEA can block alloantigen-specific stimulation of T clones in vitro. These results suggest that SEA binds to certain MHC class II molecules in a way that prevents MHC-TCR interactions.
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PMID:Inhibition of allostimulated HLA-DQ and DP-specific T cells by staphylococcal enterotoxin A. 832 Jan 32

Staphylococcal enterotoxins (SEs) are known superantigens for T cells expressing the alpha beta T-cell receptor (TCR). They bind to MHC class II molecules on antigen-presenting cells and can subsequently trigger T-cell responses by binding to V beta-gene products. The reactivity of gamma delta T cells with enterotoxins is less well defined although both proliferative and cytotoxic responses have been described. In the present study we have tested the cytotoxic reactivity of a panel of 41 gamma delta T-cell clones against target cells coated with the enterotoxins SEA, SEB, SEC1, SEC2, SEC3, SED, SEE or TSST. Three reaction patterns were observed with the gamma delta T-cell clones: (1) clones that specifically lysed SEA-coated target cells only; (2) clones that specifically lysed SEE-coated target cells only, and (3) clones that specifically lysed SEA-coated target cells only in the presence of certain human sera. The presence of SEA-specific antibodies in such human sera could be demonstrated. Moreover, gamma delta T-cell clones of this third category expressed the IgG FcRIII (CD16) which indicates that these clones are capable of mediating antibody-dependent cellular cytotoxicity towards SEA-coated target cells. Thus, the cytotoxic response of gamma delta T cells to SEs is mediated by two distinct pathways: an antibody-independent and an antibody-dependent pathway. The antibody-independent reactivity of gamma delta T cells was directed to either SEA or SEE, whereas antibody-dependent reactivity was found only towards SEA. The capacity of gamma delta T-cell clones to respond to stimulation with SEs, combined with their high cytolytic capacity in vitro, suggests that these cells can be involved in SE-directed immune responses and efficiently kill SE-coated target cells in vivo.
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PMID:Reactivity of human gamma delta T cells to staphylococcal enterotoxins: a restricted reaction pattern mediated by two distinct recognition pathways. 832 63

This study examined the emetic activity of several staphylococcal enterotoxin type A and B (SEA and SEB, respectively) mutants that had either one or two amino acid residue substitutions. New sea gene mutations were constructed by site-directed mutagenesis; gene products were obtained with glycine residues at position 25, 47, 48, 81, 85, or 86 of mature SEA. Culture supernatants from Staphylococcus aureus RN4220, or derivatives containing either sea or a sea mutation, were analyzed for the ability to stimulate proliferation of murine splenocytes, as determined by incorporation of [3H]thymidine. Culture supernatants containing SEA-N25G (a SEA mutant with a substitution of glycine for the asparagine residue at position 25), SEA-F47G, or SEA-L48G did not stimulate T-cell proliferation, unlike supernatants containing the other substitution mutants. Purified preparations of SEA-N25G had weak activity and those of SEA-F47G and SEA-L48G had essentially no activity in the T-cell proliferation assay. All mutants except SEA-V85G, which was degraded by monkey stomach lavage fluid in vitro, were tested for emetic activity. SEA-C106A and two SEB mutants, SEB-D9N/N23D and SEB-F44S (previously referred to as BR-257 and BR-358, respectively), whose construction and altered immunological properties have been reported previously, were also tested in the emetic assay. Each mutant was initially administered intragastrically at doses of 75 to 100 micrograms per animal; if none of the animals responded, the dose was increased four-to fivefold. SEA-F47G, SEA-C106A, and SEB-D9N/N23D were the only mutants that did not induce vomiting at either dose tested; these three mutants had reduced immunological activity. However, there was not a perfect correlation between immunological and emetic activities; SEA-L48G and SEB-F44S retained emetic activity, although they had essentially no T-cell-stimulatory activity. These studies suggest that these two activities can be dissociated.
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PMID:Lack of complete correlation between emetic and T-cell-stimulatory activities of staphylococcal enterotoxins. 833 47

Staphylococcal enterotoxins (SEs) are one member of a unique group of molecules known as superantigens. They are potent T-cell activators and stimulate a large number of T cells bearing specific T-cell-receptor beta-chain variable regions. It has been proposed that superantigens may trigger autoimmune disorders by stimulation of autoreactive T cells with restricted beta-chain variable-chain usage. We investigated the effects of SEs B and A (SEB and SEA) on the reactivation of experimental allergic encephalomyelitis, an animal model for multiple sclerosis. We report that SEB can reinduce encephalitis multiple times in PL/J mice that had previously recovered from an acute episode. SEB was also able to induce encephalitis in mice previously immunized with myelin basic protein but did not show clinical signs of disease. In addition, it was observed that T cells from PL/J mice that had been previously activated by myelin basic protein in complete Freund's adjuvant or in complete Freund's adjuvant alone were resistant to the induction of anergy by SEB. To determine whether reactivation of experimental allergic encephalomyelitis was specific for SEB, another superantigen, SEA, was employed. It was found that SEA was also able to reinduce experimental allergic encephalomyelitis in mice previously recovered from an acute episode and those that had been previously immunized with myelin basic protein but did not show clinical signs of disease. These results indicate that SEs are capable of reactivating autoreactive T cells and inducing autoimmune disease.
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PMID:Staphylococcal enterotoxins can reactivate experimental allergic encephalomyelitis. 837 29


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