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Crucial cytokine interactions in nitric oxide production induced by Mycoplasma arthritidis superantigen

SHIO, Marina Tiemi; OLIVIER, Martin; JANCAR, Sonia; RIBEIRO-DIAS, Fatima
Fonte: ELSEVIER SCIENCE BV Publicador: ELSEVIER SCIENCE BV
Tipo: Artigo de Revista Científica
ENG
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37.06%
Mycoplasma arthritidis causes autoimmune arthritis in rodents. It produces a superantigen (MAM) that simultaneously activates antigen presenting cells and T cells inducing nitric oxide and cytokine release. Nitric oxide is a key inducer and regulator of the immune system activation. Here, we investigated nitric oxide and cytokine production and interactions of these molecules in MAM-stimulated co-cultures of macrophages (J774A.1 cell line) with spleen lymphocytes. We found that: a) MAM-induced nitric oxide, interferon-gamma, membrane-associated tumor necrosis factor and interleukin-2 production in co-cultures of macrophages with lymphocytes from BALB/c and C3H/HePas but not from C57B1/6 mice; b) production of nitric oxide was dependent on interferon-gamma whereas that of interferon-gamma was dependent on interleukin-2 and membrane-associated tumor necrosis factor; c) these cytokines up regulated MAM-induced nitric oxide production. Unraveling the mechanisms of cell activation induced by MAM might be helpful to design strategies to prevent immune system activation by superantigens and therefore in seeking amelioration of associated immunopathologies. (C) 2008 Elsevier Masson SAS. All rights reserved.; FAPESP; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); FUNAPE/SMS/GO; FUNAPE/SMS/GO; [CNPq/470589/04-3]

Lack of evidence for superantigen activity of Toxoplasma gondii towards human T cells

Vallochi,A.L.; Yamamoto,J.H.; Schlesinger,D.; Machado,M.A.C.; Silveira,C.; Martins,M.C.; Belfort Jr.,R.; Kalil,J.; Rizzo,L.V.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/2001 EN
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37.4%
Toxoplasma gondii is an obligatory intracellular parasite whose life cycle may include man as an intermediate host. More than 500 million people are infected with this parasite worldwide. It has been previously reported that T. gondii contains a superantigen activity. The purpose of the present study was to determine if the putative superantigen activity of T. gondii would manifest towards human T cells. Peripheral blood mononuclear cells (PBMC) from individuals with no previous contact with the parasite were evaluated for proliferation as well as specific Vß expansion after exposure to Toxoplasma antigens. Likewise, PBMC from individuals with the congenital infection were evaluated for putative Vß family deletions in their T cell repertoire. We also evaluated, over a period of one year, the PBMC proliferation pattern in response to Toxoplasma antigens in patients with recently acquired infection. Some degree of proliferation in response to T. gondii was observed in the PBMC from individuals never exposed to the parasite, accompanied by specific Vß expansion, suggesting a superantigen effect. However, we found no specific deletion of Vß (or Valpha) families in the blood of congenitally infected individuals. Furthermore, PBMC from recently infected individuals followed up over a period of one year did not present a reduction of the Vß families that were originally expanded in response to the parasite antigens. Taken together...

Mouse mammary tumor viruses with functional superantigen genes are selected during in vivo infection.

Golovkina, T V; Dudley, J P; Jaffe, A B; Ross, S R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 23/05/1995 EN
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27.4%
Mouse mammary tumor virus (MMTV) encodes a superantigen that is important for viral infectivity in vivo. To determine whether superantigen function was required for infection by milk-borne MMTV, we created HYB PRO/Cla transgenic mice. These mice produced a full-length, packaged viral RNA with a frameshift mutation that caused premature termination of the superantigen protein. Young HYB PRO/Cla mice showed no deletion of their cognate V beta 14+ T cells, although they shed virus in their milk. The nontransgenic offspring of the HYB PRO/Cla mice were infected with this virus, since transgene-specific viral transcripts were detected in their mammary glands. Surprisingly, these offspring demonstrated the progressive deletion of V beta 14+ T cells characteristic of exogenous MMTV (C3H) infection. Sequence analysis demonstrated that these newly acquired viruses had reconstituted superantigen open reading frames resulting from recombination between the HYB PRO/Cla and endogenous Mtv-1 proviral RNAs. Thus, there is selection during the infection process for MMTVs with functional superantigen genes.

Antagonism of superantigen-stimulated helper T-cell clones and hybridomas by altered peptide ligand.

Evavold, B D; Sloan-Lancaster, J; Allen, P M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/03/1994 EN
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27.4%
T-cell activation by an immunogenic peptide can be antagonized by nonstimulatory analogs of that peptide. We investigated this T-cell receptor antagonism by using staphylococcal enterotoxin superantigen to stimulate hemoglobin-specific helper T (Th) cells because its activation pathway may differ from that of conventional antigen. Interestingly, superantigen activation of these Th cells was antagonized by hemoglobin peptide analogs even though agonist (superantigen) and antagonist (analog peptide) bind at different sites on the major histocompatibility complex-encoded molecule and the T-cell receptor. The antagonism appeared to be a fundamental block in T-cell activation, as phosphoinositol generation, cytokine production, and proliferation were reduced in Th1 clones, and, similarly, proliferative and cytokine responses were inhibited in Th2 cells. Even T-cell hybridoma activation (cytokine production and apoptosis) was inhibited by peptide antagonists. Furthermore, analog peptides that functioned as partial agonists for these Th cells also antagonized superantigen-induced proliferation and thus were a subset of the peptide antagonists. In summary, our results demonstrate that analogs of immunogenic peptide are potent antagonists for Th cell responses induced by superantigen as well as immunogenic peptide.

Identification of Key Amino Acids of the Mouse Mammary Tumor Virus Superantigen Involved in the Specific Interaction with T-Cell Receptor Vβ Domains

Baribaud, Frédéric; Wirth, Susanne; Maillard, Ivan; Valsesia, Sandrine; Acha-Orbea, Hans; Diggelmann, Heidi
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /08/2001 EN
Relevância na Pesquisa
27.54%
Mouse mammary tumor virus (MMTV) is a retrovirus encoding a superantigen that is recognized in association with major histocompatibility complex class II by the variable region of the beta chain (Vβ) of the T-cell receptor. The C-terminal 30 to 40 amino acids of the superantigen of different MMTVs display high sequence variability that correlates with the recognition of particular T-cell receptor Vβ chains. Interestingly, MMTV(SIM) and mtv-8 superantigens are highly homologous but have nonoverlapping T-cell receptor Vβ specificities. To determine the importance of these few differences for specific Vβ interaction, we studied superantigen responses in mice to chimeric and mutant MMTV(SIM) and mtv-8 superantigens expressed by recombinant vaccinia viruses. We show that only a few changes (two to six residues) within the C terminus are necessary to modify superantigen recognition by specific Vβs. Thus, the introduction of the MMTV(SIM) residues 314-315 into the mtv-8 superantigen greatly decreased its Vβ12 reactivity without gain of MMTV(SIM)-specific function. The introduction of MMTV(SIM)-specific residues 289 to 295, however, induced a recognition pattern that was a mixture of MMTV(SIM)- and mtv-8-specific Vβ reactivities: both weak MMTV(SIM)-specific Vβ4 and full mtv-8-specific Vβ11 recognition were observed while Vβ12 interaction was lost. The combination of the two MMTV(SIM)-specific regions in the mtv-8 superantigen established normal MMTV(SIM)-specific Vβ4 reactivity and completely abolished mtv-8-specific Vβ5...

The Superantigen Gene ypm Is Located in an Unstable Chromosomal Locus of Yersinia pseudotuberculosis

Carnoy, Christophe; Floquet, Stephanie; Marceau, Michael; Sebbane, Florent; Haentjens-Herwegh, Stephanie; Devalckenaere, Annie; Simonet, Michel
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /08/2002 EN
Relevância na Pesquisa
27.32%
Yersinia pseudotuberculosis produces YPM (Y. pseudotuberculosis-derived mitogen), a superantigenic toxin that exacerbates the virulence of the bacterium in vivo. To date, three alleles of the superantigen gene (ypmA, ypmB, and ypmC) have been described. These genes are not found in all Y. pseudotuberculosis strains and have a low GC content, suggesting their location on mobile genetic elements. To elucidate this question, the genetic environment of the superantigen-encoding genes was characterized and 11 open reading frames (ORFs) were defined. Sequence analysis revealed that the ypm genes were not associated with plasmids, phages, transposons, or pathogenicity islands and that the superantigen genes were always located in the chromosome between ORF3 and ORF4. Nonsuperantigenic strains exhibited the same genetic organization of the locus but lacked the ypm gene between ORF3 and ORF4. A new insertion sequence, designated IS1398, which displays features of the Tn3 family, was characterized downstream of the ypmA and ypmC genes. A 13.3-kb region containing the ypm genes was not found in the genome of Y. pestis (CO92 and KIM 5 strains). We experimentally induced deletion of the ypm gene from a superantigen-expressing Y. pseudotuberculosis: using the association of aph(3′)-IIIa and sacB genes...

Preferential induction of septic arthritis and mortality by superantigen-producing staphylococci.

Bremell, T; Tarkowski, A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1995 EN
Relevância na Pesquisa
27.32%
Staphylococcal enterotoxins A through D (SEA through SED) and toxic shock syndrome toxin-1 display superantigen properties, i.e., they stimulate a great fraction of T cells expressing certain T-cell receptor V beta sequences. Using a newly established rat model of septic Staphylococcus aureus arthritis, we have recently shown that an S. aureus strain producing SEA showed marked arthritogenic properties. In the present study we decided to employ another five S. aureus strains, each one producing a distinct exotoxin. Almost all rats injected with superantigen-producing strains developed arthritis. In contrast, only 20% of rats injected with an S. aureus strain lacking superantigen production displayed mild and transient arthritis. Mortality was preferentially induced among the rats inoculated with the S. aureus strains producing SEB and SED. This study emphasizes that superantigen production is an important virulence factor in the development of septic S. aureus arthritis. Differences concerning mortality between staphylococcal strains producing different exotoxins may be dependent on the degree of activation of the immune system.

A novel superantigen isolated from pathogenic strains of Streptococcus pyogenes with aminoterminal homology to staphylococcal enterotoxins B and C.

Mollick, J A; Miller, G G; Musser, J M; Cook, R G; Grossman, D; Rich, R R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1993 EN
Relevância na Pesquisa
27.32%
Streptococcus pyogenes (group A Streptococcus) has re-emerged in recent years as a cause of severe human disease. Because extracellular products are involved in streptococcal pathogenesis, we explored the possibility that a disease isolate expresses an uncharacterized superantigen. We screened culture supernatants for superantigen activity with a major histocompatibility complex class II-dependent T cell proliferation assay. Initial fractionation with red dye A chromatography indicated production of a class II-dependent T cell mitogen by a toxic shock-like syndrome (TSLS) strain. The amino terminus of the purified streptococcal superantigen was more homologous to the amino termini of staphylococcal enterotoxins B, C1, and C3 (SEB, SEC1, and SEC3), than to those of pyrogenic exotoxins A, B, C or other streptococcal toxins. The molecule, designated SSA, had the same pattern of class II isotype usage as SEB in T cell proliferation assays. However, it differed in its pattern of human T cell activation, as measured by quantitative polymerase chain reaction with V beta-specific primers. SSA activated human T cells that express V beta 1, 3, 15 with a minor increase of V beta 5.2-bearing cells, whereas SEB activated V beta 3, 12, 15, and 17-bearing T cells. Immunoblot analysis of 75 disease isolates from several localities detected SSA production only in group A streptococci...

Expression of bacterial superantigen genes in mice induces localized mononuclear cell inflammatory responses.

Dow, S W; Potter, T A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/06/1997 EN
Relevância na Pesquisa
27.62%
Bacterial superantigens are potent T cell activators, and superantigen proteins have been injected into mice and other animals to study T cell responses in vivo. When superantigen proteins are injected, however, the T cell stimulatory effects cannot be confined to specific tissues. Therefore, to target superantigen expression to specific tissues, we used gene transfer techniques to express bacterial superantigen genes in mammalian cells in vitro and in tissues in vivo. Murine, human, and canine cells transfected with superantigen genes in vitro all produced superantigen proteins both intracellularly and extracellularly, as assessed by bioassay, immunocytochemistry, and antigen ELISA. Superantigens produced by transfected eukaryotic cells retained their biologic specificity for T cell receptor binding. Intramuscular injection of superantigen plasmid DNA in vivo induced an intense intramuscular mononuclear cell infiltrate, an effect that could not be reproduced by intramuscular injection of superantigen protein. Intradermal and intravenous injection of superantigen DNA induced cutaneous and intrapulmonary mononuclear cell inflammatory responses, respectively. Thus, superantigen genes can be expressed by mammalian cells in vivo. Superantigen gene therapy represents a novel method of targeting localized T cell inflammatory reactions...

Active suppression induced by cutaneous exposure to bacterial superantigen is prevented by interleukin-12 treatment in vivo.

Saloga, J; Enk, A H; Becker, D; Bellinghausen, I; Kühn, S; Knop, J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1998 EN
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27.32%
Exposure to the bacterial superantigen staphylococcal enterotoxin B (SEB) leads to inhibition of several immune responses and the induction of regulatory cells. The aim of this study was to characterize these regulatory cells further and to investigate the effect of interleukin-12 (IL-12) on superantigen-induced suppression. For this purpose BALB/c mice were injected subcutaneously with low doses of SEB that did not deplete the SEB-reactive V beta T cells. Intravenous transfer of unseparated local-draining lymph node cells from these SEB-treated animals suppressed the proliferative response of mononuclear spleen cells of naive syngeneic recipients for at least 3 weeks. The regulatory cells did not produce the type 2 cytokines, interleukin-4 (IL-4) or interleukin-10 (IL-10), or increased amounts of transforming growth factor-beta (TGF-beta). Depletion of CD8+ or SEB-reactive V beta 7+ and V beta 8+ T cells, prior to transfer, abrogated the suppressive effect. Intraperitoneal injections of IL-12 into donors, prior to SEB treatment, prevented the induction of functional regulatory cells, and treatment of recipients with IL-12, prior to receipt of cells from SEB-treated donors, prevented the suppressive effect of regulatory cells that were already induced. The data indicate that exposure to minute amounts of superantigens directly induces superantigen-reactive and CD8+ regulatory T cells and that superantigen-induced suppression can be prevented and reversed by IL-12 treatment in vivo.

The superantigen Staphylococcus enterotoxin B induces a strong and accelerated secondary T-cell response rather than anergy.

Schultz, H; Geiselhart, A; Sappler, G; Niethammer, D; Hoffmann, M K; Dannecker, G E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1996 EN
Relevância na Pesquisa
27.32%
The primary and secondary immune response of V beta 8+ T cells to the bacterial superantigen Staphylococcus enterotoxin B was compared in BALB/c mice. Secondary responder T cells were found to up-regulate the expression of the adhesion molecule LFA-1 faster, and to enter the cell cycle earlier than primary responder T cells. Both, primary and secondary responder T cells upregulate the expression of CD2 and CD25 and turn into blast cells with superimposable time kinetics. Secondary responder T cells terminate DNA synthesis, blast formation and the upregulation of CD25 and CD2 expression earlier than primary responder T cells and become more rapidly deleted. Two days after superantigen challenge, when primary responder T cells reach peak activity in terms of DNA synthesis and blast formation, secondary responder T cells have returned to the size of microblasts and ceased to replicate their DNA. Whereas our results are consistent with the observations leading to the concept of superantigen-induced T-cell anergy, they demonstrate, by revealing the accelerated vigorous secondary T-cell response to the superantigen, that this concept requires reconsideration.

Effects of antigen presentation on superantigen-induced apoptosis mediated by Fas/Fas ligand interactions in human T cells.

Boshell, M; McLeod, J; Walker, L; Hall, N; Patel, Y; Sansom, D
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1996 EN
Relevância na Pesquisa
27.32%
Stimulation of T cells with bacterial superantigens has several distinct functional outcomes including proliferation, anergy and apoptosis. At present however, the mechanisms that dictate whether activation, anergy, or apoptosis predominate are unclear. In this study we have investigated the effects of superantigen presentation to mature superantigen-reactive human T-cell lines. Despite expressing major histocompatibility complex (MHC) class II molecules, these lines failed to proliferate in response to superantigen in the absence of antigen-presenting cells (APC) but proliferated when minimal APC were added. In the absence of APC a significant proportion of the T cells underwent apoptosis. This response was rapid, antigen dependent and largely abolished by the addition of cyclosporin A. Interestingly the response was not blocked by the addition of a number of antibodies to cell surface molecules including MHC class II and intracellular adhesion molecule-1. Using both a bioassay and messenger RNA analysis we were able to demonstrate that stimulation of these T cells with superantigen resulted in the induction of Fas-ligand expression on the T cells and furthermore, the ability of these cells to induce apoptosis was inhibited by the addition of blocking Fas antibodies as well as a Fas-Fc fusion protein. These data demonstrate that stimulation of T cells with staphylococcal enterotoxin B induces expression of Fas-ligand resulting in T-cell apoptosis; however...

Co-stimulation with B7 and targeted superantigen is required for MHC class II-independent T-cell proliferation but not cytotoxicity.

Lando, P A; Dohlsten, M; Hedlund, G; Brodin, T; Sansom, D; Kalland, T
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1993 EN
Relevância na Pesquisa
27.32%
The superantigen Staphylococcal enterotoxin A (SEA) conjugated to tumour-specific monoclonal antibodies (mAb) directs T cells to lyse tumour cells in the absence of major histocompatibility complex (MHC) class II. In contrast, the conjugate bound to MHC class II-negative tumour cells did not activate resting T cells to proliferate. The SEA-C215 mAb conjugate, when presented on the CA215 antigen-expressing Colo205 cells, required either signalling with CD28 mAb or CHO cells expressing the natural CD28 ligand, B7, to activate the T cells. The CD28/B7 co-stimulatory effect was further enhanced when the B7 and the tumour antigen were present on the same cell, decreasing the superantigen amount required for activation with a factor of 10(4). No influence of B7 was seen when the single CA215 or double CA215/B7 transfectants were used as targets for superantigen conjugate-dependent cytotoxicity. This suggests that the low affinity T-cell receptor (TcR) interaction of superantigen in the absence of MHC class II antigens is sufficient for induction of cytotoxicity but requires additional CD28/B7 signalling to result in proliferation of resting T cells.

Mutations affecting the superantigen activity of staphylococcal enterotoxin B.

Briggs, C; Garcia, C; Zhang, L; Guan, L; Gabriel, J L; Rogers, T J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1997 EN
Relevância na Pesquisa
27.32%
As a superantigen, staphylococcal enterotoxin B (SEB) possesses the ability to bind to major histocompatibility complex class II molecules and be recognized by T cells bearing certain T-cell receptor (TCR) V beta alleles. Other investigators have utilized site-specific mutagenesis to generate amino acid substitutions to identify residues that may be involved in the interaction with the TCR beta-chain. In an attempt further to define the face of the SEB molecule involved in the interaction with the beta-chain, we have employed a polymerase chain reaction (PCR)-based, site-specific mutagenesis method to generate amino acid substitutions with altered superantigen activity. Our results show that valine at position 169 appears to be involved in the function of this superantigen, since each of several substitutions at this position exhibit a significantly reduced ability to induce T-cell proliferation. Analysis of the responding T cells to the residue 169 substitution shows that the mutant toxins maintain TCR V beta selectivity. At the same time, mutation of the proximal histidine at position 166 does not alter the superantigen activity of SEB. Radiolabelled binding analysis of these H166 and V169 mutants shows that class II-binding activity is not significantly altered. When viewed in the context of other results reported in the literature...

Superantigen reactive Vβ6+ T cells induce perforin/granzyme B mediated caspase-independent apoptosis in tumour cells

Müerköster, S; Weigand, M A; Choi, C; Walczak, H; Schirrmacher, V; Umansky, V
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 04/03/2002 EN
Relevância na Pesquisa
27.46%
The endogenous viral superantigen 7 in DBA/2 mice serves as a target antigen on syngeneic ESb-MP lymphoma cells for allogeneic graft-vs-leukaemia reactive cells. Allogeneic viral superantigen 7 reactive Vβ6+ T cells are able to transfer graft-vs-leukaemia reactivity and to kill specifically viral superantigen 7+ ESb-MP tumour cells in vitro. Here we elucidate the mechanism of this superantigen specific cell lysis. Already 10 min after co-incubation with in vitro stimulated Vβ6+ T cells, viral superantigen 7+ ESb-MP tumour cells show an apoptotic phenotype (Annexin V-positivity, DNA-fragmentation). This extremely rapid type of cell death is not mediated by the death inducing ligands CD95L, TRAIL and TNF but by perforin and granzyme B. Surprisingly, neither mitochondria nor any of the known caspases appear to be involved in this type of tumour cell killing. In contrast, nitric oxide, released by activated macrophages and endothelial cells, induces in the same tumour cells another type of apoptosis which is much slower and involves mitochondria and caspase activation. A synergistic effect between the two different effector mechanisms of superantigen reactive donor cytotoxic T lymphocytes and nitric oxide releasing host macrophages and endothelial cells might explain the effective immune rejection of even advanced metastasised cancer in this graft-vs-leukaemia animal model.

Identification of Three Novel Superantigen-Encoding Genes in Streptococcus equi subsp. zooepidemicus, szeF, szeN, and szeP▿ †

Paillot, Romain; Darby, Alistair C.; Robinson, Carl; Wright, Nicola L.; Steward, Karen F.; Anderson, Emma; Webb, Katy; Holden, Matthew T. G.; Efstratiou, Androulla; Broughton, Karen; Jolley, Keith A.; Priestnall, Simon L.; Marotti Campi, Maria C.; Hughes,
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.4%
The acquisition of superantigen-encoding genes by Streptococcus pyogenes has been associated with increased morbidity and mortality in humans, and the gain of four superantigens by Streptococcus equi is linked to the evolution of this host-restricted pathogen from an ancestral strain of the opportunistic pathogen Streptococcus equi subsp. zooepidemicus. A recent study determined that the culture supernatants of several S. equi subsp. zooepidemicus strains possessed mitogenic activity but lacked known superantigen-encoding genes. Here, we report the identification and activities of three novel superantigen-encoding genes. The products of szeF, szeN, and szeP share 59%, 49%, and 34% amino acid sequence identity with SPEH, SPEM, and SPEL, respectively. Recombinant SzeF, SzeN, and SzeP stimulated the proliferation of equine peripheral blood mononuclear cells, and tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) production, in vitro. Although none of these superantigen genes were encoded within functional prophage elements, szeN and szeP were located next to a prophage remnant, suggesting that they were acquired by horizontal transfer. Eighty-one of 165 diverse S. equi subsp. zooepidemicus strains screened, including 7 out of 15 isolates from cases of disease in humans...

Negative selection by IgM superantigen defines a B cell central tolerance compartment and reveals mutations allowing escape

Duong, Bao Hoa; Ota, Takayuki; Aoki-Ota, Miyo; Cooper, Anthony Byron; Aït-Azzouzene, Djemel; Vela, José Luis; Gavin, Amanda Lee; Nemazee, David
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.4%
To analyze B lymphocyte central tolerance in a polyclonal immune system, mice were engineered to express a superantigen reactive to IgM of allotype b (IgMb). IgMb/b mice carrying superantigen were severely B cell lymphopenic, butsmall numbers of Bcells matured. Their sera contained low levels of IgG andoccasionally high levels of IgA. In bone marrow, immature B cells were normal in number, but internalized IgM and had a unique gene expression profile, compared to thoseexpressing high levels of surface IgM, including elevated recombinase activator gene expression. A comparable B cell population was defined in wild-type bone marrows, with an abundance suggesting that at steady state ∼20% of normal developing B cells are constantly encountering autoantigens in situ. In superantigen-expressing mice, as well as in mice carrying the 3H9 anti-DNA Ig heavy chain transgene, or 3H9 H along with mutation in the murine kappa deleting element RS, IgM internalization was correlated with CD19 downmodulation. CD19low bone marrow cells from 3H9;RS−/− mice were enriched in light chains that promote DNA binding. Our results suggest that central tolerance and attendant light chain receptor editing affect a large fraction of normal developing B cells.IgHa/b mice carrying the superantigen had a ∼50% loss in follicular B cell numbers...

Assessment of the Functional Regions of the Superantigen Staphylococcal Enterotoxin B

Zhang, Lily; Rogers, Thomas J.
Fonte: MDPI Publicador: MDPI
Tipo: Artigo de Revista Científica
Publicado em 22/10/2013 EN
Relevância na Pesquisa
27.4%
The functional activity of superantigens is based on capacity of these microbial proteins to bind to both the β-chain of the T cell receptor (TcR) and the major histocompatibility complex (MHC) class II dimer. We have previously shown that a subset of the bacterial superantigens also binds to a membrane protein, designated p85, which is expressed by renal epithelial cells. This binding activity is a property of SEB, SEC1, 2 and 3, but not SEA, SED, SEE or TSST. The crystal structure of the tri-molecular complex of the superantigen staphylococcal enterotoxin B (SEB) with both the TcR and class II has previously been reported. However, the relative contributions of regions of the superantigen to the overall functional activity of this superantigen remain undefined. In an effort to better define the molecular basis for the interaction of SEB with the TcR β-chain, we report studies here which show the comparative contributions of amino- and carboxy-terminal regions in the superantigen activity of SEB. Recombinant fusion proteins composed of bacterial maltose-binding protein linked to either full-length or truncated toxins in which the 81 N-terminal, or 19 or 34 C-terminal amino acids were deleted, were generated for these studies. This approach provides a determination of the relative strength of the functional activity of the various regions of the superantigen protein.

Superantigen Profiling of Staphylococcus aureus Infective Endocarditis Isolates

Chung, Jin-Won; Karau, Melissa J.; Greenwood-Quaintance, Kerryl E.; Ballard, Alessandro D.; Tilahun, Ashenafi; Khaleghi, Shahryar Rostamkolaei; David, Chella S.; Patel, Robin; Rajagopalan, Govindarajan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.4%
The frequency of superantigen production among Staphylococcus aureus isolates associated with endocarditis is not well defined. We tested 154 S. aureus isolates from definite infective endocarditis cases for the presence of staphylococcal enterotoxins A-E, H and TSST-1 by PCR, ELISA and using an HLA-DR3 transgenic mouse splenocyte proliferation assay. Sixty-three isolates (50.8%) tested positive for at least one superantigen gene, with 21 (16.9%) testing positive for more than two. tst (28.6%) was most common, followed by seb (27%), sea (22.2%), sed (20.6%), see (17.5%), and sec (11.1%). Of 41 methicillin-resistant S. aureus, 21 had superantigen genes, with sed being more frequently detected in this group compared to methicillin-susceptible S. aureus (P<0.05). Superantigen genes were not associated with mortality (P=0.81). 75% of PCR-positive isolates induced robust splenocyte proliferation. Overall, more than half of S. aureus isolates causing endocarditis carry superantigen genes of which most are functional.

Inhibierung Superantigen-induzierter T-Zellproliferation durch neue synthetische Peptide; Inhibition of superantigen-induced T-cell proliferation by new synthetic peptides

Wessels, Johannes Theodor
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
Relevância na Pesquisa
37.46%
Ziel dieser Arbeit war die Synthese neuer Peptide + deren Vergleich mit dem von Schlegel et al. beschriebenen GLAT + Kontrollen in einem Surrogatassay unter Zusatz von exogenen Superantigenen. Diese exogenen Superantigene ersetzen dabei quasi die für eine erste Welle der oligoklonalen T-Zellstimulation im Rahmen der GVHD verantwortlich scheinenden endogenen Superantigene. Dazu wurden in einem ersten Schritt die Peptide mit Hilfe der Datenbankprogramme Syfpeithi + Epipredict in ihrer Aminosäuresequenz definiert, über Fmoc-Festphasenpeptidsynthese erstellt + mittels HPLC gereinigt. In in vitro-Versuchen wurden diese Peptide unter Zugabe von Superantigenen im Assay getestet. Einige dieser definierten Peptide konnten die durch Superantigene normalerweise hervorgerufene T-Zellproliferation auf ein Minimum reduzieren + konzentrationsabhängig teilweise sogar ganz verhindern. Im Vergleich mit dem randomisierten Peptid GLAT zeigten zwei definierte Peptide bessere Inhibition. Diese Peptide besitzen beide eine an den T-Zellrezeptor bindende Sequenz mit dem Motiv YNK-KKA-TVQ-ELD. In einer bereits von G. Arad et al. (Nature Med., 2000) beschriebenen Arbeit zeigte sich ebenfalls, daß es möglich ist durch dieses Peptid eine starke Inhibition der Superantigen induzierten T-Zellproliferation in vitro zu erzielen. In in vivo Untersuchungen an Mäusen...