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)

Hypersensitivity pneumonitis (HP) and sarcoidosis are interstitial lung disorders (ILD) characterized by a lymphocytic alveolitis that, in the active phase of the disease, is sustained by different T-cell subsets, i.e., CD8+ cells in HP and CD4+ lymphocytes in sarcoid patients. To address the question of whether a bias in T-cell selection occurs in the lung of patients with HP and sarcoidosis, we analyzed the T-cell receptor beta chain variable region (TCR-Vbeta) repertoire by flow cytometry and polymerase chain reaction (PCR) analyses in blood and lung lymphocytes of 14 HP and 25 sarcoid patients. To verify whether these cells can be activated in vitro through the TCR, blood and lung lymphocytes were also assessed for their responsiveness to different superantigenic stimuli represented by staphylococcal enterotoxins, including SEA, SEB, SEC1, SEC2, SED, and SEE. Flow cytometry and PCR analyses demonstrated an overexpression of cells bearing Vbeta2, Vbeta3, Vbeta5, Vbeta6, and Vbeta8 gene segments in the lung of HP patients as compared with the peripheral blood. In sarcoid patients cells bearing Vbeta2, Vbeta5, and Vbeta6 gene segments in the lung of HP patients as compared with the peripheral blood. In sarcoid patients cells bearing Vbeta2, Vbeta5, and Vbeta6 gene segments were overrepresented in the lung rather than in the blood. Both in HP and sarcoid patients almost all T cells bearing the dominant Vbeta segment belonged to the T-cell subset that sustains the alveolitis, i.e., CD8 in HP patients and CD4 in sarcoid subjects. Follow-up studies demonstrated that the recovery of the alveolitis was characterized by the disappearance of cells bearing a limited T-cell repertoire. Interestingly, T-lymphocyte response to different superantigens demonstrated that the proliferation elicited by different staphylococcal toxins was more pronounced in the lung than in the blood. Taken together, our findings indicate a compartmentalization of cells bearing discrete Vbeta gene products in the pulmonary microenvironment and suggest that the expansion of specific Vbeta region subsets occurring in the lung might result from triggering by a specific antigen. In fact, the removal from exposure in HP patients or specific treatment in sarcoidosis resulted in the decrease of the overrepresented cell population accounting for the lymphocytic alveolitis.
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PMID:Selection of T lymphocytes bearing limited TCR-Vbeta regions in the lung of hypersensitivity pneumonitis and sarcoidosis. 903 99

Staphylococcal enterotoxin B (SEB) is a bacterial enterotoxin able to simultaneously bind to class II molecules on APCs and to selected V beta regions (including V beta 8) of the TCR complex. Administration of SEB to adult BALB/c mice results in clonal activation of T cells bearing V beta 8 receptors, leading to an excessive release of proinflammatory cytokines. This initial immune response is followed by a long-lasting state of V beta 8-specific unresponsiveness, thought to benefit both the host (as it contributes to the down-regulation of the inflammatory response) and the bacterium (through ligand-specific T cell anergy). However, it is not clear how this type of restricted unresponsiveness can effectively impair the generation of an antibacterial response. To gain insight into the mechanism by which Gram-positive bacteria subvert the host immune response, we have investigated the immune competence of SEB-treated mice 48 h following SEB administration. We demonstrate in this report that in vivo, SEB induces a transient but profound state of unresponsiveness affecting both T and Ag-presenting cell functions. Although in vivo activation by SEB appears to be V beta-restricted under our experimental conditions, SEB-treated mice displayed an early (lasting 48 to 72 h postinjection) and V beta-unrestricted unresponsive state characterized by the inability to produce IL-2 in response to polyclonal TCR mitogens including third party bacterial superantigens (staphylococcal enterotoxin A and toxic shock syndrome toxin 1, SEA and TSST-1, respectively), Abs to non-SEB reactive V beta regions (V beta 6), anti-CD3 epsilon Abs, and a lectin (Con A). Spleen cell populations from SEB-treated mice also displayed defective APC functions, possibly related to a selective decrease in splenic dendritic cells numbers. Taken together, these observations indicate that SEB induces an early and transient state of immunodeficiency in vivo, representing a potential mechanism for escaping host immune surveillance.
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PMID:Staphylococcal enterotoxin B induces an early and transient state of immunosuppression characterized by V beta-unrestricted T cell unresponsiveness and defective antigen-presenting cell functions. 905 96

In this report, we show that despite an overall amino acid residue identity of more than 80% between the staphylococcal enterotoxins (SE) A and E, these proteins markedly differ in their absolute requirement for the MHC class II during T cell activation. The superantigens were produced as C215Fab-SE fusion proteins and analyzed for their ability to activate T cells in a MHC class II-independent manner, using C215 Ag expressing cell lines as pseudo super-APCs. C215Fab-SEA, but not C215Fab-SEE, induced T cell cytotoxicity and proliferation in these MHC class II-independent systems. Introduction of a region from SEA, comprising amino acids 20-27, to SEE transferred the ability to engage T cells in the absence of MHC class II. Analysis of the Vbeta specificity of the chimeric SEA/SEE molecules and a panel of SEA mutants demonstrated that the site for TCR interaction covers the edge surrounding the shallow cavity on top of the SEA molecule.
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PMID:Functional characterization of the interaction between the superantigen staphylococcal enterotoxin A and the TCR. 912 86

Molecular techniques are becoming increasingly important in the analysis of NHL, both for diagnostic purposes and in order to evaluate prognosis accurately. The increasing number of techniques available renders evaluation of their relative roles important and a review of their informativity in NHL at diagnosis timely. Molecular equivalents of chromosomal translocations generate either a qualitative change due to the expression of a chimaeric, relatively tumour specific, protein, such as the NPM-ALK associated with the t(2;5) in ALCL or a quantitative change in the extent, stage or site of expression of a full length protein, due to its juxtapositioning to and deregulation by an Ig or TCR gene. The latter represents errors of the somatic recombination process which lymphoid precursors undergo. In NHL, this category includes BCL1/CCND1, BCL2, BCL6 and MYC. The molecular characteristics, the functional consequences and the main clinical correlations of each of these abnormalities is reviewed. At diagnosis, immunological detection of the deregulated 'protooncogene' may well provide the simplest, most appropriate screening technique for CCND1 and NPM-ALK induced ALK expression. BCL6 abnormalities demonstrate similarities to BCL2 and MYC and a combination of immunophenotypic, FISH, Southern blot and PCR techniques are useful in their characterization. For the approximately 50% of NHL without one of the above markers, identification of a clonal Ig or TCR rearrangement can provide a useful 'pan' B or T molecular equivalent, provided that the limitations of the detection techniques are appreciated. Appropriate use of these techniques will transform our ability to classify, stratify and eventually treat in a risk adapted manner, patients with NHL.
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PMID:Practical role of molecular diagnostics in non-Hodgkin's lymphomas. 913 11

We investigated the capacity of the Staphylococcal enterotoxin (SE) B, a superantigen (SAg) specific for TCR V beta domain, to modulate V beta 8+ thymocytes selection in adult mice. Thymocytes were collected at various time intervals after SEB injection (10 and 100 micrograms) and V beta 8+ modulation was analysed by three color flow cytometry. SEB failed to affect V beta 8+ thymocytes comprised in the less mature compartments, namely, CD4+8+ and CD4-CD8-, whereas it selectively affected V beta 8+CD4+8+ (downward modulation) and V beta 8+CD4-8+ thymocytes (upward modulation). The different response to SEB challenge between CD4+8- and CD4-8+ thymocytes appeared dependent on the CD4/MHC class II interaction, as V beta 8+CD4-8+ thymocytes carrying a transgenic CD4 molecule capable of interacting with MHC class II showed the same response of V beta 8+CD4+8- thymocytes. At variance with thymocytes, however, V beta 8+CD4+8- and V beta 8+CD4-8+ splenic T lymphocytes responded to SAg challenge in identical manner (upward modulation) highlighting the importance of maturation status and/or microenvironment in SAg response. V beta 8+ thymocytes remaining in the thymus were assessed for their capacity to respond to a SAg challenge. Thus, thymocytes were obtained at various time intervals after SEB injection and cultured in the presence of SEB or SEA, a Sag specific for V beta 10 as control. A reduced mitotic response to SEB but not to SEA was noticed irrespective of the number of V beta 8+ responding cells present in culture. It is concluded that SAgs affect TCR specific thymocytes by conditioning their redistribution and inducing an anergic status.
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PMID:The expression of CD4 and CD8 molecules conditions the behavior of V beta + murine thymocytes upon superantigenic challenge. 915 79

Recent experiments have elucidated two molecular mechanisms that may account for the failure of anergic T cell clones to initiate IL-2 gene transcription following TCR stimulation. First, a block has been identified in the ERK and JNK mitogen-activated protein kinase pathways; the block results from a failure to activate p21ras. It leads to reduced induction of c-Fos and JunB proteins and to a failure to form and phosphorylate the activator protein (AP)-1 heterodimers required for IL-2 gene transcriptional activation. Second, repressor molecules (Nil-2-a and a molecule related to AP-1) have been characterized that dominantly inhibit IL-2 gene transcription.
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PMID:T cell clonal anergy. 920 8

Superantigens are microbial products which bind both to the TCR beta-chain and, with moderate affinity, to MHC class II molecules. Class II-bearing cells bind the superantigen and present the superantigen to T cells expressing certain TCR beta-chain variable region alleles. We have previously reported that the superantigen staphylococcal enterotoxin B (SEB) binds with moderate affinity to the protein p85 expressed on COS-1, an African Green Monkey kidney fibroblast-like cell line. In the present report we carry out a structural analysis to examine the basis for the interaction of superantigen to p85. We show that SEC1, SEC2, and SEC3 also bind to p85 based on inhibition of the binding of radiolabeled SEB. On the other hand, SEA, SED, SEE and toxic shock syndrome toxin-1 do not exhibit detectable binding. In an effort to characterize the structural basis for the SEB binding to p85, we have generated both amino- and carboxy-terminal truncations of SEB expressed as fusion proteins with the maltose-binding protein of Escherichia coli. Our results show that the full-length SEB fusion protein and a truncation missing the 81 amino-terminal amino acids both compete successfully with native SEB for binding. On the other hand, carboxy-terminal truncations in which 19 or 34 residues are deleted both fail to compete for binding. These results are consistent with results which show that monoclonal anti-SEB antibodies specific for carboxy-terminal determinants block SEB binding to p85, but an amino-terminal mAb fails to exhibit any alteration in binding. These results suggest that residues at or near the carboxy-terminus of SEB play a role in binding to p85.
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PMID:Structural basis for the interaction of superantigen with the alternative superantigen-binding receptor p85. 922 68

We and others have shown that overexpression of SLP-76 augments TCR-stimulated IL-2 promoter activity in the Jurkat T cell line. In this report we investigate the signaling mechanisms through which SLP-76 mediates its effect on T cell activation. We show that overexpressed SLP-76 acts downstream of TCR-stimulated protein tyrosine kinases, but does not affect calcium signaling. Overexpression of SLP-76 does, however, augment TCR stimulation of both ERK (extracellular signal-regulated kinase) activity and a reporter construct driven by activating protein-1 binding sites. Structure/function analysis reveals that three distinct regions of SLP-76, each important for protein associations, are required for augmentation of TCR-induced nuclear factor-AT activity. These data suggest that SLP-76 functions as an adapter molecule that requires three unique domains to link proximal TCR signals in T cells.
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PMID:Three domains of SLP-76 are required for its optimal function in a T cell line. 925 23

Stimulation through the TCR is known to induce tyrosine phosphorylation of a number of proteins, which leads to functional activation of T cells. Identification of the substrates that become phosphorylated and defining their interactions with other signaling molecules will provide insight into the mechanisms controlling T cell activation. Focal adhesion kinase (FAK) and the recently described Pyk2 kinase are homologous members of a non-receptor protein tyrosine kinase family. FAK has been shown to become phosphorylated upon TCR stimulation, but its role, if any, in T cell activation remains to be defined. Although Pyk2 has been shown to play a role in neuronal cell activation stimulated through G-protein-coupled receptors, a role in T cell activation has not been described. In this study we show that FAK and Pyk2 are two of the major 115-to-120-kDa proteins that become tyrosine phosphorylated in T cells following TCR complex stimulation. Furthermore, coincident with the increase in tyrosine phosphorylation, we show an association of these kinases with the SH2 domain of the tyrosine kinase Lck in vivo. The increase in tyrosine phosphorylation of both FAK and Pyk2, however, occurs in Lck-deficient cells suggesting that phosphorylation of both of these kinases does not require Lck. Taken together, these results suggest that FAK and Pyk2, perhaps in coordination with Lck, play a role in T cell activation.
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PMID:T cell receptor engagement induces tyrosine phosphorylation of FAK and Pyk2 and their association with Lck. 925 37

Superantigens stimulate naive CD4+ and CD8+ T cells in a TCR V beta-specific manner. However, it has been reported that memory T cells are unresponsive to superantigen stimulation. In this study, we show that staphylococcal enterotoxins (SE) can activate influenza virus-specific CD8+ memory cytotoxic T cells. In vivo SEB challenge of mice that had recovered from influenza virus infection (memory mice) resulted in the generation of vigorous influenza-specific cytotoxic T lymphocyte (CTL) activity and in vitro SEA or SEB stimulation of splenic T cells from memory mice, but not naive mice, also induced influenza-specific CTL. Analysis of the mechanism of activation suggested that although there may be a component of cytokine-mediated bystander activation, the CTL activity is largely generated in response to direct TCR engagement by superantigen. Moreover, influenza-specific CTL could be generated from purified CD8+ CD62L loCD44hi (memory phenotype) T cells cultured in the presence of T cell-depleted splenic antigen-presenting cells and SE. Purified CD8+ memory T cells also secreted lymphokines and synthesized DNA in response to superantigen. These results definitively demonstrate that CD8+ memory T cells respond to SE stimulation by proliferating and developing appropriate effector function. Furthermore, the data raise the possibility that otherwise inconsequential exposure to bacterial superantigens may perturb the CD8+ T cell memory pool.
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PMID:Bacterial superantigens reactivate antigen-specific CD8+ memory T cells. 931 Aug 43


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