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

---

Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A patient with ataxia telangiectasia was treated with recombinant interleukin-2 (rIL-2) and the resulting immunological effects evaluated. The patient lacked IL-2 production, and immunoglobulin synthesis was also impaired. Treatment with IL-2 selectively increased serum IgM without any significant side effects. Therapy also restored B-cell function in vitro. IgM production as well as the proliferative response to Staphylococcus aureus strain Cowan I. These results suggest that IL-2 treatment may correct both T-cell and B-cell defects.
...
PMID:Administration of recombinant IL-2 augments the level of serum IgM in an IL-2 deficient patient. 266 15

We used the autologous mixed lymphocyte reaction (AMLR) to test T cell function in four patients with Ataxia-telangiectasia (AT), in 11 first-degree relatives and in 20 controls. There was a marked reduction of AMLR in the patients and in three relatives compared to the age-matched controls. In the AT patients the defect in AMLR was intrinsic to the CD4 subpopulation, since exogenous IL-2 did not improve the response of isolated CD4 cells. In contrast to normal controls, pre-incubation of autologous B cells with Epstein-Barr virus (EBV) did not enhance the reduced AMLR in the AT patients and the three first-degree relatives. We conclude that in both patients with AT and in some of their family members there is an intrinsic defect in CD4 T cells. This defect leads to diminished reactivity to EBV infected autologous B cells, and may explain in part the high incidence of malignancies observed in such families.
...
PMID:Impaired autologous mixed lymphocyte reaction (AMLR) in patients with ataxia-telangiectasia and their family members. 285 98

The expression of Fc epsilon R on human lymphocytes was studied with the anti-Fc epsilon R mAbs. Fc epsilon R was expressed on most mu+,delta+ circulating B cells, whereas T cells did not express Fc epsilon R even in patients with hyper-IgE syndrome. B cells with gamma, alpha, or epsilon phenotype did not express Fc epsilon R, moreover its expression could not be induced, suggesting that the Fc epsilon R expression was correlated with isotype switching. mu+delta+ B cells in bone marrow did not express Fc epsilon R, but PHA-sup (supernatant from PHA-stimulated cell cultures) could induce its expression, and the addition of IgE augmented this induction. Recombinant IL-2, IL-1, IFN-gamma or -beta, or purified B cell differentiation factor (BSF-2 B cell-stimulatory factor 2) could not induce Fc epsilon R expression in bone marrow B cells. IFN-gamma inhibited the Fc epsilon R expression induced by PHA-sup, suggesting that the human counterpart of BSF-1 may be responsible for Fc epsilon R expression in bone marrow B cells. B cells from patients with common variable immunodeficiency and ataxia telangiectasia did not express Fc epsilon R, but PHA-sup could induce its expression, indicating that circulating B cells of these patients are at a differentiation stage similar to B cells in bone marrow. The study showed that Fc epsilon R is a B cell-specific differentiation marker, the expression of which is restricted to a defined stage of B cell differentiation.
...
PMID:Fc epsilon receptor, a specific differentiation marker transiently expressed on mature B cells before isotype switching. 294 90

The expression of CD3 molecules by the lymphocytes of five patients with ataxia-telangiectasia was examined using the murine monoclonal antibody OKT3. By immunofluorescent staining, fewer of the patients' peripheral blood mononuclear cells and purified T cells expressed CD3 compared with normals. The proliferative response of the patients' cells to OKT3 was also less than normal. However, the mononuclear cells from all five patients produced IL-2 after OKT3 stimulation; in four patients IL-2 was normal, while one patient produced greater than normal levels. While the expression of cellular IL-2 receptors and the release of these receptors into culture supernatants was generally less in ataxia-telangiectasia patients, the levels of receptor expression were not significantly less than normal. As analysed by sodium dodecyl sulphate polyacrylamide gel electrophoresis, the CD3 molecules from ataxia-telangiectasia patients' lymphocytes were no different from those of normal individuals. These results suggest that patients with ataxia-telangiectasia have structurally normal CD3 molecules which may be used to activate cells normally for some but not all T cell functions.
...
PMID:Analysis of CD3 antigen expression in patients with ataxia-telangiectasia. 311 44

Tenascin (TN) is an extracellular matrix protein that is expressed widely in the fetus and sparingly in the adult, but reappears at high levels in certain areas of tissue insult such as tumor matrices and sites of wound healing. We show here that soluble TN inhibits proliferation of human T cells in response to alpha CD3 Ab co-immobilized with the extracellular matrix protein fibronectin (FN). TN also inhibits proliferation driven by alpha CD3/IL-2 or by phorbol ester/IL-2, and it prevents high level induction of IL-2R. The presence of TN in culture medium does not detectably alter the pattern of tyrosine phosphorylation resulting from T cell triggering with alpha CD3, but at later time points prevents the appearance of functional NF-AT1 transcription factor complexes in T cell nuclear extracts. These findings are consistent with the postulated role for TN as a natural antagonist to FN action, and suggest that T cell responses occurring at tissue sites in which TN is expressed could be influenced by its presence.
...
PMID:Inhibition of T cell activation by the extracellular matrix protein tenascin. 751 30

We have demonstrated earlier that the crosslinkage of the CD3/TCR complex with the CD2 antigen results in the proliferation of normal human T cells. The effect of this synergism was perceptible at the level of induction of the IL-2 gene, a process critical for T cell growth. To further understand the molecular and nuclear basis for this synergism, we have explored the induction of DNA-binding proteins in highly purified normal human T cells signaled via the CD3 and/or CD2 proteins. The effect of transmembrane signaling of T cells with ionomycin, and/or sn-1,2 dioctanoyl glycerol, was also determined. The emergence of nuclear binding proteins was investigated using interleukin-2 sequence specific oligonucleotide probes in the electrophoretic mobility shift assay. Our studies demonstrate for the first time that CD3 antigen-derived signals and CD2 antigen-derived signals are synergistic in inducing the emergence of transcription factors that bind to the NF-AT1, AP-1, and NF-kB sites located in the promoter/enhancer region of the IL-2 gene. Moreover, cyclosporine, at concentrations readily accomplished in clinical practice, was found to inhibit the emergence of these DNA-binding proteins in normal human T cells signaled via cell surface proteins implicated in antigen-dependent T cell activation and in T cells stimulated by mobilization of cellular calcium and activation of protein kinase C.
...
PMID:Synergism between the CD3 antigen- and CD2 antigen-derived signals. Exploration at the level of induction of DNA-binding proteins and characterization of the inhibitory activity of cyclosporine. 809 81

The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors using the common gamma-chain. Mice deficient in Jak3 have mature T cells, all of which have an activated/memory cell phenotype but are unresponsive to in vitro stimulation. Due to this activated phenotype, it has been impossible to determine whether Jak3 plays a role in the responsiveness of naive/resting T cells. To circumvent this difficulty, we generated naive/resting Jak3-negative T cells by two genetic approaches. After stimulation, these cells failed to produce significant amounts of IL-2. Although no signaling defect could be detected, we did find that naive/resting Jak3-negative T cells have substantially reduced levels of the transcription factor NF-AT1 and moderately reduced levels of c-Jun and c-Fos. On the basis of these data, we propose that Jak3-dependent cytokine signals may be required to maintain the normal levels of basal transcription factors required for immediate responsiveness to Ag activation.
...
PMID:The Jak family tyrosine kinase Jak3 is required for IL-2 synthesis by naive/resting CD4+ T cells. 1055 66

OX40 (CD134) is a member of the tumor necrosis factor (TNF) receptor superfamily first identified as a rat T cell activation marker. We previously identified the rat ligand for OX40 (OX40L) by molecular cloning. In the present study, we newly generated an anti-rat OX40L mAb (ATM-2) that can inhibit the binding of OX40 to rat OX40L and thus efficiently inhibits the T cell costimulatory activity of rat OX40L. Flow cytometric analyses using ATM-2 and an anti-rat OX40 mAb (MRC OX40) indicated that OX40 was inducible on splenic CD4(+) T cells by stimulation with immobilized anti-CD3 mAb, while OX40L was not expressed on resting or activated T cells. OX40L was expressed on splenic B cells after stimulation with lipopolysaccharide (LPS), but not on peritoneal macrophages. Interestingly, splenic dendritic cells (DC) expressed OX40L constitutively, which was further upregulated by LPS stimulation. The potent costimulatory activities of splenic DC for anti-CD3-stimulated rat CD4(+) T cell proliferation and cytokine (IL-2, IFN-gamma, IL-10, and IL-13) production were substantially inhibited by ATM-2. These results indicated that OX40L is expressed on professional antigen-presenting cells (APC), and may be involved in humoral immune responses via T-B interaction and in cellular immune responses via T-DC interaction in the rat system.
...
PMID:Characterization of rat OX40 ligand by monoclonal antibody. 1077 47

In the genetic disorder ataxia telangiectasia (AT), humoral (B) and cellular (T) immunological abnormalities are frequently observed. As a consequence, AT patients are predisposed to life-threatening sinopulmonary infections. The pathogenic mechanisms remain unknown, but a role for ATM in signal transduction from membrane receptors has been proposed. We have explored the effects of a defective ATMgene on isolated human T-lineage cells from 13 AT patients with proven T cell dysfunction by transforming their CD4(+) and CD8(+) T lymphocytes with Herpesvirus saimiri, and analyzing their signaling behavior as compared to normal controls. Several functional parameters were assayed in response to both membrane (anti-CD3 and IL-2) and transmembrane (phorbol myristate acetate plus the calcium ionophore ionomycin) stimuli: (i) calcium mobilization, (ii) induction of activation molecules (CD25, CD40 ligand, CD69 and CD71), (iii) cytokine synthesis (IL-2 and tumor necrosis factor-alpha) and (iv) proliferation. All these early and late activation events were found to be normal in the transformed ATM-/-T cells, indicating that ATM is not necessary for their induction. As expected, ATM-/- transformed T cells showed an increased radiosensitivity by both radioresistant DNA synthesis and cell survival assays. In contrast to an earlier report testing transformed B lymphocytes, our results indicate that transformed mature peripheral T lymphocytes from AT patients do not have intrinsic immune function defects. Rather, the described T-lineage signaling impairments observed in patients may be secondary in vivo to extrinsic ATM-dependent suppressive factors and/or to a developmental defect. These transformed T cells may help to understand the distinct biological role of ATM in different cell types and to develop rational therapies for the immunological dysfunction of AT patients.
...
PMID:Membrane and transmembrane signaling in Herpesvirus saimiri-transformed human CD4(+) and CD8(+) T lymphocytes is ATM-independent. 1083 20

Endogenous N-acyl dopamines such as N-arachidonoyldopamine (NADA) and N-oleoyldopamine have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. As endocannabinoids show immunomodulatory activity, and T cells play a key role in the onset of several diseases that affect the CNS, we have evaluated the immunosuppressive activity of NADA and N-oleoyldopamine in human T cells, discovering that both compounds are potent inhibitors of early and late events in TCR-mediated T cell activation. Moreover, we found that NADA specifically inhibited both IL-2 and TNF-alpha gene transcription in stimulated Jurkat T cells. To further characterize the inhibitory mechanisms of NADA at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-kappaB, NF-AT, and AP-1 transcription factors in Jurkat cells. We found that NADA inhibited NF-kappaB-dependent transcriptional activity without affecting either degradation of the cytoplasmic NF-kappaB inhibitory protein, IkappaBalpha, or DNA binding activity. However, phosphorylation of the p65/RelA subunit was clearly inhibited by NADA in stimulated cells. In addition, NADA inhibited both binding to DNA and the transcriptional activity of NF-AT and AP-1, as expected from the inhibition of NF-AT1 dephosphorylation and c-Jun N-terminal kinase activation in stimulated T cells. Finally, overexpression of a constitutively active form of calcineurin demonstrated that this phosphatase may represent one of the main targets of NADA. These findings provide new mechanistic insights into the anti-inflammatory activities of NADA and highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.
...
PMID:Immunosuppressive activity of endovanilloids: N-arachidonoyl-dopamine inhibits activation of the NF-kappa B, NFAT, and activator protein 1 signaling pathways. 1476 3


1 2 Next >>

---