Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aging is characterized by increased T cell lymphopenia, T cell dysfunction, and increased serum TNF levels. In this study, we have examined the role of TNF-induced apoptosis in T cell deficiency in lymphocytes from aged humans. The constitutive expression of TNF receptors (TNFRI and TNFRII) and the adapter molecules, including TNFR-associated death domain protein (TRADD), TNFR-associated factor 2 (TRAF-2), and receptor interacting protein (RIP), were analyzed both at the protein level by flow cytometry or Western blotting, and at the mRNA level using quantitative PCR or Northern blotting in lymphocytes from aged and young subjects. The susceptibility of T cells to undergo TNF-induced apoptosis was analyzed using terminal deoxynucleotidyltransferase-mediated UTP-end-labeling (TUNEL) and DNA ladder assays. Caspase (caspase-8 and caspase-3) activation was compared between aged and young subjects using Western blotting and colorimetric assays. In lymphocytes from aged humans, there was an increased susceptibility of CD4+ and CD8+ T cells to undergo TNF-alpha-induced apoptosis, as observed by TUNEL assay and DNA fragmentation ladder assay. Increased TNF-alpha-induced apoptosis was also observed in both CD45RA+ and CD45RO+ T cells from aging subjects. An increased constitutive expression of TNFRI and TRADD and decreased expression of TNFRII and TRAF-2 were observed in lymphocytes from aged as compared with young controls. In addition, there was an early and increased activation of caspases (caspase-8 and caspase-3) involved in TNFR/TNF signaling pathway, as evident by early cleavage of caspase-8, poly(ADP-ribose) polymerase (PARP), and caspase-3 substrate DEVD-p-nitroamilide NA. These data suggest that an increased TNF-alpha-induced apoptosis may play a role in T cell deficiency associated with human aging.
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PMID:Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: changes in TNF-alpha receptor expression and activation of caspases. 997 90

In this study, we investigated a role of apoptosis in lymphopenia and progressive cell-mediated immunodeficiency associated with aging. We examined two major signaling pathways of apoptosis in lymphocytes from aged humans and compared them with lymphocytes from young subjects. Both CD4+ and CD8+ T cell subsets from aged subjects demonstrated increased sensitivity to TNFR-mediated and Fas-mediated apoptosis that was associated with overexpression of death receptors and adapter molecules associated with death signaling. An increased expression and activity of both initiator (caspase 8) and effector (caspase 3) caspases was observed in lymphocytes from aged subjects as compared to young individuals. Furthermore, an increased expression of Bax and decreased expression of Bcl-2 (both at the protein and mRNA level) was found in lymphocytes from aged subjects. These data suggest that increased sensitivity of lymphocytes from aged subjects to death signals may play an important role in the pathogenesis of lymphopenia and T cell deficiency associated with the aging process.
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PMID:Molecular and biochemical pathways of apoptosis in lymphocytes from aged humans. 1068 34

Tumor necrosis factor-alpha (TNF-alpha) induces apoptosis predominantly via TNF-receptor I (TNF-RI). We have examined the molecular and biochemical pathways of TNF-alpha-induced apoptosis in T cells from aged and young subjects. Aged subjects show absolute lymphopenia and decreased numbers of both CD4+ and CD8+ T cells. T cells from aged subjects show increased sensitivity to TNF-alpha-induced apoptosis that is associated with increased expression of TNF-RI and decreased expression of TNF-RII in both CD4+ and CD8+ T cells. Agonistic TNF-RI also induced greater apoptosis in T cells from aged subjects as compared to young subjects, suggesting that increased TNF-alpha-induced apoptosis in aging is predominantly mediated via TNF-RI. There was an increased expression of FADD and increased activation of caspase 8 and caspase 3 in lymphocytes from aged humans as compared to young subjects. A role of impaired TNF-RII-mediated signaling in increased apoptosis in aged subjects is also discussed.
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PMID:Tumor necrosis factor-alpha-induced apoptosis in T cells from aged humans: a role of TNFR-I and downstream signaling molecules. 1177 15

Clinical reports suggest that acute ethanol intoxication is often associated with lymphopenia. Previously, ethanol was reported to invoke thymocyte apoptosis. We studied the effect of ethanol on T cell apoptosis. In addition, we evaluated the molecular mechanism of ethanol-induced T cell apoptosis. Human T cells harvested from healthy subjects after an alcohol drinking binge showed enhanced T cell apoptosis (before, 0.4 +/- 0.2% versus after, 19.6 +/- 2.5% apoptotic lymphocytes/field; P < 0.001). In in vitro studies, ethanol in a concentration of 50 mm and higher enhanced the apoptosis of Jurkat cells. DNA isolated from ethanol-treated Jurkat cells displayed integer multiples of 180 base pairs. Ethanol decreased Jurkat cell expression of Bcl-2, whereas ethanol increased Jurkat cell expression of Bax. Jurkat cells treated with ethanol also showed translocation of cytochrome C into cytosol. Moreover, a caspase-9 inhibitor partially inhibited ethanol-induced Jurkat cell apoptosis. In in vivo studies, after binge drinking, T cell expression of Bcl-2 also decreased. In addition, binge drinking induced the cleavage of caspase-3, suggesting activation of caspase-3 in T cells. These results suggest that ethanol promotes T cell apoptosis through the activation of intrinsic or mitochondrial pathway.
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PMID:Ethanol promotes T cell apoptosis through the mitochondrial pathway. 1260 97

The immunopathogenesis of leukopenia and thrombocytopenia in patients with severe acute respiratory syndrome (SARS) is unclear. In order to explore the leukopenia mechanism, we studied 15 SARS patients who were previously healthy, and 15 age-matched normal controls in a paired design. Soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble Fas ligand (sFasL) in plasma were measured by ELISA, and intracellular activated caspase-3 fragment in different leukocytes was determined by flow cytometry. Patients with SARS had significantly lower lymphocyte and platelet counts and significantly higher sVCAM-1 and sFasL levels compared to healthy controls. sVCAM-1 levels correlated negatively with total leukocytes and platelet counts, but positively with plasma sFasL levels. Intracellular cleaved caspase-3 expression was also significantly higher in lymphocytes from SARS patients in acute phase than in convalescent stage. Lymphopenia and thrombocytopenia in SARS patients may be caused, in part, by enhanced vascular sequestration associated with increased sVCAM-1 levels. However, lymphopenia may be due to enhanced cell death. Inhibition of cell adhesion and caspase-3 activation could, therefore, have prevented SARS patients from developing thrombocytopenia and lymphopenia.
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PMID:Role of vascular cell adhesion molecules and leukocyte apoptosis in the lymphopenia and thrombocytopenia of patients with severe acute respiratory syndrome (SARS). 1618 92

Profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type I IFN-dependent loss of CD8 T cells immediately preceding the development of the antiviral T cell response. Most memory (CD44(high)) and some naive (CD44(low)) CD8 T cells are susceptible to IFN-induced attrition, and we show in this study that the IFN-induced attrition of CD8(+)CD44(high) T cells is associated with elevated activation of caspase-3 and caspase-8. We questioned whether TCR engagement by Ag would render CD8 T cells resistant to attrition. We tested whether a high concentration of Ag (GP33 peptide) would protect lymphocytic choriomeningitis (LCMV)-specific naive CD8 T cells (TCR transgenic P14 cells specific for the GP33 epitope of LCMV) and memory CD8 T cells (GP33-specific LCMV-immune cells) from depletion. Both naive P14 and memory GP33-specific donor CD8 T cells decreased substantially 16 h after inoculation with the Toll receptor agonist and IFN inducer, poly(I:C), regardless of whether a high concentration of GP33 peptide was administered to host mice beforehand. Moreover, donor naive P14 and LCMV-specific memory cells were depleted from day 2 LCMV-infected hosts by 16 h posttransfer. These results indicate that Ag engagement does not protect CD8 T cells from the IFN-induced T cell attrition associated with viral infections. In addition, computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells.
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PMID:IFN-induced attrition of CD8 T cells in the presence or absence of cognate antigen during the early stages of viral infections. 1654 66

T cell-based therapies have much promise in cancer treatment. This approach may be enhanced if used in combination with radiotherapy provided that tumor-specific T cells can be protected against the effects of radiotherapy. Previously, we demonstrated that administration of TLR9 ligand into mice decreased activation- and serum deprivation-induced cell death in T cells. We hypothesized that TLR9 engagement on T lymphocytes decreased apoptosis after cellular stress. We show that TLR9 engagement on murine CD4 T cells reduces gamma-radiation-induced apoptosis as judged by decreased annexin-V/PI staining, caspase-3 activation, and PARP cleavage. TLR9-stimulated cells show heightened accumulation at the G2 cell-cycle phase and increased DNA repair rates. Irradiated, TLR9-engaged cells showed higher levels of phosphorylated Chk1 and Chk2. While the levels of activated ATM in response to IR did not differ between TLR9-stimulated and unstimulated cells, inhibition of ATM/ATR and Chk1/Chk2 kinases abolished the radioprotective effects in TLR9-stimulated cells. In vivo, TLR9-stimulated cells displayed higher radio resistance than TLR9-stimulated MyD88(-/-) T cells and responded to antigenic stimulation after total body irradiation. These findings show, for the first time, that TLR9 engagement on CD4 T cells reduces IR-induced apoptosis by influencing cell-cycle checkpoint activity, potentially allowing for combinatorial immunotherapy and radiotherapy.
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PMID:TLR9 engagement on CD4 T lymphocytes represses gamma-radiation-induced apoptosis through activation of checkpoint kinase response elements. 1808 70

Despite the widespread use of antenatal glucocorticosteroids (GCs), the possibility of adverse effects on the immune response in preterm neonates remains a major concern. GCs stimulate lymphocyte apoptosis, resulting in lymphopenia and functional disorders, which have been associated with sepsis-related death in critically ill neonates. We sought to assess the effect of antenatal betamethasone (BM) on lymphocyte apoptosis in preterm neonates. Fifty preterm neonates exposed to antenatal BM and 50 controls were studied prospectively. Lymphocyte apoptosis was assessed using the annexin-V/propidium iodide (PI) assay, analysis of cell cycle after staining with PI, and intracellular caspase-3 activity. The two groups did not differ significantly as regards absolute lymphocyte counts and the percentage of lymphocytes being annexin-V (+)/PI (-) (early apoptotic) or lymphocytes in the subG1 peak after staining with PI and those with intracellular caspase-3 activation. The lymphocyte number and apoptosis were not associated with the time elapsed between antenatal BM administration and delivery. A single course of antenatal BM does not influence apoptosis of neonatal lymphocytes. This is of significant importance with respect to the preservation of lymphocyte-associated immune response in preterm neonates.
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PMID:Antenatal betamethasone does not influence lymphocyte apoptosis in preterm neonates. 1926 38

Post-traumatic immune suppression renders individuals with spinal cord injury (SCI) susceptible to infection. Normally, proper immune function is regulated by collaboration between the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis and involves the controlled release of glucocorticoids (GCs) and norepinephrine (NE). Recently, we showed that after high thoracic (T3) SCI, aberrant levels of GCs and NE accumulate in the blood and spleen, respectively. These changes are associated with splenic atrophy, splenic leucopenia, increased intrasplenic caspase 3 levels, and suppressed B lymphocyte function. As GCs boost SNS function, in part by increasing the expression and affinity of beta2 adrenergic receptors (beta2ARs) while simultaneously preventing beta2AR down-regulation, we predicted that surges in stress hormones (i.e., GCs and NE) in the blood and spleen of mice with high-level SCI would act concurrently to adversely affect lymphocyte function and survival. Here, we show that post-SCI concentrations of GCs enhance the sensitivity of lymphocytes to beta2AR stimulation causing an increase in intracellular Bcl-2 interacting mediator of cell death (Bim) and subsequent apoptosis. In vivo, the combined antagonism of GC receptors and beta2ARs significantly diminished lymphocyte Bim levels and SCI-induced splenic lymphopenia. Together, these data suggest that pharmacological antagonists of the HPA/SNS axes should be considered as adjunct therapies for ameliorating post-traumatic immune suppression in quadriplegics and high paraplegics.
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PMID:Stress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury. 1954 80

Pathogenic lymphocytes in the enteric wall of inflammatory bowel disease patients display various abnormalities, including reduced sensitivity to apoptosis. We evaluated a therapeutic approach to elimination of cytotoxic cells, using two IL-2 fusion proteins, a diphtheria toxin (IL2-DT) and a caspase-3 (IL2-cas) conjugate. In models of acute (dextran sodium sulfate and trinitrobenzene sulfonic acid) and chronic (dextran sodium sulfate) toxic colitis, therapeutic doses of the fusion proteins improved survival and prevented colon shortening. While both chimeric proteins eradicated CD4(+)CD25(+)Foxp3(+) T cells in mesenteric LN, IL2-DT caused severe lymphopenia. In contrast, IL2-cas was equally protective and increased fractional expression of Foxp3. Similar effects of the fusion proteins were observed in healthy mice: IL2-DT caused lymphopenia and IL2-cas increased fractional expression of FoxP3. The fusion proteins induced apoptosis in CD25(+) T cells in vitro, with lower toxicity of IL2-cas to Foxp3(+) T cells. These data infer that targeted depletion of cells expressing the IL-2 receptor has therapeutic potential in models of inflammatory colitis, despite depletion of CD25(+) Treg. The IL2-cas fusion protein is particularly relevant to inflammatory bowel disease, as direct internalization of toxic moieties overcomes multiple pathways of resistance to apoptosis of colitogenic T cells.
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PMID:Targeted therapy to the IL-2R using diphtheria toxin and caspase-3 fusion proteins modulates Treg and ameliorates inflammatory colitis. 1973 74


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