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)

Rat immune-associated nucleotide 4-like 1 (Ian4l1) encodes an antiapoptotic protein, which is essential for T-cell survival. A frameshift mutation at codon 85 in the biobreeding diabetes-prone (BBDP) rat is the cause of their life-long T-cell lymphopenia, which includes lack of regulatory T-cells--a prerequisite for spontaneous autoimmune destruction of their beta-cells. This study reports the identification of seven Ian4l1 mRNA variants. The genomic organization of the exons indicates three promoter regions. The promoter of two of the mRNAs was characterized. Rapid amplification of cDNA ends (RACE) and ribonuclease protection assay (RPA) demonstrated multiple transcription start sites (TSS) with two major sites. The localization of the core promoter and regulatory regions was identified by a luciferase assay of the 2.7-kb upstream of the TSS. The regulatory regions functioned similarly in two cell lines--one expressing Ian4l1 and one not expressing it. This indicates that the cell-specific expression is controlled by regions outside the 2.7-kb region, or by the chromatin structure or chromatin methylation level. The core promoter is TATA-less and initiator element-less, and contains putative binding sites for YY1, Sp1, and MED-1, the latter being an element believed to be important for transcription from TATA-less promoters.
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PMID:The antiapoptotic gene Ian4l1 in the rat: genomic organization and promoter characterization. 1547 97

Interleukin 7 (IL-7) is a key factor in the survival, development and proliferation of B and T lymphocytes. Elevation of plasma IL-7 has been reported in several lymphopenia cases such as HIV-1 patients. After patients started to receive antiretroviral drugs and their CD4(+) cell counts had recovered, IL-7 in plasma decreased to normal levels. There are considerable variations in the levels of plasma IL-7 as well as the rate of CD4(+) T-cell restoration. Although pre-treatment plasma IL-7 levels have been shown to be prognostic for the rate of post-treatment CD4(+) T-cell restoration, the mechanisms responsible for the variations in plasma IL-7 and rate of CD4(+) T-cell restoration are still completely unknown. In the study here, we searched for genetic polymorphisms that might affect levels of IL-7 gene expression. For this purpose, we used 1658-bp PCR-amplified fragments of the IL-7 gene containing 1470 bp of the upstream non-coding region obtained from 151 Japanese and 234 Thai subjects. We found two novel human genetic polymorphisms in the upstream non-coding region of the IL-7 gene. The luciferase reporter assay demonstrated that one of those polymorphisms could increase the gene expression of IL-7. We speculate that this polymorphism, a three base ATC deletion just upstream of an out-of-frame ATG codon in the upstream non-coding region of the IL-7 gene, reduces the efficiency of translation from the upstream, out-of-frame ATG, resulting in increased translation efficiency from the authentic ATG of IL-7. Although the frequency of this allele is very low, it would be interesting to analyse this polymorphism in HIV-1-infected individuals with different rates of immune reconstitution after treatment with a highly active antiretroviral therapy.
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PMID:A three-base-deletion polymorphism in the upstream non-coding region of human interleukin 7 (IL-7) gene could enhance levels of IL-7 expression. 1737 35

It is commonly believed that T cells have difficulty reaching tumors located in the brain due to the presumed "immune privilege" of the central nervous system (CNS). Therefore, we studied the biodistribution and anti-tumor activity of adoptively transferred T cells specific for an endogenous tumor-associated antigen (TAA), gp100, expressed by tumors implanted in the brain. Mice with pre-established intracranial (i.c.) tumors underwent total body irradiation (TBI) to induce transient lymphopenia, followed by the adoptive transfer of gp100(25-33)-specific CD8+ T cells (Pmel-1). Pmel-1 cells were transduced to express the bioluminescent imaging (BLI) gene luciferase. Following adoptive transfer, recipient mice were vaccinated with hgp100(25-33) peptide-pulsed dendritic cells (hgp100(25-33)/DC) and systemic interleukin 2 (IL-2). This treatment regimen resulted in significant reduction in tumor size and extended survival. Imaging of T cell trafficking demonstrated early accumulation of transduced T cells in lymph nodes draining the hgp100(25-33)/DC vaccination sites, the spleen and the cervical lymph nodes draining the CNS tumor. Subsequently, transduced T cells accumulated in the bone marrow and brain tumor. BLI could also detect significant differences in the expansion of gp100-specific CD8+ T cells in the treatment group compared with mice that did not receive either DC vaccination or IL-2. These differences in BLI correlated with the differences seen both in survival and tumor infiltrating lymphocytes (TIL). These studies demonstrate that peripheral tolerance to endogenous TAA can be overcome to treat tumors in the brain and suggest a novel trafficking paradigm for the homing of tumor-specific T cells that target CNS tumors.
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PMID:Anti-tumor activity and trafficking of self, tumor-specific T cells against tumors located in the brain. 1825 32

The sphingosine-1-phosphate (S1P) analogue FTY720 is therapeutically efficacious in multiple sclerosis and in the prevention of transplant rejection. It prevents the migration of lymphocytes to sites of pathology by trapping them within the peripheral lymph nodes, mesenteric lymph nodes (MLNs), and Peyer's patches. However, evidence suggests that its clinical use may increase the risk of mucosal infections. We investigated the impact of FTY720 treatment on susceptibility to gastrointestinal infection with the mouse enteric pathogen Citrobacter rodentium. This attaching and effacing bacterium induces a transient bacterial colitis in immunocompetent mice that resembles human infection with pathogenic Escherichia coli. FTY720 treatment induced peripheral blood lymphopenia, trapped lymphocytes in the MLNs, and prevented the clearance of bacteria when mice were infected with luciferase-tagged C. rodentium. FTY720-treated C. rodentium-infected mice had enhanced colonic inflammation, with significantly higher colon mass, colon histopathology, and neutrophil infiltration than vehicle-infected animals. In addition, FTY720-treated infected mice had significantly lower numbers of colonic dendritic cells, macrophages, and T cells. Gene expression analysis demonstrated that FTY720-treated infected mice had an impaired innate immune response and a blunted mucosal adaptive immune response, including Th1 cytokines. The data demonstrate that the S1P analogue FTY720 adversely affects the immune response to and clearance of C. rodentium.
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PMID:The sphingosine-1-phosphate analogue FTY720 impairs mucosal immunity and clearance of the enteric pathogen Citrobacter rodentium. 2261 52

T-helper cell type 17 (Th17) mediated inflammation is associated with various diseases including autoimmune encephalitis, inflammatory bowel disease and lung diseases such as chronic obstructive pulmonary disease and asthma. Differentiation into distinct T helper subtypes needs to be tightly regulated to ensure an immunological balance. As microRNAs (miRNAs) are critical regulators of signalling pathways, we aimed to identify specific miRNAs implicated in controlling Th17 differentiation. We were able to create a regulatory network model of murine T helper cell differentiation by combining Affymetrix mRNA and miRNA arrays and in silico analysis. In this model, the miR-212~132 and miR-182~183 clusters were significantly up-regulated upon Th17 differentiation, whereas the entire miR-106~363 cluster was down-regulated and predicted to target well-known Th17 cell differentiation pathways. In vitro transfection of miR-18b, miR-106a and miR-363-3p into primary murine Cd4+ lymphocytes decreased expression of retinoid-related orphan receptor c (Rorc), Rora, Il17a and Il17f, and abolished secretion of Th17-mediated interleukin-17a (Il17a). Moreover, we demonstrated target site-specific regulation of the Th17 transcription factors Rora and nuclear factor of activated T cells (Nfat) 5 by miR-18b, miR-106a and miR-363-3p through luciferase reporter assays. Here, we provide evidence that miRNAs are involved in controlling the differentiation and function of T helper cells, offering useful tools to study and modify Th17-mediated inflammation.
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PMID:microRNA cluster 106a~363 is involved in T helper 17 cell differentiation. 2861 45