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

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AIDS encephalitis is a common sequela to HIV-1 infection in humans and simian immunodeficiency virus (SIVmac) infection in macaques. Although lentiviral-infected macrophages comprise parenchymal inflammatory infiltrates in affected brain tissue, the mechanisms responsible for leukocyte trafficking to the central nervous system in AIDS are unknown. In this study, we investigated the expression of various endothelial-derived leukocyte adhesion proteins in SIVmac-induced AIDS encephalitis. Encephalitic brains from SIVmac-infected macaques, but not uninflamed brains from other SIVmac-infected animals, were found to express abundant vascular cell adhesion molecule-1 (VCAM-1) protein on the majority of arteriolar, venular, and capillary endothelial cells. Soluble VCAM-1 concentrations in cerebrospinal fluid (CSF) from encephalitic animals were increased approximately 20-fold above those from animals without AIDS encephalitis. Expression of other endothelial-related adhesion molecules, including E-selectin, P-selectin, and intercellular adhesion molecule-1 (ICAM-1), was not uniformly associated with AIDS encephalitis. Thus, the presence of VCAM-1 in both brain and CSF was uniformly associated with SIVmac-induced disease of the central nervous system, and this expression may, at least in part, influence monocyte and lymphocyte recruitment to the central nervous system during the development of AIDS encephalitis. Moreover, measurement of soluble VCAM-1 in CSF may assist in the clinical assessment of animals or people with AIDS.
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PMID:Elevated vascular cell adhesion molecule-1 in AIDS encephalitis induced by simian immunodeficiency virus. 127 78

Because the mechanisms associated with recruitment of monocytes to brain in AIDS encephalitis are unknown, we used tissues from rhesus monkeys infected with simian immunodeficiency virus (SIV) to examine the relative contributions of various adhesion pathways in mediating monocyte adhesion to endothelium from encephalitic brain. Using a modified Stamper and Woodruff tissue adhesion assay, we found that the human monocytic cell lines, THP-1 and U937, and the B cell line, Ramos, preferentially bound to brain vessels from monkeys with AIDS encephalitis. Using a combined tissue adhesion/immunohistochemistry approach, these cells only bound to vessels expressing vascular cell adhesion molecule-1 (VCAM-1). Furthermore, pretreatment of tissues with antibodies to VCAM-1 or cell lines with antibodies to VLA-4 (CD49d) inhibited adhesion by more than 70%. Intercellular adhesion molecule-1 (ICAM-1)/beta 2 integrin interactions were not significant in mediating cell adhesion to the vasculature in encephalitic simian brain using a cell line (JY) capable of binding rhesus monkey ICAM-1. In addition, selectin-mediated interactions did not significantly contribute to cell binding to encephalitic brain as there was no immunohistochemical expression of E-selectin and P-selectin in either normal or encephalitic brain, nor was there a demonstrable adhesive effect from L-selectin using L-selectin-transfected 300.19 cells on simian encephalitic brain. These results demonstrate that using the tissue adhesion assay, THP-1, U937, and Ramos cells bind to vessels in brain from animals with AIDS encephalitis using VCAM-1/alpha 4 beta 1 integrin interactions and suggest that VCAM-1 and VLA-4 may be integral for monocyte recruitment to the central nervous system during the development of AIDS encephalitis.
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PMID:Monocyte adhesion to endothelium in simian immunodeficiency virus-induced AIDS encephalitis is mediated by vascular cell adhesion molecule-1/alpha 4 beta 1 integrin interactions. 750

By reverse transcriptase polymerase chain reaction on messenger RNA from human polymorphonuclear cells, we have isolated a sequence identical to the cDNA coding for intracellular interleukin 1 receptor antagonist (icIL-1ra), but containing an additional in-frame 63-bp sequence located three codons downstream of the translation start of icIL-1ra. This additional sequence is inserted between the first and second exon of the intracellular form, the latter of which is colinear with part of the first exon of the secreted form of IL-1ra. The additional sequence is coded by an extra exon located 2 kb downstream the first icIL-1ra-specific exon. The complementary DNA sequence of the alternatively spliced form of icIL-1ra shows that the predicted protein differs from classical icIL-1ra in the NH2 terminus by insertion of a leaderless sequence of 21 amino acids rich in glycine and glutamic acid residues. Transcripts coding for this new form of icIL-1ra were detected in activated fibroblasts, keratinocytes, and at low levels in myelomonocytic cells. The recombinant protein expressed in COS cells had an apparent molecular mass in sodium dodecyl sulfate polyacrylamide gel electrophoresis of 25 kD compared to 22 kD of classical icIL-1ra, and was mostly intracellular. The ability of this new form of icIL-1ra to inhibit IL-1 activity, in terms of induction of E-selectin and human immunodeficiency virus replication, was comparable to that of classical icIL-1ra. We propose to refer to this new form of icIL-1ra as icIL-1ra type II.
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PMID:Cloning and characterization of a new isoform of the interleukin 1 receptor antagonist. 762 20

tat protein, a human immunodeficiency virus (HIV) gene product that functions as a transactivator for HIV replication, is known to be secreted extracellularly by infected cells. To determine the potential role of tat in the dissemination of HIV into extravascular tissue, this protein was examined for its ability to activate human endothelial cells. The results show that tat does indeed stimulate endothelial cells. This is evidenced by their expression of the endothelial-leukocyte adhesion molecules, E-selectin, critical for the initial binding of leukocytes to the blood vessel wall, and their increased synthesis of interleukin-6 (IL-6), a cytokine known to enhance endothelial cell permeability. Furthermore, tat acts synergistically with low concentrations of tumor necrosis factor-alpha to enhance IL-6 secretion. These data suggest that extracellular tat protein secreted or released into the microenvironment may contribute significantly to the determination of specific sites of leukocyte binding to blood vessels, to transmigration into tissue, and to eventual dissemination of HIV-infected cells or free virions into tissue.
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PMID:Exogenous tat protein activates human endothelial cells. 751 13

The A20 gene product is a novel zinc finger protein originally described as a tumor necrosis factor alpha (TNF)-inducible early response gene in human umbilical vein endothelial cells (HUVEC). Its described function is to block TNF-induced apoptosis in fibroblasts and B lymphocytes, but more recently it has also been shown to play a role in lymphoid cell maturation. The mechanism of action of A20 is unknown. The aim of our study was to assess the effect of A20 upon endothelial cell activation. By transfecting bovine aortic endothelial cells (BAEC) with A20 as well as reporter constructs consisting of the promoters of genes known to be up-regulated during endothelial cell activation, i.e. E-selectin, interleukin (IL)-8, tissue factor (TF), and inhibitor of nuclear factor kappaBalpha (IkappaBalpha), we demonstrate that A20 expression inhibits gene up-regulation associated with TNF, lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA), and hydrogen peroxide (H2O2)-induced endothelial cell (EC) activation. The mechanism of action of A20 is in part, or totally, due to the blockade of nuclear factor kappaB (NF-kappaB), as shown by its ability to suppress the activity of a NF-kappaB reporter. This effect is specific, as A20 does not block a noninducible, constitutively expressed reporter, Rous sarcoma virus-luciferase (RSV-LUC); nor does it block the c-Tat-inducible, NF-kappaB-independent reporter, human immunodeficiency virus-chloramphenicol acetyltransferase (HIV-CAT). How A20 blocks NF-kappaB is unclear, although we demonstrate that it does not affect p65 (RelA)-mediated gene transactivation. The inhibition of endothelial cell activation by A20 is a novel function for A20.
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PMID:A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism. 866 99

Clinical and serological studies provide evidence for a pathogenetically relevant vasculopathy in acquired immune deficiency syndrome (AIDS); however, the morphological status of the endothelium under conditions of human immunodeficiency virus (HIV)-1 infection is only sparsely documented. In this study we adapted an en face preparation technique of endothelium for use in immunohistochemistry and investigated the aortic endothelium of pre-AIDS and AIDS patients (n = 32) in comparison with an HIV-negative group (n = 17). The control group showed a regular pattern of evenly distributed aortic endothelial cells, whereas the endothelial cell pattern in the HIV-1-infected patients was clearly disturbed. Simultaneously, the degree of leukocyte adherence on the aortic endothelium increased significantly. These changes were accompanied by an up-regulation of the vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (ELAM-1). The endothelium turnover increased, and one-half of the HIV-1-infected patients exhibited HLA-DR (major histocompatibility complex class II) antigen in the aortic endothelium. Our results provide evidence for a profound and repeated injury with regeneration and activation of the endothelium in HIV-1 infection. Injury as well as activation of the endothelium impairs its normal regulatory properties. This could have consequences for the maintenance of the blood-brain barrier; it might influence the immunologically important interaction of the endothelium with T cells; and it might trigger Kaposi's sarcoma.
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PMID:Aortic endothelium in HIV-1 infection: chronic injury, activation, and increased leukocyte adherence. 895 25

The human immunodeficiency virus type 1 (HIV)-associated dementia complex (ADC) is a neuroimmunological disorder fueled by viral replication in mononuclear phagocytes (MP) (brain macrophages and microglia). The elucidation of MP inflammatory factors involved in neurological dysfunction is pivotal for unraveling pathogenic mechanisms and in developing new therapies for this disease. Recent advances in animal model systems for ADC and its associated encephalitis have provided important insights into how virus-infected macrophages cause brain injury. Indeed, the stereotactic inoculation of HIV infected monocytes into the basal ganglia/cortex of mice with severe combined immunodeficiency disease (SCID) results in pathological features similar to those of human HIV-1 encephalitis (HIVE). We used this SCID model to study the roles of macrophage secretory factors in HIVE. The expression of interleukin-1 (IL-1 beta, IL-6, IL-10), tumor necrosis factors-alpha (TNF alpha), vascular endothelial growth factor (VEGF), and adhesion molecules (E-selectin, intracellular cell adhesion molecule (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1)) in encephalitic brains of mice and humans was evaluated by semi-quantitative polymerase chain reaction (PCR). In SCID mice with HIVE, human and mouse TNF alpha, and mouse IL-6, VEGF, VCAM-1 and E-selectin were expressed at high levels. These results paralleled, to a great extent, those in HIVE brain tissues. Laser scanning confocal microscopy performed to assess the associated neuronal damage showed that microtubule associated protein-2 (MAP-2) immunoreactive dendrites were significantly reduced in both the ipsilateral and contralateral hemispheres of encephalitic mice. These results demonstrate the importance of macrophage inflammatory products in the pathogenesis of HIVE and further validates this model of viral encephalitis in SCID mice.
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PMID:An analysis of HIV-1-associated inflammatory products in brain tissue of humans and SCID mice with HIV-1 encephalitis. 947 12

The molecularly cloned viruses known as SIVmac239/R17Y and SIVmac239/YEnef cause extensive lymphocyte activation and induce an acute disease syndrome in macaque monkeys. One manifestation of this syndrome is a severe diffuse cutaneous maculopapular exanthem that is similar to the exanthem associated with HIV-1 infection. To examine the pathogenesis of this exanthem, biopsies obtained throughout the course of clinically evident rash were examined for the presence of virus by in situ hybridization and immunohistochemistry, and the cellular infiltrate was characterized with respect to cellular immunophenotype and chemokine receptor expression. The onset of rash was associated with abundant simian immunodeficiency virus nucleic acid and protein within perivascular dermal infiltrates and occasionally within intraepithelial cells. Analysis of cellular infiltrates showed that biopsies, obtained on the day of rash onset, were composed of equal numbers of CD4+ and CD8+ lymphocytes and abundant alphaEbeta7 positive cells surrounding vessels with upregulated endothelial E-selectin. Moreover, by examining virus expression in sequential skin biopsies from the same animal, the clearance of virus and the resolution of rash were associated with an increase in the percentage of cells expressing CD8, the chemokine receptor CXCR3, and GMP-17, a marker of cytotoxic granules. These results suggest that activated cytotoxic T cells are trafficking to sites of inflammation in the skin and directly or indirectly affect levels of viral replication at these sites.
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PMID:Characterization of the cutaneous exanthem in macaques infected with a Nef gene variant of SIVmac239. 962 Feb 96

Human immunodeficiency virus-1 (HIV-1)-Tat, the transactivating gene product of HIV-1, has been shown to interact with different cell types, inducing gene expression, altering their growth and migratory behavior. In this study we examined whether Tat might affect functions of acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphoma (NHL), relevant to the in vivo dissemination. Our results show that Tat significantly augmented the motility of the two AIDS-related Burkitt's lymphoma cell lines (AS283 and PA682PB) and AIDS-primary effusion lymphoma cell line (HBL-6-AIDS-PEL). Mutations in RGD or basic domain of Tat (KGE-MBP and LxI-MBP, respectively) sharply reduced migration compared with wild type, suggesting that both domains are required for migration. In contrast, a Tat protein mutation outside the active domains (NH(2)-TAT-GST) did not reduce lymphoma cell migration. The treatment of lymphoma cells with Tat did not influence their adhesion to matrix proteins or to human vascular endothelial cells, but endothelial cells treated with Tat became more adhesive to lymphoma cells. Flow cytometric analysis showed that treatment of endothelial cells with Tat induced the cell surface expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and E-selectin and increased the expression of intercellular adhesion molecule-1 (ICAM-1). Only antibodies against VCAM-1 on endothelial cells or against the VLA-4 integrin expressed on AS283 cells inhibited the increment of adhesion, indicating the relevance of this pathway in the adhesion of lymphoma cells to vascular endothelium. In our work, we show for the first time that Tat can enhance the migration of lymphoma cells and their adhesion to endothelial cells, two processes that may contribute to the malignant behavior of NHL in patients with AIDS.
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PMID:Human immunodeficiency virus-1 (HIV-1)-Tat protein promotes migration of acquired immunodeficiency syndrome-related lymphoma cells and enhances their adhesion to endothelial cells. 1047

Leukocyte adhesion deficiency type II (LADII) is a rare inherited disorder of fucose metabolism. Patients with LADII lack fucosylated glycoconjugates, including the carbohydrate ligands of the selectins, leading to an immunodeficiency caused by the lack of selectin-mediated leukocyte-endothelial interactions. A simple and effective therapy has recently been described for LADII, based on the administration of oral fucose. Parallel to this treatment the lack of E- and P-selectin ligands on neutrophils was corrected, and high peripheral neutrophil counts were reduced to normal levels. This study reports that discontinuation of this therapy leads to the complete loss of E-selectin ligands within 3 days and of P-selectin ligands within 7 days. Peripheral neutrophil counts increased parallel to the decrease of selectin ligands. Selectin ligands reappeared promptly after resumption of the fucose therapy, demonstrating a causal relationship between fucose treatment and selectin ligand expression and peripheral neutrophil counts.
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PMID:Discontinuation of fucose therapy in LADII causes rapid loss of selectin ligands and rise of leukocyte counts. 1113 80


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