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)

CD16+ monocytes represent 5-10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16+ monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16+ monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16+ monocyte trafficking and show that migration of CD16+ and CD16- monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16- monocytes, CD16+ monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendothelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1 alpha (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16+ monocytes arrested on cell surface-expressed FKN under flow with higher frequency compared with CD16- monocytes. These results demonstrate that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.
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PMID:Fractalkine preferentially mediates arrest and migration of CD16+ monocytes. 1281 Jun 88

Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). G protein-coupled chemokine receptors are used by HIV-1 as coreceptors to enter the host cells. In this study, we assessed the effects of shikonin on chemokine receptor function and HIV-1 replication. The results showed that, at nanomolar concentrations, shikonin inhibited monocyte chemotaxis and calcium flux in response to a variety of CC chemokines (CCL2 [monocyte chemoattractant protein 1], CCL3 [macrophage inflammatory protein 1alpha], and CCL5 [regulated upon activation, normal T-cell expressed and secreted protein]), the CXC chemokine (CXCL12 [stromal cell-derived factor 1alpha]), and classic chemoattractants (formylmethionyl-leucine-phenylalanine and complement fraction C5a). Shikonin down-regulated surface expression of CCR5, a primary HIV-1 coreceptor, on macrophages to a greater degree than the other receptors (CCR1, CCR2, CXCR4, and the formyl peptide receptor) did. CCR5 mRNA expression was also down-regulated by the compound. Additionally, shikonin inhibited the replication of a multidrug-resistant strain and pediatric clinical isolates of HIV in human peripheral blood mononuclear cells, with 50% inhibitory concentrations (IC(50)s) ranging from 96 to 366 nM. Shikonin also effectively inhibited the replication of the HIV Ba-L isolate in monocytes/macrophages, with an IC(50) of 470 nM. Our results suggest that the anti-HIV and anti-inflammatory activities of shikonin may be related to its interference with chemokine receptor expression and function. Therefore, shikonin, as a naturally occurring, low-molecular-weight pan-chemokine receptor inhibitor, constitutes a basis for the development of novel anti-HIV therapeutic agents.
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PMID:Shikonin, a component of chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1. 1293 78

The duration and severity of the symptomatology present during the early phase of human immunodeficiency virus (HIV) infection (known as the acute retroviral syndrome) is associated with alterations in the clinical profile of infection, such as a shortening of duration between infection with HIV and the onset of neurocognitive impairment and acquired immunodeficiency syndrome (AIDS). Viral-specific CD8+ cytotoxic T lymphocytes (CTLs) and CD8+ natural killer (NK) cells play a key role in antiviral immunity. Loss of CD8+ cells or their functional impairment during the early period of infection is associated with a rapid progression to AIDS in nonhuman primate studies. However, no studies have determined whether CD8+ cell loss or impairment is associated with symptoms of acute retroviral illness such as fever. In this study, the authors compared the early phase of simian immunodeficiency virus (SIV) infection in animals that were treated with the anti-CD8 monoclonal antibody cM-T807 to deplete CD8+ cells during the early period of infection (SIV+ CD8- group) to those with intact CD8+ cells (SIV+ CD8+ group). The SIV+ CD8- group had an enhanced acute retroviral syndrome when compared to the SIV+ CD8+ group. The SIV+ CD8- group also had prolonged high viral loads and distinct alterations in the proinflammatory cytokines interleukin (IL)-6 and interferon (IFN)-alpha, as well as in monocyte chemoattractant protein (MCP)-1. CD8+ cell depletion, therefore, appears to enhance symptoms of the acute retroviral syndrome and alters several of the immunological factors associated with the early phase of infection.
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PMID:CD8+ cell depletion amplifies the acute retroviral syndrome. 1498 41

Recent studies on the coreceptor usage of human immunodeficiency virus (HIV) strains associated with acquired immunodeficiency syndrome (AIDS) dementia have shown that both X4 and R5 viruses are involved in the process. The disease is associated with enhanced virus replication and monocyte chemoattractant protein (MCP)-1 production in macrophages in the brain. Using the macaque model of the disease, the authors show here that X4, macrophage-tropic simian human immunodeficiency virus (SHIV) required the enhancing effect of interleukin (IL)-4 to achieve equivalent concentrations of virus and MCP-1 that are produced in macrophages infected with R5 viruses alone. Confocal microscopy showed that macrophages in the encephalitic brains were the major producers of MCP-1. The authors surmise, therefore, that whereas R5 viruses maybe capable of causing the disease as a primary pathogen, X4 viruses may require IL-4, induced by opportunistic pathogens, for induction of the neuropathological syndrome.
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PMID:Role of interleukin-4 and monocyte chemoattractant protein-1 in the neuropathogenesis of X4 simian human immunodeficiency virus infection in macaques. 1498 50

Increased postcontrast enhancement in contrast-enhanced magnetic resonance imaging (CE-MRI) of the central nervous system (CNS) is a predictor of human immunodeficiency virus (HIV) dementia severity in HIV-infected subjects. The present study confirms this earlier finding in a mildly impaired patient cohort, and demonstrates that the increased postcontrast enhancement is correlated with increased cerebrospinal fluid (CSF) levels of monocyte chemoattractant protein (MCP)-1, an inflammatory chemokine, and increased CNS levels of mI, a microglial marker. These results suggest that early CNS inflammation may underlie the microvascular changes observed, and may be a factor in the development of HIV dementia.
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PMID:Inflammatory changes and breakdown of microvascular integrity in early human immunodeficiency virus dementia. 1537 Nov 52

It is well established that most G protein-coupled receptors are able to form homo- and heterodimers, although the functional consequences of this process often remain unclear. CCR5 is a chemokine receptor that plays an important role in inflammatory diseases and acts as a major coreceptor for human immunodeficiency viruses. CCR5 was previously shown to homodimerize and heterodimerize with CCR2b, a closely related receptor. In the present study, we have analyzed the functional consequences of this dimerization process, in terms of ligand binding, stimulation of intracellular cascades, and internalization. Bioluminescence resonance energy transfer and coimmunoprecipitation assays demonstrated that CCR5 and CCR2b heterodimerize with the same efficiency as they homodimerize. In contrast to what has been reported previously, no cooperative signaling was observed after costimulation of the two receptors by their respective ligands. However, we observed that CCR5-specific ligands that are unable to compete for monocyte chemoattractant protein (MCP-1) binding on cells expressing CCR2b alone efficiently prevented MCP-1 binding when CCR5 and CCR2b were coexpressed. The extent of this cross-competition was correlated with the amount of CCR5 expressed in cells, as determined by fluorescence-activated cell sorting analysis. Similar observations were made for the CCR2b-selective ligand MCP-1 that competed efficiently for macrophage inflammatory protein-1beta binding on cells expressing both receptors. Internalization assays did not allow us to demonstrate cointernalization of the receptors in response to agonist stimulation. Together, our observations suggest that CCR5 and CCR2b form homo- and heterodimers with similar efficiencies and that a receptor dimer can only bind a single chemokine.
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PMID:Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers. 1550 16

Increased central nervous system (CNS) levels of monocyte chemoattractant protein 1 [CC chemokine ligand 2 (CCL2) in the systematic nomenclature] have been reported in chronic neurological diseases such as human immunodeficiency virus type 1-associated dementia, amyotrophic lateral sclerosis, and multiple sclerosis. However, a pathogenic role for CCL2 has not been confirmed, and there is no established model for the effects of chronic CCL2 expression on resident and recruited CNS cells. We report that aged (>6 months) transgenic (tg) mice expressing CCL2 under the control of the human glial fibrillary acidic protein promoter (huGFAP-CCL2hi tg+ mice) manifested encephalopathy with mild perivascular leukocyte infiltration, impaired blood brain barrier function, and increased CD45-immunoreactive microglia, which had morphologic features of activation. huGFAP-CCL2hi tg+ mice lacking CC chemokine receptor 2 (CCR2) were normal, showing that chemokine action via CCR2 was required. Studies of cortical slice preparations using video confocal microscopy showed that microglia in the CNS of huGFAP-CCL2hi tg+ mice were defective in expressing amoeboid morphology. Treatment with mutant CCL2 peptides, a receptor antagonist and an obligate monomer, also suppressed morphological transformation in this assay, indicating a critical role for CCL2 in microglial activation and suggesting that chronic CCL2 exposure desensitized CCR2 on microglia, which in the CNS of huGFAP-CCL2hi tg+ mice, did not up-regulate cell-surface expression of major histocompatibility complex class II, CD11b, CD11c, or CD40, in contrast to recruited perivascular macrophages that expressed enhanced levels of these markers. These results indicate that huGFAP-CCL2hi tg+ mice provide a useful model to study how chronic CNS expression of CCL2 alters microglial function and CNS physiology.
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PMID:Chronic expression of monocyte chemoattractant protein-1 in the central nervous system causes delayed encephalopathy and impaired microglial function in mice. 1585 90

Chronic renal failure (CRF) patients display an immunodeficiency state, and uremic solutes that accumulate during CRF may be involved in this immunodeficiency. In this study, we examined whether the uremic solute para-cresol (p-cresol), at concentrations similar to those found in patients, alters leukocyte transmigration in vitro. We found that p-cresol significantly inhibited monocyte THP-1 cell line and PBMCs transmigration across IL-1beta-stimulated human umbilical vein endothelial cell (HUVEC) in a static two-compartment model. This inhibitory effect of p-cresol persisted in the presence of a physiologic concentration of human serum albumin. In order to investigate the mechanism involved, expression of endothelial chemokines, fractalkine, monocyte chemoattractant protein 1 (MCP-1) and IL-8 and membrane expression of junctional adhesion molecule A (JAM-A or JAM-1) were studied. We found that p-cresol decreased mRNA expression of the chemokine fractalkine in IL-1beta-stimulated HUVEC, without modifying mRNA expression of MCP-1 and IL-8. In addition, p-cresol decreased IL-1beta-induced expression of membrane-bound and soluble forms of fractalkine and impaired the membrane expression of JAM-A. Taken together, these results suggest that p-cresol, by impairing leukocyte transendothelial migration, plays a role in the immune dysfunction of uremic patients.
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PMID:The uremic solute p-cresol decreases leukocyte transendothelial migration in vitro. 1695 66

The objective of the study was to assess the feasibility of measuring human immunodeficiency virus 1 (HIV-1) proviral deoxyribonucleic acid (DNA) and associated single-nucleotide polymorphism (SNP) of monocyte chemoattractant protein 1 (MCP1) in pediatric cerebrospinal fluid (CSF). The importance of HIV DNA and MCP1 SNP has been suggested to be independently important in progression to acquired immune deficiency syndrome (AIDS) and neurocognitive impairment in adults. In children, measuring both factors in the CSF may help us understand the neuropathogenic process leading to HIV-1-associated encephalopathy (HAE). Repository specimens from 27 perinatally HIV-1-infected children with HAE were assessed for HIV DNA copy by real-time polymerase chain reaction and compared with MCP1 2578G SNP mutations measured by digesting amplified 361 bp fragments. When compared with MCP1 2578G SNP, a significant number with the mutation had high HIV DNA compared with those with wild type (p < .01), with no levels detected in HIV-1-seronegative control specimens. There were six CSF specimens with enough supernatant to measure MCP1 levels by enzyme-linked immunosorbent assay, which showed high levels in those with the MCP1 2578G mutation. This study demonstrates, for the first time, that CSF HIV DNA and MCP1 SNP can be measured and could be potential tools in future clinical studies to understand the pathogenesis of pediatric HAE.
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PMID:Feasibility assessment of cerebrospinal fluid from HIV-1-infected children for HIV proviral DNA and monocyte chemoattractant protein 1 alleles. 1716 71

Human metapneumovirus (hMPV) can cause acute upper and lower respiratory tract infections that are particularly severe in young children, elderly subjects, and immunocompromised patients. To date, no treatments or vaccines are available for hMPV infections. Our objective was to assess the inhibitory potential of several peptides derived from the heptad repeat A and B (HRA and HRB) domains of the hMPV fusion protein. Nine candidate peptides were expressed in Escherichia coli or obtained synthetically and tested in vitro and in an animal model. Excellent in vitro inhibition of an hMPV strain of the A1 subgroup was obtained with five peptides, with 50% inhibitory concentrations ranging from 1.4 nM to 3.3 microM. One peptide, HRA2, displayed very potent activity against all four hMPV subgroups. It was also moderately active against human respiratory syncytial virus (strain A2) but displayed no activity against human parainfluenza virus type 3. BALB/c mice that received the HRA2 peptide and a lethal hMPV intranasal challenge simultaneously were completely protected from clinical symptoms and mortality. On day 5 postinfection, HRA2-treated mice had undetectable lung viral loads which were significantly less than those of untreated mice (3 x 10(4) 50% tissue culture infective doses/lung). Pulmonary inflammation, levels of proinflammatory cytokines/chemokines (RANTES, gamma interferon, and monocyte chemoattractant protein 1) and airway obstruction were also significantly decreased in HRA2-treated mice. The results of this study demonstrate that potent antivirals can be derived from the hMPV fusion protein HR domains. Moreover, hMPV, compared to other paramyxoviruses and to the human immunodeficiency virus, seems to be more susceptible to HRA- than HRB-derived peptides.
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PMID:Identification and evaluation of a highly effective fusion inhibitor for human metapneumovirus. 1796 6


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