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)

Topical anti-human immunodeficiency virus (HIV) microbicides are being sought to reduce the spread of HIV type 1 (HIV-1) during sexual intercourse. The success of this strategy depends upon the selection of formulations compatible with the natural vaginal mucosal barrier. This study applied ex vivo-modeled human cervicovaginal epithelium to evaluate experimental solid-dosage forms of the anti-HIV-1 microbicide cellulose acetate 1,2-benzenedicarboxylate (CAP) and over-the-counter (OTC) vaginal products for their impact on inflammatory mediators regarded as potential HIV-1-enhancing risk factors. We assessed product-induced imbalances between interleukin-1alpha (IL-1alpha) and IL-1beta and the natural IL-1 receptor antagonist (IL-1RA) and changes in levels of IL-6, tumor necrosis factor alpha, IL-8, gamma interferon inducible protein 10 (IP-10), and macrophage inflammatory protein 3alpha (MIP-3alpha), known to recruit and activate monocytes, dendritic cells, and T cells to the inflamed mucosa. CAP film and gel formulation, similarly to the hydroxyethylcellulose universal vaginal placebo gel and the OTC K-Y moisturizing gel, were nontoxic and caused no significant changes in any inflammatory biomarker. In contrast, OTC vaginal cleansing and contraceptive films containing octoxynol-9 or nonoxynol-9 (N-9) demonstrated similar levels of toxicity but distinct immunoinflammatory profiles. IL-1alpha, IL-1beta, IL-8, and IP-10 were increased after treatment with both OTC vaginal cleansing and contraceptive films; however, MIP-3alpha was significantly elevated by the N-9-based film only (P < 0.01). Although both films increased extracellular IL-1RA, the cleansing film only significantly elevated the IL-1RA/IL-1 ratio (P < 0.001). The N-9-based film decreased intracellular IL-1RA (P < 0.05), which has anti-inflammatory intracrine functions. This study identifies immunoinflammatory biomarkers that can discriminate between formulations better than toxicity assays and should be clinically validated in relevance to the risk of HIV-1 acquisition.
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PMID:Biocompatibility of solid-dosage forms of anti-human immunodeficiency virus type 1 microbicides with the human cervicovaginal mucosa modeled ex vivo. 1703 May 62

Patients with HIV infection exhibit deficits in bacterial and fungal clearance, and possibly depressed innate immunity. In this study, we observed that neutrophils from HIV-infected patients have a profound defect in chemotaxis in response to endogenous (IL-8) and bacterial (fMLP) chemoattractants, which was directly correlated with peripheral CD4(+) lymphocyte levels but not plasma viral load. A similar chemotactic defect was observed in the feline immunodeficiency virus (FIV) model of HIV infection. Intravital microscopy of FIV-infected animals revealed marked impairment in the in vivo recruitment of leukocytes; specifically integrin-dependent neutrophil adhesion and emigration induced by bacterial products. Treatment of FIV-infected animals with GM-CSF re-established both neutrophil recruitment (rolling, adhesion, and emigration) and in vitro chemotaxis to the levels seen in uninfected animals. This restoration of neutrophil responses was not due to GM-CSF-mediated priming. Rather, HIV and FIV infections resulted in defective neutrophil development, with an ensuing reduction in neutrophil granularity and chemotactic receptor expression. GM-CSF therapy restored neutrophil granularity, implying restoration of normal neutrophil development. Together, our findings underscore the fundamental defects in innate immunity caused by lentivirus infections, while also indicating that GM-CSF may be a potential immunorestorative therapy for HIV-infected patients.
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PMID:HIV and other lentiviral infections cause defects in neutrophil chemotaxis, recruitment, and cell structure: immunorestorative effects of granulocyte-macrophage colony-stimulating factor. 1705 72

As a result of improved diagnosis, treatment, and supportive care for HIV-infected patients, AIDS in developed countries has now become a chronic infection with prolonged survival time, but longterm complications are increasing contributors to morbidity and mortality. HIV-infected patients are at increased risk for the development of pulmonary complications, including chronic obstructive pulmonary disease (COPD); however, the mechanisms associated with this increased susceptibility have not been defined. Infectious agents may contribute to the development of COPD by upregulating inflammatory mediators in the lung that act in concert with cigarette smoke to promote lung pathology. Studies in human subjects and non-human primate models of AIDS suggest that the inflammatory response to asymptomatic carriage or colonization by the opportunistic pathogen, Pneumocystis sp. (Pc), is similar to that of COPD, which is characterized by influx of CD8+ T cells, neutrophils, and macrophages into the lungs. We have shown a high frequency of Pc colonization among asymptomatic HIV-infected subjects and in non-HIV infected subjects with COPD. To investigate the role of Pc in the progression of obstructive lung disease in HIV infections, we developed a non-human primate model of Pc colonizatoin and infection in simian immunodeficiency virus (SIV)-infected macaques. These animals develop a prolonged colonization state characterized by a persistent influx of CD8+ T cells and neutrophils, and local increases in IL-8, IFN-gamma, and TNF-alpha. SIV-infected Pc-colonized monkeys show progressive decline in pulmonary function compared to SIV-infected monkeys. We hypothesize that in the context of AIDS-immune dysfunction, Pc colonization induces inflammatory responses leading to changes in pulmonary function and architecture similar to that seen in emphysema. Information gained from these studies will lead to the development of interventions to prevent lung injury associated with Pc colonization and the development of HIV-associated COPD.
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PMID:Pneumocystis colonization, airway inflammation, and pulmonary function decline in acquired immunodeficiency syndrome. 1733 78

The functional capacity of alveolar macrophages (AM) in human immunodeficiency virus (HIV)-infected patients with pulmonary tuberculosis (TB) is not completely understood. To investigate the capacity of AM to mediate inflammatory responses, we obtained AM from human subjects by bronchoalveolar lavage (BAL) and studied the cells ex vivo. We compared AM from HIV-infected patients with suspected pulmonary TB to AM from healthy, HIV-negative controls for their capacity to produce TNF-alpha or IL-6 spontaneously and upon stimulation with lipopolysaccharide (LPS). Cytokine-producing cells were identified by macrophage markers and intracellular cytokine staining and flow cytometry. A higher proportion of AM from patients with microbiologically confirmed pulmonary TB than patients with probable TB or controls spontaneously expressed TNF-alpha shortly after isolation (geometric means: 38.5%, 23.7% and 15.8%, respectively), suggesting endogenous cytokine production. The proportions of AM spontaneously expressing TNF-alpha positively correlated with peripheral blood CD4(+) T-lymphocyte counts in patients (partial r=0.60, p=0.003) but not controls. Stimulation with LPS resulted in a significant increase in the proportions of TNF-alpha- and IL-6-positive AM from patients and controls (p<0.01). Bronchoalveolar lavage fluid (BALF) from confirmed TB patients also contained higher concentrations of the inflammatory cytokines predominantly produced by macrophages, IL-6 and IL-8, than controls (geometric mean cytokine concentrations per gram of BALF albumin were 1291 pg/g vs. 115 pg/g, p=0.03 for IL-6 and 4739 pg/g vs. 704 pg/g, p=0.03 for IL-8). We concluded that AM from HIV-infected patients with pulmonary TB produced and released inflammatory cytokines in vivo and retained their innate ability to respond to stimulation by LPS.
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PMID:Alveolar macrophages from HIV-infected patients with pulmonary tuberculosis retain the capacity to respond to stimulation by lipopolysaccharide. 1764 88

Human cytomegalovirus (HCMV) and human immunodeficiency virus type-1 (HIV-1) infect the female genital tract. A human cervical explant model was developed to study single and dual infection by these viruses in the genital compartment. An HCMV strain expressing green fluorescent protein, and two clinical HCMV strains produced peak viral DNA copies at 14 to 21 days post-infection. Peak levels of HIV-1(Ba-L) p24 antigen occurred at 7 days post-infection. HIV-1(Ba-L) appeared to enhance HCMV in co-infected tissues. Singly and dually infected explants produced increased levels of cytokines IL-6, IL-8, and GRO-alpha in culture supernatants. Immunohistochemical and flow cytometric analysis showed HCMV infection of leukocytes with the phenotype CD45+/CD1a+/CD14+/HLA-DR+ but not stromal or endothelial cells. Cells expressing both GFP and HIV-1 p24 antigen were detected in co-infected tissues. The cervical explants provide an ex vivo human model for examining mechanisms of virus-virus interaction and pathogenesis in clinically relevant tissue.
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PMID:Human cytomegalovirus and human immunodeficiency virus type-1 co-infection in human cervical tissue. 1771 3

In this second review on chemokines, we focus on the polymorphisms and alternative splicings and on their consequences in disease. Because chemokines are key mediators in the pathogenesis of inflammatory, autoimmune, vascular and neoplastic disorders, a large number of studies attempting to relate particular polymorphisms of chemokines to given diseases have already been conducted, sometimes with contradictory results. Reviewing the published data, it becomes evident that some chemokine genes that are polymorphic have alleles that are found repeatedly, associated with disease of different aetiologies but sharing some aspects of pathogenesis. Among CXC chemokines, single nucleotide polymorphisms (SNPs) in the CXCL8 and CXCL12 genes stand out, as they have alleles associated with many diseases such as asthma and human immunodeficiency virus (HIV), respectively. Of CC chemokines, the stronger associations occur among alleles from SNPs in CCL2 and CCL5 genes and a number of inflammatory conditions. To understand how chemokines contribute to disease it is also necessary to take into account all the isoforms resulting from differential splicing. The first part of this review deals with polymorphisms and the second with the diversity of molecular species derived from each chemokine gene due to alternative splicing phenomena. The number of molecular species and the level of expression of each of them for every chemokine and for each functionally related group of chemokines reaches a complexity that requires new modelling algorithms akin to those proposed in systems biology approaches.
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PMID:The chemokine network. II. On how polymorphisms and alternative splicing increase the number of molecular species and configure intricate patterns of disease susceptibility. 1784 70

Development of novel vaginal spermicides and anti-human immunodeficiency virus (HIV) microbicides requires careful assessment of their potential to recruit and activate CD4+ HIV-1 host cells in the female genital tract mucosa, two events that facilitate HIV-1 infection. Leukocyte traffic and activation are mediated by proinflammatory cytokines and chemokines, e.g. interleukin (IL)-1, IL-6 and IL-8, which have been detected in vaginal secretions in association with epithelial damage and infections. These proinflammatory mediators, however, have bidirectional, destructive as well as beneficial, effects on the mucosal barrier, and may be counterbalanced by endogenous inhibitors. Here we propose additional biomarkers for the evaluation of compound-induced cervicovaginal mucosal inflammation. Displaying different temporal patterns of detection, the levels of soluble E-selectin, vascular adhesion molecule-1, CD14 and myeloperoxidase in vaginal secretions reflected the mucosal leukocyte reaction to proinflammatory compounds being evaluated for safety in an improved rabbit vaginal irritation model. These biomarkers, which were also detected in human vaginal secretions, may be used to enhance the characterization of mucosal safety of vaginally applied compounds, both in animal as well as clinical studies.
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PMID:Biomarkers of leukocyte traffic and activation in the vaginal mucosa. 1785 80

Infection with human immunodeficiency virus (HIV) may affect the clinical presentation of pulmonary tuberculosis (TB). To investigate the association between sputum smear status at presentation and local pulmonary immune responses in HIV-infected patients with pulmonary TB, we compared the cellular and cytokine profiles in bronchoalveolar lavage (BAL) fluid obtained from the site of lung disease in 22 sputum smear- and culture-positive, and 17 sputum smear-negative but culture-positive pulmonary TB patients. Smear-positive patients had significantly higher BAL fluid concentrations of IL-6 (p=0.007), IL-8 (p=0.02), IL-10 (p=0.03) and IFN-gamma (p=0.008) than smear-negative patients. No significant differences in the proportions of examined BAL cells were found. We concluded that sputum smear-positive TB was associated with greater pro-inflammatory and immunomodulatory cytokine responses at the site of lung disease than sputum smear-negative disease. The local immune responses may affect the clinical presentation of active pulmonary TB in HIV-infected patients.
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PMID:Association between sputum smear status and local immune responses at the site of disease in HIV-infected patients with pulmonary tuberculosis. 1791 85

CXCL8 is a CXC chemokine that recruits leukocytes to sites of inflammation. Expression of CXCL8 in the CNS has been demonstrated in neuroinflammatory diseases, including human immunodeficiency virus (HIV-1) encephalitis, but the mechanism of secretion of this chemokine is not fully understood. CD40 is a 50-kDa protein on the surface of microglia, and we have previously shown that it is increased in expression in HIV-1-infected brain tissue as well as by interferon-gamma (IFNgamma) in tissue culture. We examined the expression and regulation of CXCL8 in cultured human fetal microglia after ligation of CD40 with soluble trimeric CD40 ligand (sCD40L) as well as the expression of CXCL8 on microglia in HIV encephalitic brain tissue sections. Treatment of cultured microglia with IFNgamma + sCD40L resulted in significant induction of CXCL8. This expression was mediated by activation of the ERK1/2 MAPK pathway, as demonstrated by ELISA and Western blot using a specific inhibitor (U0126). Gel shift analyses demonstrated that NFkappaB and AP-1, but not C/EBPbeta, mediate microglial CXCL8 production. We also found increased colocalization of CXCL8 with CD68/CD40-positive cells in HIV encephalitic brain tissue compared with HIV-infected nonencephalitic and normal tissue. Thus, CD40-CD40L interactions facilitate chemokine expression, leading to the influx of inflammatory cells into the CNS. These events can lead to the pathology that is associated with neuroinflammatory diseases.
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PMID:CD40-CD40 ligand interactions in human microglia induce CXCL8 (interleukin-8) secretion by a mechanism dependent on activation of ERK1/2 and nuclear translocation of nuclear factor-kappaB (NFkappaB) and activator protein-1 (AP-1). 1791 46

Hyper IgE syndromes (HIES) are primary immunodeficiency disorders of unknown pathogenesis. Patients are typically affected with 'cold' abscesses of the skin, recurrent cyst-forming pneumonia, chronic mucocutaneous candidiasis and other less frequent features such as progressive skeletal abnormalities. Defective signaling in the Toll-like receptor (TLR) pathways has been suggested as a responsible pathologic mechanism, however, in previous reports, 10 patients revealed no defect in inflammatory cytokine responses to different TLR ligands. Here, we report the increase in pro-inflammatory cytokines TNF-alpha and IL-8, following TLR2 and TLR4 stimulation in a larger cohort of 25 additional patients with HIES, and provide a meta-analysis of the TLR data in HIES.
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PMID:Toll-like receptor stimulation induces higher TNF-alpha secretion in peripheral blood mononuclear cells from patients with hyper IgE syndrome. 1826 86


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