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)

The transforming growth factor-beta family of polypeptides includes three related isoforms with pervasive effects on immune system function. In this study, the authors evaluated human brains with human immunodeficiency virus (HIV)-1 encephalitis for transforming growth factor beta (TGFbeta)1, TGFbeta2, and TGFbeta3 immunoreactivity using isoform-specific polyclonal antibodies and avidin-biotin immunohistochemistry. Normal brains and those with progressive multifocal leukoencephalopathy, toxoplasma encephalitis, and cryptococcal meningitis were used as controls. In normal controls, TGFbeta1, TGFbeta2, and TGFbeta3 immunoreactivity were confined to arachnoid cells and blood vessels. In 9 of 10 cases of HIV-1 encephalitis, all three isoforms were also detected in arachnoid cells. In addition, variable, predominantly TGFbeta2 and TGFbeta3 immunoreactivity were also detected in reactive astrocytes and mononuclear cells of white matter lesions. Extensive TGFbeta3 immunoreactivity was also detected in multinucleated giant cells in one case. In a case of cryptococcal meningitis, all three isoforms were detected in arachnoid cells and macrophages. Lesions of progressive multifocal leukoencephalopathy and toxoplasma encephalitis also exhibited TGFbeta1, TGFbeta2, and TGFbeta3 immunostaining in reactive astrocytes. These findings suggest that TGFbeta isoforms are present in HIV-1 encephalitis and may participate in the pathogenesis of this and other inflammatory central nervous system (CNS) lesions associated with acquired immunodeficiency syndrome (AIDS).
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PMID:Distribution of transforming growth factor-beta isoforms in human immunodeficiency virus-1 encephalitis. 869 6

Central nervous system (CNS) involvement is common during human immunodeficiency virus type-1 (HIV-1) infection. The neurologic disease of the CNS most frequently observed during acquired immunodeficiency syndrome (AIDS) is HIV-1-associated cognitive/motor complex or AIDS dementia complex (ADC), which is most likely a direct consequence of HIV-1 infection of the CNS. The peripheral nervous system (PNS) is also affected in HIV-1-infected individuals and there are several features of immune- and cytokine-related pathogenesis in both the CNS and PNS that are reviewed. Several lines of evidence demonstrate aspects of immune activation in the CNS and peripheral nervous system (PNS) of HIV-1-infected individuals. The relative paucity of HIV-1 expression in contrast to widespread functional and pathologic changes in the CNS and PNS of AIDS patients, and the lack of evidence of productive infection of HIV-1 in neuronal cells in vivo lead to the possibility of indirect or immunopathogenic mechanisms for HIV-1-related neurologic diseases. Proposed mechanisms of neuronal and glial cell damage are injury of oligodendrocytes by tumor necrosis factor-alpha (TNF-alpha) released from activated macrophage/microglia, calcium-dependent excitoneurotoxicity induced by gp120 HIV-1 envelope protein, N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity by quinolinic acid (a product of activated macrophages), cell injury by HIV-1-specific cytotoxic T cells, and apoptosis of oligodendrocytes or neurons triggered by interaction between cell surface receptors and HIV-1 gp120 protein. Common to those mechanisms is the dependence on cellular activation with expression of proinflammatory cytokines (TNF-alpha, interleukin-1). Amplification of activation signals through the cytokine network by macrophage/astrocyte/endothelial cell interactions, and cell-to-cell contact between activated macrophages and neural cells by upregulation of adhesion molecules dramatically enhances the toxic effect of macrophage products. Expression of immunosuppressive cytokines such as interleukin-4, interleukin-6, and transforming growth factor-beta is also increased in the CNS and PNS of HIV-1-infected patients. This may serve as neuroprotective and regenerative mechanism against insults to nervous system tissue.
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PMID:Role of immune activation and cytokine expression in HIV-1-associated neurologic diseases. 874 77

The introduction of molecular therapy through the delivery of nucleic acids either as oligonucleotides or genetic constructs holds enormous promise for the treatment of renal disease. Significant barriers remain, however, before successful organ-specific molecular therapy can be applied to the kidney. These include the development of methods to target the kidney selectively, the definition of vectors that transduce renal tissue, the identification of appropriate molecular targets, the development of constructs that are regulated and expressed for long periods of time, the demonstration of efficacy in vivo, and the demonstration of safety in humans. As the genetic and pathophysiologic basis of renal disease is clarified, obvious targets for therapy will be defined, for example, polycystin in polycystic kidney disease, human immunodeficiency virus (HIV) type 1 in HIV-associated nephropathy, alpha-galactosidase A in Fabry's disease, insulin in diabetic nephropathy, and the "minor" collagen IV chains in Alport's syndrome. In addition, several potential mediators of progressive renal disease may be amenable to molecular therapeutic strategies, such as interleukin-6, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta(TGF-beta). To test the in vivo efficacy of molecular therapy, appropriate animal models for these disease states must be developed, an area that has received too little attention. For the successful delivery of genetic constructs to the kidney, both viral and nonviral vector systems will be required. The kidney has a major advantage over other solid organs since it is accessible by many routes, including intrarenal artery infusion, retrograde delivery through the uroexcretory pathways, and ex vivo during transplantation. To further restrict expression to the kidney, tropic vectors and tissue-specific promoters also must be developed. For the purpose of inhibition of endogenous or exogenous genes, current therapeutic modalities include the delivery of antisense oligodeoxynucleotides or ribozymes. For these approaches to succeed, we must gain a much better understanding of the nature of their transport into the kidney, requirements for specificity, and in vivo mechanisms of action. The danger of a rush to clinical application is that superficial approaches to these issues will likely fail and enthusiasm will be lost for an area that should be one of the most exciting developments in therapeutics in the next decade.
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PMID:Molecular therapy for renal diseases. 884 Sep 36

Limited information is available about the pathogenesis of acquired immune deficiency syndrome (AIDS)-associated idiopathic interstitial pneumonitis, a common noninfectious complication of human immunodeficiency virus (HIV) infection. Infection of C57B1/6 mice with LP-BM5 retrovirus, a murine model of AIDS, leads to development of a diffuse interstitial pneumonitis that displays many features of human AIDS-associated interstitial pneumonitis. To further characterize the cellular and molecular features of this lung disease, the temporal development of cellular infiltration, cytokine expression, and virus replication were evaluated in lung tissue of virus-infected mice. Persistent expression of viral RNA was detectable in lungs as early as 1 wk after infection. Infiltration of the lungs by CD4+ and CD8+ T cells, by IgG+ and IgA+ B cells, and by macrophages was observed by 4 wk after infection and continued through 8 wk of infection. Histologically, cellular infiltration was most pronounced in peribronchial and perivascular regions, whereas inflammation of alveolar septae and alveolar spaces was minimal. In contrast to normals, T cells from infected lungs were immunodeficient in that they failed to proliferate in response to the mitogen concanavalin A (ConA). However, evaluation of cytokine mRNA expression by interstitial lung lymphoid cells indicated that cells from infected lungs were chronically activated, in that elevated expression of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) was observed throughout the course of infection. Similarly, expression by interstitial lung lymphoid cells of mRNA for the proinflammatory cytokine IL-1 and the fibrogenic cytokine transforming growth factor-beta (TGF-beta) was also increased following infection. These results indicate that retrovirus-induced immunodeficiency in mice is associated with infiltration and chronic activation of lymphoid cells in the lungs. Furthermore, simultaneous expression of IL-10, IFN-gamma, and TGF-beta suggests that cytokine-expressing cells in infected lungs may be unresponsive to inhibitory and antiinflammatory effects of IL-10 and/or TGF-beta, thus contributing to chronicity of inflammation in this disorder.
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PMID:Pulmonary lymphoid cell activation and cytokine expression in murine AIDS-associated interstitial pneumonitis. 903 22

Both macrophages and cytokines are components of the immune defense against viral infections. Among cytokines, interferons have been the most studied and interferon-gamma which is secreted by T cells and NK cells activates macrophages which synthesize both interferon-alpha and -beta which have powerful antiviral activity. Aside from interferons other cytokines such as tumor necrosis factor-alpha and transforming growth factor-beta display an antiviral activity. Nevertheless often cytokines could mediate distinct actions in regard to viral infection and this has been demonstrated extensively in AIDS pathogenesis. We reviewed among others the interactions between human immunodeficiency virus type-1, macrophages and cytokines and would like to forward a new model for AIDS pathogenesis based on the involvement of the TNF receptor superfamily.
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PMID:Cytokines, viruses and macrophages: an interactive network. An immune dysregulation involving the members of the tumor necrosis factor (TNF) receptor superfamily could be critical in AIDS pathogenesis. 924 33

Thrombocytopenia is a common finding in infection with equine infectious anaemia virus (EIAV), a lentivirus with some homology to human immunodeficiency virus (HIV). The thrombocytopenia of EIA, like that in some HIV patients, appears to have a multifactorial pathogenesis. To investigate the decreased platelet production seen in experimental EIA, the levels of three potential negative regulators of platelet production--tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interferon-alpha (IFN-alpha)--were measured in serum and bone marrow of six severe combined immunodeficient (SCID) foals and ten immunocompetent EIAV-infected foals. Levels of cytokines in pre-infection foal sera and bone marrow were compared with levels observed during clinical EIA. Mean serum levels of TNF-alpha and IFN-alpha were significantly higher (P < 0.05) on days -4 to 0 of thrombocytopenia than before infection. Serum TGF-beta was significantly elevated on all days except day -1 of thrombocytopenia. Bone marrow TNF-alpha levels were significantly increased in infected foals just before clinical thrombocytopenia. TGF-beta activity was not different in pre-infection and pre-thrombocytopenia bone marrows, but levels of TGF-beta protein as determined by immunohistochemical staining were significantly higher in pre-thrombocytopenia bone marrow. IFN-alpha activity in bone marrow increased just before thrombocytopenia, but the difference was not significant at P < 0.05. Serum TNF-alpha levels were 2-2.5 times higher in SCID foals on three of the days prior to thrombocytopenia than in immunocompetent foals. No significant differences were found between the levels in SCID and immunocompetent foals of serum and bone marrow TGF-beta or IFN-alpha at any of the times examined.
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PMID:Elevation of cytokines associated with the thrombocytopenia of equine infectious anaemia. 934 75

1. This manuscript describes two different strategies to progress from the clinical assessment of patients to the identification of disease-causing mutations. In the first disease, recognition of a metabolic abnormality allowed direct molecular analysis of the causal gene. In contrast, localization of the second disease gene by linkage analysis was critical to implicate a gene with a previously unsuspected disease role. 2. Two sisters with chronic respiratory disease and recurrent infections were identified as the first cases of adult onset immunodeficiency due to adenosine deaminase deficiency. Autosomal recessive inheritance of two mutations in the adenosine deaminase gene was demonstrated. Enzyme replacement therapy improved the patients' immunological and clinical status. 3. Individuals with pulmonary arteriovenous malformations were used to identify families with hereditary haemorrhagic telangiectasia (HHT, Rendu-Osler-Weber Syndrome). Linkage studies mapped the HHT disease gene in some families to chromosome 9, and demonstrated genetic heterogeneity. The chromosome 9 disease interval was refined, and several candidate genes were assessed. Following the first description of disease-segregating mutations, a complete analysis of the endoglin gene (which encodes an endothelial cell transforming growth factor-beta receptor) identified seven novel mutations. Two mutations did not produce mutant mRNA, and disease severity was comparable between families, indicating that HHT results from stoichiometric insufficiency of endoglin. 4. Each study has implications extending beyond the relatively rare disease analysed. The adenosine-deaminase-deficient patients highlight a treatable cause of HIV-negative CD4+ lymphopenia in adults, perhaps accounting for further cases of 'non-HIV AIDS'. The HHT studies have illuminated a novel area of vascular pathophysiology, with potential relevance to further disease states.
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PMID:Glaxo/MRS Young Investigator Medal. Molecular studies on adenosine deaminase deficiency and hereditary haemorrhagic telangiectasia. 961 53

Reactive oxygen species are implicated in the pathogenesis of several diseases, including Alzheimer's disease, multiple sclerosis, human immunodeficiency virus, and liver fibrosis. With respect to liver fibrosis, we have investigated differences in antioxidant enzymes expression in stellate cells (SCs) and parenchymal cells from normal and CCl(4)-treated rat livers. We observed an increase in the expression of catalase in activated SCs. Treatment with transforming growth factor-beta (TGF-beta) increased the production of H(2)O(2). Treatment with catalase decreased TGF-beta expression. Addition of H(2)O(2) resulted in increased TGF-beta production. 3-Amino-1,2,4-triazole abolished the capacity of SCs to remove H(2)O(2). A paradoxical increase in capacity was observed when the cells were pretreated with diethyl maleate. Treatment with 3-amino-1, 2,4-triazole increased TGF-beta production. A paradoxical decrease of TGF-beta production was observed with diethyl maleate. Treatment of the cells with N-acetylcysteine resulted in increased TGF-beta production. TGF-beta decreased the capacity of the SCs to remove H(2)O(2.) An increase in the capacity to remove H(2)O(2) was observed when TGF-beta was removed by neutralizing antibodies. In conclusion, our results suggest: 1) a link between cellular GSH levels and TGF-beta production and 2) that cellular GSH levels discriminate whether H(2)O(2) is the result of oxidative stress or acts as second messenger in the TGF-beta signal transduction pathway.
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PMID:Glutathione levels discriminate between oxidative stress and transforming growth factor-beta signaling in activated rat hepatic stellate cells. 1056 49

Since it was first described as having the ability to inhibit macrophage activation, transforming growth factor-beta (TGF-beta) has been analyzed for its role in regulating immune responses to a variety of pathogens, including viruses, bacteria, yeast, and protozoa. Most of the studies have involved organisms that infect macrophages, and this discussion will attempt to highlight these findings. Perhaps the most work has been performed with protozoan pathogens, including Trypanosoma cruzi and a variety of Leishmania species, so the discussion will begin with these organisms. Other studies have focused on mycobacteria and viruses, including human immunodeficiency virus, so these areas will also be emphasized in the discussion. For the most part, investigators have reported that TGF-beta has, as expected, a negative influence on host responses and a beneficial effect on the survival and growth of intracellular pathogens. However, other studies have found that TGF-beta may have a positive or beneficial effect in some models of infection. This review will attempt to highlight studies and conclusions on the roles of TGF-beta in infection.
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PMID:TGF-beta in infections and infectious diseases. 1061 60

To identify potential roles of cytokines in retroviral pathogenesis, we used reverse transcription-quantitative competitive polymerase chain reaction (RT-qcPCR) assays to characterize mRNA levels of 19 different lymphokines, chemokines, monokines and hematopoietic growth factors in three feline cell lines productively infected with subgroup A feline leukemia virus (FeLV-A) or various feline immunodeficiency virus (FIV) strains. Infection of a CD8+, CD5- large granular lymphocyte (LGL) cell line with FeLV-A activated expression of interleukin-7 (IL-7), induced modest (4-fold) increases in granulocyte/macrophage colony-stimulating factor (GM-CSF) and leukemia inhibitory factor (LIF) transcripts, and decreased transforming growth factor-beta (TGF-beta) mRNA (4-fold). The LGL cells were not susceptible to infection by FIV. Infection of MYA-1 cells, a CD4+ T-lymphoblastoid cell line, with FeLV-A activated expression of macrophage inflammatory protein-1alpha (MIP-1alpha), increased transcript levels of GM-CSF (8-fold), macrophage CSF (M-CSF) (16-fold) and stem cell factor (SCF) (250-fold), and decreased (4-fold) expression of IL-10 and tumor necrosis factor-alpha (TNF-alpha). Productive infection with four different FIV molecular clones caused progressive MYA-1 cell death; however, the mRNA expression profiles were unchanged except for 2- to 4-fold increases in M-CSF and 16- to 500-fold increases in SCF. Thus, FIV-induced MYA-1 cytopathicity was not associated with dysregulation of pro-apoptotic or survival factor transcript levels. Lastly, productive infection of PNI cells, a marrow-derived fibroendothelial cell line, with FeLV-A or any of three FIV strains induced 4-fold higher levels of IL-12p40 transcripts and variably higher levels (4- to 64-fold) of GM-CSF. Two viral strains, the FIV-14 molecular clone and the clinical isolate FIV-5122, caused syncytia formation and unique activation of IL-1beta and stromal cell-derived factor-1 (SDF-1) expression, suggesting a potential role for those factors in viral spread and/or cytopathicity. In addition, infection with FIV-5122, but not the other FIV strains or FeLV-A, induced significant increases in mRNA levels of the hematopoietic inhibitors TNF-alpha and MIP-1alpha, along with increased concentrations of soluble proteins in culture supernatants. Consistent with this, supernatant from FIV-5122 infected PNI cells suppressed hematopoietic progenitor growth in colony assays, compared to supportive activities in supernatants from other infected or uninfected PNI cell cultures. Together, these data demonstrate that feline retroviruses alter cytokine mRNA levels in general and strain-specific patterns. These changes may result in specific alterations in cell function and contribute to retroviral pathogenesis. Our observations provide a basis for directed studies of candidate factors within the hematopoietic, thymic and lymphoid microenvironments.
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PMID:The effects of feline retroviruses on cytokine expression. 1062 77


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