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 product of the obese gene (ob) is the protein leptin, which is synthesized in and secreted from adipocytes. Fasting serum leptin concentrations are closely related to body fat content and are higher in obese than in normal-weight individuals. Leptin may contribute to body weight regulation. Overproduction of leptin in certain pathologic conditions such as acquired immunodeficiency syndrome (AIDS) might in principle contribute to the low body fat content associated with body wasting. We measured fasting serum leptin levels by radioimmunoassay in individuals infected with the human immunodeficiency virus (HIV) and in a group of healthy lean men to determine whether HIV infection increases leptin levels. Thirteen HIV-infected men aged 26 to 50 years with a body mass index (BMI) of 15 to 26 kg/m2 and 4 to 24 kg body fat (7% to 29% body fat) had serum leptin levels (3.4 +/- 1.6 ng/mL) that were not elevated compared with the levels in 17 healthy men (4.0 +/- 1.4 ng/mL) matched for age (23 to 47 years), BMI (18 to 26 kg/m2), and body fat (5 to 21 kg; 9% to 28%). In both groups of men, serum leptin concentrations were correlated with percent body fat and body fat content (P < .001), and these relationships were not different between the two groups. In both groups, leptin concentrations were not correlated with lean body mass (P > or = .24). Energy intake in the HIV-infected men, assessed from 3-day intake records, was within the normal range. These findings extend the hypothesis that circulating leptin concentrations directly reflect adipose tissue mass, even in HIV-infected men with low body fat content. These findings do not support the hypothesis that HIV infection is associated with high circulating leptin concentrations, and suggest that low leptin levels do not stimulate food intake in HIV-infected individuals.
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PMID:Serum leptin concentrations in human immunodeficiency virus-infected men with low adiposity. 905 74

Malnutrition, secondary to deficiency in uptake of proteins, metal elements or vitamins, consistently results in changes in the thymus gland. The organ undergoes a severe atrophy due to apoptosis-induced thymocyte depletion, particularly affecting the immature CD4(+) CD8(+) cells, as well as a decrease in cell proliferation. Such a feature is apparently linked to a hormonal imbalance, involving decrease of leptin and consequent raise of glucocorticoid hormone levels in the serum. Interestingly, this picture can be reversed after appropriate diet rehabilitation. The thymic microenvironment is also affected in malnutrition: morphological changes in thymic epithelial cells were found, together with a decrease of thymic hormone production by these cells. Additionally, intrathymic contents of extracellular proteins, such as fibronectin, laminin and collagens, are increased in the thymuses from malnourished children. Conjointly, the bulk of data discussed herein clearly points to the notion that the thymus gland is a target in malnutrition. Nevertheless, further relevant information regarding the physiology of the thymus, including the cytokine/chemokine secretion as well as the positive and negative selection events driven by TCR/MHC-peptide interactions in malnutrition, remains to be defined. These are questions that need to be answered in order to have a better understanding of the immunodeficiency seen in malnourished individuals.
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PMID:The thymus gland is a target in malnutrition. 1214 62

Highly active antiretroviral therapy, which includes a combination of protease inhibitors, is highly successful in controlling human immunodeficiency virus (HIV) infection and reducing the morbidity and mortality of autoimmune deficiency syndrome (AIDS). However, the benefits of HIV protease inhibitors are compromised by numerous undesirable side effects. These include peripheral fat wasting and excessive central fat deposition (lipodystrophy), overt hyperlipidemia, and insulin resistance. The mechanism associated with protease inhibitor-induced metabolic abnormalities is multifactorial. One major effect of the protease inhibitor is its suppression of the breakdown of the nuclear form of sterol regulatory element binding proteins (nSREBP) in the liver and adipose tissues. Hepatic accumulation of nSREBP results in increased fatty acid and cholesterol biosynthesis, whereas nSREBP accumulation in adipose tissue causes lipodystrophy, reduces leptin expression, and promotes insulin resistance. The HIV protease inhibitors also suppress proteasome-mediated breakdown of nascent apolipoprotein (apo) B, thus resulting in the overproduction and secretion of triglyceride-rich lipoproteins. Finally, protease inhibitor also suppresses the inhibition of the glucose transporter GLUT-4 activity in adipose and muscle. This latter effect also contributes directly to insulin resistance and diabetes. These adverse effects need to be alleviated for long-term use of protease inhibitor therapy in treatment of HIV infection.
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PMID:Effects of HIV protease inhibitor therapy on lipid metabolism. 1254 52

The relationship between the adipocyte-derived hormone leptin, insulin resistance, and fat redistribution in patients with human immunodeficiency virus (HIV) infection has not been established. We classified a cohort of HIV type 1 (HIV-1)-infected patients with >or=6 months of antiretroviral exposure as having no lipodystrophy (51 patients [43% of the cohort]), lipoatrophy (23 patients [19% of the cohort]), mixed lipodystrophy (29 patients [24% of the cohort]), or lipohypertrophy (17 patients [14% of the cohort]), on the basis of physical examination, anthropometric measurements, and the findings of dual-emission x-ray absorptiometry and computed tomography. Measurements of insulin resistance were higher for patients with each category of lipodystrophy, compared with those observed for patients with no lipodystrophy (P<.001). Mean leptin levels (+/- standard deviation) were lowest in patients with lipoatrophy (1.76+/-1.20 ng/mL), highest in patients with lipohypertrophy (9.10+/-6.86 ng/mL), and significantly different from those in patients without lipodystrophy (3.14+/-2.30 ng/mL; both P<.01). In this cohort of antiretroviral-experienced HIV-infected patients, a low serum level of leptin was independently associated with insulin resistance in patients with lipoatrophy, after controlling for total and regional body fat.
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PMID:Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. 1262 66

Lipodystrophy (LD) is a well-recognised clinical syndrome of peripheral fat atrophy and central adiposity, often associated with laboratory abnormalities such as dyslipidemia and glucose intolerance, and probably linked to insulin resistance. The long-term consequences of LD and its potential association with cardiovascular disease remain unknown. The visceral fat accumulation is characterised by the increased, abundant secretion of a number of peptides such as leptin, insulin-like growth factor (IGF), adiponectin and the recently reported resistin and visfatin hormones. Elevated resistin and tumour necrosis factor (TNF-alpha) levels and low levels of adiponectin secretion may have implications for the risk of development of type 2 diabetes and cardiovascular disease. LD is observed not only in rare autosomal syndromes, but also in patients positive for the human immunodeficiency virus (HIV) who have been treated with protease inhibitors. Both the origin of LD and its treatment deserve more attention and further research in clinical settings.
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PMID:Health risks of lipodystrophy and abdominal fat accumulation: therapeutic possibilities with leptin and human growth hormone. 1291 18

The lipodystrophy syndrome (adipose tissue redistribution and metabolic abnormalities) observed with highly active antiretroviral therapy (HAART) during human immunodeficiency virus (HIV) infection may be related to increased proinflammatory cytokine activity. We measured acute cytokine (TNF-alpha, IL-6, leptin), glycerol, and lactate secretion from abdominal subcutaneous adipose tissue (SAT), and systemic cytokine levels, in HIV-infected subjects with and without lipodystrophy (HIVL+ and HIVL-, respectively) and healthy non-HIV controls. Lipodystrophy was confirmed and characterized as adipose tissue redistribution in HIVL+ compared with HIVL- and controls, by dual-energy X-ray absorptiometry and by whole body MRI. TNF-alpha secretion from abdominal SAT and circulating levels of IL-6, soluble TNF receptors I and II, and insulin were elevated in HIVL+ relative to HIVL- and/or controls, particularly in HIVL+ undergoing HAART. In the HIV-infected group as a whole, IL-6 secretion from abdominal SAT and serum IL-6 were positively associated with visceral fat and were negatively associated with the relative amount of lower limb adipose tissue (P < 0.01). Decreased leptin and increased lactate secretion from abdominal SAT were specifically associated with HAART. In conclusion, increased cytokine secretion from adipose tissue and increased systemic proinflammatory cytokine activity may play a significant role in the adipose tissue remodeling and/or the metabolic abnormalities associated with the HIV-lipodystrophy syndrome in patients undergoing HAART.
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PMID:Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy. 1453 65

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia. Leptin has been implicated as an antiapoptotic compound as well as a stimulant of the immune response. Leptin administration is capable of reversing the immune deficiency that occurs upon starvation. We investigated a possible role for leptin in CVID; a condition associated with lowered plasma leptin levels. Thirty-eight patients were studied. Addition of leptin to the tissue culture media of PBMC from CVID patients increased the proliferative response of lymphocytes to mitogens and decreased activation-induced apoptosis of these cells. IL-2 and specially IL-4 production also increased significantly upon addition of leptin to the PBMC cultures. Our results suggest that leptin may be involved in some of the cellular defects observed in CVID and indicate a novel therapeutic strategy to improve immune function in these patients.
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PMID:Exogenous leptin restores in vitro T cell proliferation and cytokine synthesis in patients with common variable immunodeficiency syndrome. 1563 48

The development of active tuberculosis after infection with Mycobacterium tuberculosis is almost invariably caused by a persistent or transient state of relative immunodeficiency. Leptin, the product of the obese (ob) gene, is a pleiotropic protein produced mainly by adipocytes and is down-regulated during malnutrition and starvation, conditions closely connected with active tuberculosis. To investigate the role of leptin in tuberculosis, we intranasally infected wild-type (Wt) and leptin-deficient ob/ob mice with live virulent M. tuberculosis. Ob/ob mice displayed higher mycobacterial loads in the lungs after 5 and 10 weeks of infection, although the difference with Wt mice remained 1 log of M. tuberculosis colony forming unit. Nevertheless, ob/ob mice were less able to form well-shaped granuloma and lung lymphocyte numbers were reduced compared with Wt mice early during infection. In addition, ob/ob mice had a reduced capacity to produce the protective cytokine IFNgamma at the site of the infection early during infection and upon antigen-specific recall stimulation, and showed reduced delayed-type hypersensitivity reaction to intra-dermal tuberculin purified protein derivative. Leptin replacement restored the reduced IFNgamma response observed in ob/ob mice. Mortality did not differ between ob/ob and Wt mice. These data suggest that leptin plays a role in the early immune response to pulmonary tuberculosis.
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PMID:Pulmonary Mycobacterium tuberculosis infection in leptin-deficient ob/ob mice. 1614 Dec 43

Nonviral gene transfer is markedly enhanced by the application of in vivo electroporation (also denoted electro-gene transfer or electrokinetic enhancement). This approach is safe and can be used to deliver nucleic acid fragments, oligonucleotides, siRNA, and plasmids to a wide variety of tissues, such as skeletal muscle, skin and liver. In this review, we address the principles of electroporation and demonstrate its effectiveness in disease models. Electroporation has been shown to be equally applicable to small and large animals (rodents, dogs, pigs, other farm animals and primates), and this addresses one of the major problems in gene therapy, that of scalability to humans. Gene transfer can be optimized and tissue injury minimized by the selection of appropriate electrical parameters. We and others have applied this approach in preclinical autoimmune and/or inflammatory diseases to deliver either cytokines, anti-inflammatory agents or immunoregulatory molecules. Electroporation is also effective for the intratumoral delivery of therapeutic vectors. It strongly boost DNA vaccination against infectious agents (e.g., hepatitis B virus, human immunodeficiency virus-1) or tumor antigens (e.g., HER-2/neu, carcinoembryonic antigen). In addition, we found that electroporation-enhanced DNA vaccination against islet-cell antigens ameliorated autoimmune diabetes. One of the most likely future applications, however, may be in intramuscular gene transfer for systemic delivery of either endocrine hormones (e.g., growth hormone releasing hormone and leptin), hematopoietic factors (e.g., erythropoietin, GM-CSF), antibodies, enzymes, or numerous other protein drugs. In vivo electroporation has been performed in humans, and it seems likely it could be applied clinically for nonviral gene therapy.
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PMID:Electroporation-enhanced nonviral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases. 1661 Oct 45

Lipodystrophy (lipo) and metabolic derangements associated with an increased cardiovascular risk are observed frequently in human immunodeficiency virus (HIV)-infected patients who receive antiretroviral treatment (ART). The objective of the study was to provide detailed biochemical information about metabolic syndrome in this condition. One hundred forty-six HIV-infected male and female patients on ART for more than 6 months were compared with 156 body mass index (BMI)-matched healthy subjects. Lipodystrophy was diagnosed upon patient and physician concordance. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. Plasma adiponectin (AD) and leptin were measured by radioimmunoassay. Insulin resistance (IR) was assessed by the homeostasis model assessment (HOMA). The prevalence of metabolic syndrome was higher in HIV-infected patients on ART than in non-HIV-infected healthy controls (15.8% vs 3.2%; P < .001). Patients with metabolic syndrome are older (44.6 +/- 6 vs 39.8 +/- 8 years; P = .004), have an increased BMI (24.9 +/- 3.8 vs 22.9 +/- 9.8 kg/m(2); P = .01), present with a reduced AD-to-leptin ratio log(10) (-0.19 +/- 0.4 vs 0.5 +/- 0.4; P = .04), and show increased IR (HOMA, 5.6 +/- 2.7 vs 3.8 +/- 2.2; P = .001; plasma fasting insulin, 22.9 +/- 9.8 vs 16.6 +/- 9.7 ng/mL; P < .001). In multivariate analysis, the diagnosis of lipo and HOMA were independently and significantly related to metabolic syndrome. In conclusion, the prevalence of metabolic syndrome is significantly increased in HIV-infected patients on ART and its presence is associated with lipo, increased age and BMI, IR, and a reduced plasma AD-to-leptin ratio.
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PMID:Lipodystrophy and metabolic syndrome in HIV-infected patients treated with antiretroviral therapy. 1678 68


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