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:C0409974 (lupus)
22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon (IFN) resistance is an important factor in the pathophysiology of neoplastic disorders, certain viral infections (e.g., AIDS), and autoimmune diseases (e.g., lupus erythematosus and Wegner's granulomatosis). In addition, in some of these disorders, there is also decreased ability to produce IFNs. The capacity of viruses and neoplastic processes to interfere with the IFN system are thought to represent a "virus-against-host" or "cancer-against-host" defense mechanism. Four resistance factors have been identified: 1) release of free IFN-alpha/beta type 1 receptors into the circulation that, at appropriate concentrations, capture and inactivate IFNs; 2) a new IFN inhibitory protein has been isolated and its chemical structure is under study; 3) prostaglandin E2, which is produced by certain tumor cells, inhibits IFN production; and 4) high levels of cAMP phosphodiesterases present, for example in certain tumor cells, reduces cAMP, an important second messenger in IFN synthesis. Studies are under way to reverse these inhibitory effects and to increase endogenous interferon production.
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PMID:Interferons and interferon inhibitory activity in disease and therapy. 1504 11

The heart is one of a number of organs that may be affected in systemic lupus erythematosus (SLE), a prototypic autoimmune disease. Potential anatomical sites of involvement include the myocardium, pericardium, endocardium, valves, conduction system and blood vessels that subserve the heart. Typically, the severity of cardiovascular disease in lupus correlates with the degree of systemic inflammation, which is mirrored by the level of C-reactive protein (CRP) in the plasma. C-reactive protein, in turn is regulated by proinflammatory cytokines, such as interleukins (ILs) 1beta and 6. These cytokines have been found in functionally and/or structurally damaged areas of the heart and have been implicated in disease pathogenesis. It has been assumed that the source of these putatively pathogenetically relevant cytokines in the compromised heart is infiltrating mononuclear cells. This study tests the hypothesis that cardiomyocytes per se may contribute to proinflammatory cytokine production in the setting of systemic inflammation. Using as the experimental model MRL/MpJ-Tnfrs6(lpr) (MRL-lpr/lpr) mice, which spontaneously manifest an autoimmune syndrome that has clinical features of SLE, we show that ventricular homogenates and ventricular cardiomyocytes constitutively overexpress genes encoding the proinflammatory cytokines IL-1beta, IL-6, IL-10, and gamma interferon. The results suggest the possibility that proinflammatory cytokines emanating from the heart may actually contribute to the high levels of CRP that appear to aid in predicting subsequent cardiac events. Viewed in this setting, CRP becomes a footprint of an ongoing pathogenic process mediated, in part, by the heart muscle itself.
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PMID:Proinflammatory cytokine genes are constitutively overexpressed in the heart in experimental systemic lupus erythematosus: a brief communication. 1538 94

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a complex pathogenesis involving multiple genetic and environmental contributions. DNA microarray technology has recently been applied to unravel some of this complexity through genomewide profiling. Early studies using microarray analysis of peripheral blood mononuclear cells (PBMCs) from SLE patients revealed dysregulation of inflammatory cytokines, chemokines, and immune response-related genes, as well as genes involved in apoptosis, signal transduction, and the cell cycle. More recently, using arrays containing many more genes, 4 independent research groups have found that interferon (IFN)-regulated genes are highly overexpressed in the peripheral blood and kidney glomeruli of SLE patients, supporting a crucial role for interferon in SLE. Future studies focusing on target tissues or organs in lupus, including the kidney, may further contribute to our understanding of lupus pathogenesis while providing new targets for therapy.
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PMID:Gene expression profiling in the study of the pathogenesis of systemic lupus erythematosus. 1554 98

Recent studies have suggested that type I interferons (IFN) play a role in the pathogenesis of lupus erythematosus (LE), an autoimmune disease of unknown aetiology. Natural interferon-producing plasmacytoid cells have been demonstrated in cutaneous LE (CLE) lesions, along with elevated levels of IFN-alpha mRNA. The hypothesis in the current study was that local production of type I IFNs in CLE induces Th1-biased inflammation via induction of IFN-inducible chemokines such as IP10/CXCL10 leading to the recruitment of chemokine receptor CXCR3 expressing T-cells into skin lesions. Skin biopsies from 21 patients suffering from different types of active cutaneous LE were analysed for the expression of MxA, a protein specifically induced by type I interferons, the IFN-inducible protein IP10/CXCL10, and the chemokine receptor CXCR3, characteristic for Th1 cells, by immunohistochemistry. Additionally, peripheral CD4+ and CD8+ T-cells were investigated for the expression of MxA and CXCR3 by flow cytometry. Cutaneous LE lesions were characterized by strong expression of MxA indicating the induction of localized type I IFN signalling in the skin. Large numbers of infiltrating CXCR3 positive lymphocytes were detected in CLE skin lesions, and correlated closely with lesional MxA expression (epidermis: Spearman's rho = 0.56, p < 0.001; dermis: rho = 0.82, p < 0.001). Intracellular MxA levels of circulating CD4+ and CD8+ T-cells were significantly enhanced in patients with active CLE lesions. The percentage of peripheral T-cells expressing CXCR3 was significantly decreased in specific CLE subtypes. Expression of IP10/CXCL10 in the epidermis links type I IFN signalling and recruitment of CXCR3+ T cells. These results suggest an important role for type I interferon signalling in the pathogenesis of cutaneous lupus erythematosus. It is proposed that type I IFNs induce a Th1-biased inflammatory immune response, with recruitment of CXCR3-expressing T-lymphocytes into the skin.
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PMID:Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus. 1568 90

Crohn's disease is a T helper type 1 response immune disease characterized by increased production of interleukin-12 tumor necrosis factor-a (TNF-a), and interferon-g. Clinical trials have demonstrated that inhibition of TNF is effective for the treatment of Crohn's disease. Adverse events reported in patients treated with anti-TNF agents include immunogenicity, acute infusion reactions, delayed hypersensitivity-type reactions, autoimmune diseases including drug-induced lupus and demyelination, and infection. This article reviews new concepts in the treatment of Crohn's disease and ulcerative colitis with a variety of anti-TNF biologic therapies: infliximab, adalimumab, CDP870, CDP571, etanercept, and onercept.
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PMID:New concepts in anti-tumor necrosis factor therapy for inflammatory bowel disease. 1574 28

In face of numerous benefits induced by therapy based on interferon (IFN) associated with ribavirin for the treatment of chronic hepatitis C, there is an increasing concern regarding its tolerance, which can, in some cases, reduce the quality of life as well as compliance of patients. Among the less common side effects, there are the autoimmune ones which can be globally divided into appearance or increase in titres of auto-antibodies and/or manifestation of overt autoimmune pathologies. Whereas the former may concern more than 50% of treated subjects, the latter is reported in only 1-2% of patients under therapy. Thyroid dysfunction represents the well-studied autoimmune disorder. The presence of pre-existing anti-thyroid antibodies and being of female sex, constitute relevant risk factors for the development of a disease involving this gland. Often the treatment of thyropathy must be continuous in spite of IFN discontinuation because the disturbance usually does not abate with stopping antiviral therapy. Some observations have pointed out to the fact that IFN can lead to the development of insulin-dependent diabetes mellitus. Sometimes, during, as well as after IFN treatment, the appearance of anti-islet cell antibodies has been shown, but its interrelationship with the development of disease is uncertain. While being treated with IFN for chronic hepatitis C, the finding of non-organ specific antibodies at baseline can increase the likelihood of the development of autoimmune hepatitis. However, their presence does not constitute an absolute contraindication to the treatment, except in case of high titre. Other disorders, such as a lupus erythematosus-like syndrome, haemolytic anaemia, and immune-mediated thrombocytopenia have been reported. In conclusion, although the presence of auto-antibodies is considered to be an epiphenomenon without pathogenic significance in most patients suffering from chronic hepatitis C, it poses a problem when they need to be treated with IFN. This antiviral drug can induce or exacerbate a multitude of autoimmune-related disorders, however, clinically overt immune-mediated diseases are rare and affect a subset of subjects who have an underlying autoimmune diathesis.
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PMID:Autoimmune manifestations during interferon therapy in patients with chronic hepatitis C: the hepatologist's view. 1575 46

There have been many proposed theories for effectively treating melanoma, especially through the regulation of histamine. Histamine has been proven to be a major regulator of the immune system's T-helper cell subset balance and major shifts in this balance towards TH2 cytokines have contributed to diseases such as asthma, lupus and cancer. Histamine also causes suppression of interferon-induced proteins needed for anti-tumor response and activates T-suppressor cell function in cancers such as squamous cell carcinoma and melanoma. Scientific evidence has suggested the possibility of an anthistamine approach as treatment to these diseases and for melanoma, there has been great promise. This is due to the fact that melanotic cells have been elucidated to express histamine receptors and as a result, regulation of histamine could occur specifically at the site of these epidermal growths. Another factor to consider is how effective an inflammatory response can be when combined with regulation of histamine. Inflammation is a very powerful tool against pathogenic environments by causing cytokine recruitment and migration of dendritic cells to infected sites. Adequate stimulation of an inflammatory response at the specific site of any cancerous region would greatly weaken its evasive mechanisms. However, there are no reports showing high efficacy utilizing the benefits of regulating inflammation and histamine that could cause TH1 subset levels to predominate, down-regulate T-suppressor cells, up-regulate interferon-induced proteins and properly sustain migration of dendritic cells concurrently. These benefits have been proven in separate instances for a range of diseases but have not been assessed as a combined modality for melanoma therapy. Therefore successful melanoma treatment should integrate these principles involving: the use of H2 antagonists for preventing the negative effects of histamine, monoclonal antibodies to ensure an effective dendritic cell response, and routine pro-inflammatory induction at the specific site of the melanotic tissue to ensure recognition of the cancer that has evaded immunity.
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PMID:Site specific therapy: an integrative approach to treating melanoma. 1582 92

Proteinase 3 (PR3) is a pleiotropic and destructive serine protease and it is also a major target for autoantibodies in systemic small vessel vasculitis. We have shown recently that patients in stable remission have increased circulating levels of PR3, independent of autoantibody titre, inflammation, neutrophil degranulation and renal function. Here we explore the possibility of increased PR3 gene transcription. RNA was purified from peripheral blood monocytes from vasculitis patients and controls. Specific mRNA was measured by TaqMan real-time polymerase chain reaction (PCR). The monocyte-like cell lines THP-1 and U937 and human peripheral blod monocytes from healthy controls were stimulated with cytokines and lipopolysaccharide (LPS) for different time periods. PR3 protein was measured in plasma with enzyme-linked immunosorbent assay (ELISA). The median result for PR3 mRNA was 9.6 (1.8-680) for 22 patients, compared to 1 (0.1-2.8) for the 15 healthy controls. Elastase expression was also significantly increased, whereas myeloperoxidase and interleukin-8 were not. Stimulation of monocytes with tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma or LPS did not result in any increase of PR3 or elastase transcription, whereas interleukin (IL)-8 transcription was increased 10-fold. Circulating monocytes from patients with systemic vasculitis display increased PR3 gene transcription compared to healthy controls and patients with sytemic lupus erythematosus (SLE). This may be important for the development of vasculitis. Our results do not favour a role for cytokines, antineutrophil cytoplasmic antibodies (ANCA) or immunosuppressive medication in the upregulation of PR3 transcription in vasculitis.
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PMID:Increased monocyte transcription of the proteinase 3 gene in small vessel vasculitis. 1595 84

Interferon alfa-2a is a cytokine produced by recombinant DNA techniques and has antiproliferative, antiviral and immunomodulating effects. A number of case reports in the past have suggested relative safety of alpha-interferons during pregnancy with little or no effect on the fetus. A 15-year-old adolescent became pregnant while receiving alpha-interferon for essential thrombocythemia. She delivered a small-for-gestational age baby girl at 33 weeks gestation. The infant displayed a facial rash characteristic of neonatal lupus and transient thrombocytopenia; maternal and neonatal serologies were typical for drug-induced lupus. These findings suggest probable association between maternal use of alpha interferon and adverse effects in the fetus.
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PMID:Neonatal lupus and IUGR following alpha-interferon therapy during pregnancy. 1604 33

Lupus patients selectively produce autoantibodies against nucleoproteins. Since the RNA/DNA components of these autoantigens are endogenous TLR ligands capable of stimulating Type I interferon (IFN-I) production, we asked whether autoantibodies against the ribonucleoproteins Sm/RNP and Ro60 and double-stranded DNA are associated with high levels of IFN-I. IFN-I levels were increased in SLE (n = 88) vs. other autoimmune diseases (n = 82) and controls (n = 57) (P < 0.0001) and were associated positively with autoantibodies against Sm/RNP, Ro60/La, and dsDNA but negatively with anti-phospholipid. Low numbers of circulating plasmacytoid and myeloid dendritic cells also were associated with these autoantibodies. The IFN-I and dendritic cell abnormalities correlated with disease severity and were not therapy-related. These findings suggest that immunostimulatory nucleic acid components of autoantigens may act as endogenous adjuvants by promoting IFN-I production and dendritic cell maturation, helping to explain the high prevalence of autoantibodies against nucleoprotein antigens in SLE.
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PMID:Association of anti-nucleoprotein autoantibodies with upregulation of Type I interferon-inducible gene transcripts and dendritic cell maturation in systemic lupus erythematosus. 1612 5


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