Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although elevated levels of transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) have been implicated in renal disease, the tissue distribution and cellular localization of the induced cytokines is not well established. In this study, we investigated the expression of these cytokines during the progression of lupus nephritis in MRL lpr/lpr mice. The concentration of both cytokines increased in the plasma of these animals in an age-dependent manner, and there was an age-dependent induction of TGF-beta and TNF-alpha mRNAs in their kidneys. Although the increase in TGF-beta mRNA was specific for the kidney, the increase in TNF-alpha mRNA was widespread and also could be demonstrated in the liver, lung, and heart. In situ hybridization analysis of renal tissues from the lupus-prone mice localized TGF-beta mRNA to the glomerulus, and more specifically, to resident glomerular cells and inflammatory cells infiltrating periglomerular spaces in the nephritic lesions. The signals for TNF-alpha mRNA were detected only in inflammatory cells and were distributed throughout the nephritic kidney. Plasminogen activator inhibitor-1 (PAI-1) is known to be elevated in the glomeruli of MRL lpr/lpr mice, and intraperitoneal administration of either TGF-beta or TNF-alpha into normal mice markedly induced the expression of this potent inhibitor of fibrinolysis in renal glomerular or tubular cells in vivo. These results suggest that the increased renal expression of both cytokines may contribute to the development of lupus nephritis in this model and raise the possibility that PAI-1 may be involved. The fact that TGF-beta is specifically induced in the kidney whereas TNF-alpha increases in a variety of tissues, supports the hypothesis that the renal specificity of this disorder reflects the abnormal expression of TGF-beta.
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PMID:Expression of transforming growth factor-beta and tumor necrosis factor-alpha in the plasma and tissues of mice with lupus nephritis. 1104 73

The aim of our review is to summarize common genetic variations of some receptors associated with clinical consequences, which were not outlined in the previous special issue of this journal. Because of the multiple pathomechanisms of diseases, a set of genetic variation can play a role in the development of pathological conditions. From the data available three articles would merit a greater interest. In systemic lupus erythematosus the associations related to some polymorphisms of Fc-, tumor necrosis factor (TNF) alpha- and interferon receptor may explore new autoimmunological and inflammatorical pathomechanisms. In the endocrinology, the androgen receptor repeat polymorphism will exert significant aspects in the development of prostate cancer. The pleoitropic responsibility of vitamin D3 receptor polymorphism in the pathogenesis of immunological disorders (primary biliary cirrhosis, inflammatory bowel disease, type 1 diabetes mellitus) and of malignancies (malignant melanoma, breast cancer) shed light on the importance of common nuclear receptors. Nevertheless, in the future studies a more consistent approach minimizing requirement bias in the selection of patients will approve our understanding the role of genetic influence on the pathogenesis of diseases.
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PMID:Receptor polymorphisms and diseases. 1123 Sep 90

A minority of children suffering from severe rheumatic diseases are unresponsive to conventional treatments. These patients can now be managed with a variety of immunosuppressive therapies. Methotrexate is considered the first choice disease-modifying agent for adult and juvenile rheumatoid arthritis. In patients unresponsive to low doses of methotrexate, medium or high-doses can be useful. Instead of methotrexate, a recently developed immunosuppressive drug, mycophenolate-mofetil, which inhibits T- and B-lymphocyte proliferation, can be used. Another possibility for refractory rheumatic diseases, with no increase in toxicity, is combination therapy, for example methotrexate plus cyclosporine, or methotrexate plus salazopyrine or intravenous pulses of cyclophosphamide and methylprednisone. More recently two distinct inhibitors of tumor necrosis factor (etanercept and infliximab have been used successfully for intractable rheumatic diseases (juvenile idiopathic arthritis, psoriatic arthritis, spondyloarthropathies) but the follow-up is still too short to establish their long-term effectiveness. If all these treatments are unsuccessful, an autologous bone marrow transplantation can be proposed to selected patients. Interesting results have been obtained in pediatric rheumatic diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus and systemic sclerosis. Further studies are required to assess the best procedures able to induce remission with a minimal risk of fatal events.
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PMID:Autologous bone marrow transplantation versus alternative drugs in pediatric rheumatic diseases. 1126 32

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology accompanied by central nervous system involvement in up to 60% of patients. The current study chronicles the expression of cerebellar dysfunction in SLE using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRL-lpr/lpr mice manifest severe and progressive behavioral disturbances indicative of cerebellar dysfunction beginning at 11 weeks of age. Although the lpr gene is known to induce autoimmune features, immunologically normal mice rendered congenic for lpr failed to exhibit disturbances in cerebellar function. Because lupus is a cytokine-driven disease and overexpression of certain proinflammatory cytokines has been associated with neurodegeneration, the relationship between cerebellar dysfunction and cytokine gene expression was examined. Relative to immunologically normal CBA/J mice, the cerebellum of young (11-15 weeks of age) MRL-lpr/lpr mice contained high levels of interleukin (IL)-6 and interferon-gamma (IFNgamma) mRNA, which became even more pronounced in old (22-30 weeks of age) autoimmune mice. mRNA levels for the cytokines IL-1beta and IL-10 were elevated in the cerebellum of old, but not young, MRL-lpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for IL-3 and tumor necrosis factor-alpha were comparable in autoimmune and normal mice, indicating that enhanced gene expression of IL-6, IFNgamma, IL-1beta, and IL-10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE.
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PMID:Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus. 1127 48

B-cell maturation protein (BCMA) is a member of the tumor necrosis factor (TNF) receptor family and is expressed in B lymphocytes. BCMA binds two TNF family members, BAFF and APRIL, that stimulate cellular proliferation. BAFF in particular has been shown to influence B-cell survival and activation, and transgenic mice overexpressing BAFF have a lupus-like autoimmune disorder. We have inactivated BCMA in the mouse germ line. BCMA(-/-) mice have normal B-cell development, and the life span of mutant B lymphocytes is comparable to that of wild-type B cells. The humoral immune responses of BCMA(-/-) mice to T-cell-independent antigens as well as high and low doses of T-cell-dependent antigens are also intact. In addition, mutant mice have normal splenic architecture, and germinal centers are formed during an ongoing immune response. These data suggest a functional redundancy of BCMA in B-cell physiology that is probably due to the presence of TACI, another TNF receptor family member that is expressed on B cells and that can also bind BAFF and APRIL.
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PMID:B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. 1135 13

Most disease modifying antirheumatic drugs (DMARD) are discontinued within 5 years because of loss of clinical efficacy or toxicity. As a result, there has been a concerted effort to develop new immunomodulatory agents, particularly biological agents, that block the putative proinflammatory cytokines. Among the agents developed thus far, inhibitors of tumor necrosis factor (TNF) have shown perhaps the greatest promise as therapeutic agents for rheumatoid arthritis (RA). Two TNF-blocking agents, etanercept (Enbrel) and infliximab (Remicade), have been approved in the US and more recently in Europe, for the treatment of patients with RA. The results of randomized placebo controlled trials have shown that both agents significantly decrease the intensity of synovitis and prevent or retard the progression of cartilage destruction, especially when combined with methotrexate. Their side effect profiles appear to be acceptable, although rare cases of lupus-like diseases and of severe infections have been reported. Although the early clinical experience with these agents has been encouraging, their longterm safety and continuing efficacy in the general population with RA, as well as in high risk patient subsets (i.e., patients with malignancies or chronic infections), remain to be determined. In addition, the costs of these newer agents must be justified on clinical grounds. Because of the questions still surrounding these new treatment principles, several consensus conferences have been held in Europe and the US to address the role of the new biologicals in the current RA armamentarium.
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PMID:How do the biologics fit into the current DMARD armamentarium? 1140 55

The tumor necrosis factor (TNF)-related ligand B lymphocyte stimulator (BLyS) binds two TNF receptor family members, transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI) and B cell maturation molecule (BCMA). Mice that are transgenic for BLyS show B cell accumulation, activation and autoimmune lupus-like nephritis. The existence of at least two distinct BLyS receptors raises the question of the relative contribution of each to B cell functions. We therefore generated mice that were deficient in TACI. TACI-/- mice showed increased B cell accumulation and marked splenomegaly. Isolated TACI-/- B cells hyperproliferated and produced increased amounts of immunoglobulins in vitro. In vivo antigen challenge resulted in enhanced antigen-specific antibody production. Thus, TACI may play an unexpected inhibitory role in B cell activation that helps maintain immunological homeostasis.
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PMID:Activation and accumulation of B cells in TACI-deficient mice. 1142 37

The objective of this study was to determine the effect of quinagolide (Norprolac) on serum level of cytokines in systemic lupus erythematosus (SLE) patients. In 20 SLE patients treated with a low dose of quinagolide, and in 17 healthy persons who constituted the control group, concentration of serum prolactin (PRL), interleukins (ILs), soluble tumor necrosis factor receptors (sTNF Rs) preceded by calculation of disease activity index (SLEDAI) were tested at entry and then after 3 months in 16 patients and after 6 months in 11 patients who completed the study. Serum PRL level was higher (though insignificantly) in the SLE group than in the controls and decreased significantly after 6 months of therapy. A raised SLEDAI score at entry was significantly reduced during therapy but a weak correlation with PRL level was revealed. A significant increase in IL-6 level in SLE group as compared to controls was observed (respectively 14.57 +/- 13.25 and 5.04 +/- 3.35 microg/ml) as well as a significantly decreased level after 6 months of treatment (4.30 +/- 2.51 pg/ml). There was a significant difference between sTNF RI concentration before and after 3 months of quinagolide treatment (respectively 1140.83 +/- 312.08 and 1454.58 +/- 465.54 pg/ml). After 6 months of treatment a statistically significant correlation between concentration of PRL and level of IL-6 and a negative correlation between PRL and sTNF RI was revealed. Quinagolide treatment may have a role in the management of SLE patients.
Lupus 2001
PMID:Selected serum cytokines in systemic lupus erythematosus treated with quinagolide. 1143 78

B cells and B-cell/T-cell collaborations are instrumental in the pathophysiology of systemic lupus erythematosus (SLE). This commentary highlights in particular the newly discovered role of B-cell-activating factor (BAFF; also known as TALL-1, THANK, BlyS, and zTNF4) as a positive regulator of B-cell functions, such as B-cell activation and differentiation. Two members of the tumor necrosis factor(TNF)-receptor superfamily were recently identified as receptors for BAFF on B cells. The interaction between BAFF and its receptors may be important in the pathogenesis of lupus. Advances in our understanding of abnormalities in immune regulation in lupus might provide the opportunity to improve our current therapeutic approaches to this disorder.
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PMID:B cells, BAFF/zTNF4, TACI, and systemic lupus erythematosus. 1143 34

Production of pathogenic autoantibodies in systemic lupus erythematosus (SLE) requires T cell help, along with ligation of the B cell surface immunoglobulin receptor by antigen. It is likely that macrophages, dendritic cells, and endothelial cells are also activated by interactions with T cells and contribute to lupus pathology. CD40 ligand (CD40L, CD154), a member of the tumor necrosis factor family of cell surface molecules, mediates these contact dependent signals delivered by CD4 + T helper cells to CD40 + target cells. Recent data from SLE patients and murine lupus models have demonstrated prolonged expression of CD40L on lupus T cells and its capacity to mediate excessive B cell activation. This review summarizes the current information regarding transcriptional and post-transcriptional regulation of CD40L expression in normal and SLE T cells. More complete characterization of the mechanisms that regulate the magnitude and duration of CD40L expression should suggest new approaches to modulate this promising therapeutic target.
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PMID:Regulation of CD40 ligand expression in systemic lupus erythematosus. 1160 89


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