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)

MRL-lpr/lpr mice develop an autoimmune disease similar to human systemic lupus erythematosus (SLE). The main characteristics of this disease are increasing autoantibody formation, elevated plasma levels of immune complexes, a massive lymphoproliferation, a rising proteinuria, and arthritic symptoms. Finally, the mice die at an age of about 6 months due to a fatal immune complex glomerulonephritis. Macrophages are involved in the development of SLE due to their functions as antigen-presenting as well as cytokine-producing cells. T and B cells are involved in the disease by secreting cytokines and producing antibodies. Pentoxifylline (PTX), a xanthine derivative, is known to exert different effects on functions of leukocytes and erythrocytes and has been used in clinical studies, e.g., in septic shock syndrome. In our studies we first investigated the in vitro effect of PTX on macrophages and lymphocytes derived from MRL-lpr mice. Our investigations concerning production of superoxide anion and TNF-alpha by LPS and/or IFN-gamma activated bone marrow and peritoneal macrophages, MHC class II expression on these cells, and the proliferative capacity and Il-2 production of mitogen activated lymphocytes, revealed that PTX reduces the activation and the inflammatory response of these cells. Based on these results, we further investigated the effect of in vivo treatment with PTX. MRL-lpr mice treated with PTX showed diminished proteinuria, reduced titer of dsDNA-autoantibodies in the plasma and an increased survival rate. Our data clearly demonstrate that PTX is able to diminish the severity of the disease and to prolong the life of MRL-lpr/lpr mice.
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PMID:In vitro and in vivo effects of pentoxifylline on macrophages and lymphocytes derived from autoimmune MRL-lpr/lpr mice. 785 38

The MRL-lpr/lpr and MRL-(++) mice were studied for the expression of cytokines in the spleen, lymph node, thymus, kidney and brain through the reverse transcription-polymerase chain reaction (RT-PCR). The frequencies of IL-4 and TNF-alpha expression in the thymus and spleen were significantly higher in MRL-lpr/lpr mice than in MRL-(++) mice from the age of 17 to 32 weeks. More importantly, IL-4 transcript was demonstrated in the early rather than in the terminal stage of the lupus disease. At the 20th week, MRL-lpr/lpr mice with active disease exhibited higher concentrations of IL-1 alpha, IL-6 and TNF-alpha in serum than MRL-(++) mice. Interestingly, in MRL-lpr/lpr but not MRL-(++) mice, the IL-6 concentration in cultured supernatants of the thymic cells was significantly higher than that of the splenic or lymph node cells. On the other hand, IL-6 and IL-1 beta were expressed in the brain and kidney of MRL-lpr/lpr mice but not of MRL-(++) mice. Cultured MRL-lpr/lpr mesangial cells could also express IL-6 but to a lesser extent. These results suggest that the abnormal splenic and thymic IL-4 and TNF-alpha expression may predispose the development of autoimmune reactions. The expression of IL-1 beta and IL-6 in the brain and kidney may be implicated in the damage of these two organs in MRL-lpr/lpr mice.
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PMID:Abnormal splenic and thymic IL-4 and TNF-alpha expression in MRL-lpr/lpr mice. 786 62

Fourteen individuals with complete C2 deficiency from 11 families and 3 heterozygous C2-deficient individuals from two families were investigated. In all the 24 independent C2-deficient haplotypes, the complotype S042 was present and the majority (21/24) was [HLA-B18,S042,DR2]. All carried the type I C2 deficiency C2 pseudogene with its characteristic 28 bp deletion. All but two haplotypes had 10 AC/GT repeats in the TNF alpha microsatellite polymorphism and all but one of the haplotypes were identical at or near HLA-B as assessed by RFLP using BstEII digestion and two genomic probes, R5A and M20A, located 100 and 38 kb centromeric to HLA-B, respectively. The exceptional haplotype was HLA-B40 with four AC/GT repeats at TNF-alpha. Three of the haplotypes were not DR2 based on generic and sequence-specific oligonucleotide typing. Another four haplotypes showed different DO-variants detected by RFLP analysis using BglIIand Mspl digestion. Thus, the [HLA-B18,S042,DR2] haplotype appears to be more fixed in the region between the complement genes and the HLA-B locus (96%) than in the region between the complement genes and DR (88%) and DO loci (71%). Of the 14 individuals studied, six had SLE or SLE-like syndromes and six had a history of severe infections although two were apparently healthy. Three of the six SLE patients and two individuals with repeated infections were homozygous for [HLA-B18,S042,DR2] and also homozygous for DQB1*0602 and the common DO variant. Thus, MHC class II genes linked to the C2 pseudogene do not appear to determine different clinical consequences of C2 deficiency.
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PMID:Characterization of type I complement C2 deficiency MHC haplotypes. Strong conservation of the complotype/HLA-B-region and absence of disease association due to linked class II genes. 790 Dec 82

Although systemic lupus erythematosus (SLE) is known to be positively associated with certain major histocompatibility complex (MHC) class I and/or class II antigens, it is not clear whether the MHC genes are the predisposing genes of the disease rather than markers for other closely linked gene(s). Because of the involvement of tumor necrosis factor (TNF) in the inflammation process and localization of the TNF genes in the proximity of the HLA-B locus, we studied the restriction fragment length polymorphism (RFLP) of the TNF-alpha and -beta genes in 20 SLE patients and 23 normal individuals using restriction endonuclease NcoI. The frequency of a 5.5 kb NcoI fragment from SLE patients was significantly higher than that from normal controls. This result suggests that the polymorphic TNF genes may be involved in the pathogenesis of SLE.
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PMID:Restriction fragment length polymorphism (RFLP) analysis in the TNF genes of patients with systemic lupus erythematosus (SLE). 790 14

Despite an extensive literature dealing with IL2-induced cytolytic activity, noncytotoxicity-related effects of IL2 on peripheral blood mononuclear cells (PBMC) or T cell function have received less attention. We have focused on the effects of irradiated, IL2-activated PBMC (PBMC*rIL2) on anti-CD3- and formalin-fixed heat-killed Staphylococcus aureus-induced polyclonal B cell differentiation in secondary cultures. PBMC*rIL2 act directly on B cells and cross major histocompatibility complex barriers to augment polyclonal B cell differentiation as measured by plaque-forming cell (PFC) generation. These effects are preferentially mediated by T (both CD4+ and CD8+) cells, and physical contact between effector PBMC*rIL2 and target B cells is not absolutely required for enhanced PFC generation. PBMC*rIL2 must be present for the initial 24 hr of the secondary cultures, indicating that some soluble B cell differentiation factor rapidly released by PBMC*rIL2 mediates the PFC-enhancing effect. Of IL2, IL4, IL5, IL6, IL10, IFN-gamma, and TNF-alpha, only IFN-gamma mRNA is appreciably and reproducibly increased in irradiated, IL2-activated T cells (T cells*rIL2). Nevertheless, exogenous rIFN-gamma cannot mimic and anti-IFN antibodies cannot block the PFC-enhancing effects of T cells*rIL2, indicating that some unidentified soluble factor(s) apart from or in addition to IFN-gamma is involved. IL2-induced effects on T cell noncytolytic function may help explain certain observed immune anomalies in IL2-treated patients, and a better understanding of the IL2-induced effects on T cell noncytolytic function may have ramifications for autoimmune diseases such as SLE.
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PMID:Enhancing effects of interleukin 2-treated peripheral blood mononuclear cells on subsequent B cell differentiation. 806 23

Lupus-prone mice show reduced production of TNF-alpha and, upon long-term treatment with recombinant TNF-alpha, significant protection from disease development. Mutational analysis of the 5'-untranslated region (UTR) and 3'-UTR of the mouse TNF-alpha gene reveals a marked degree of polymorphism. Transient expression experiments in the RAW 264.7 macrophage-like cell line using the luciferase reporter system suggest an important role for the mutations in the 3'-UTR in the biosynthesis of TNF-alpha, and provide a molecular explanation for the reduced TNF-alpha production in lupus-prone NZW mice.
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PMID:Mutational analysis of TNF-alpha gene reveals a regulatory role for the 3'-untranslated region in the genetic predisposition to lupus-like autoimmune disease. 860 27

The authors have recently shown that antibodies with anti-idiotype (Id) specificity to pathogenic Ids of lupus nephritis may occasionally occur in several intravenous immune globulin (IVIG) preparations because they are present in healthy donors and the healthy relatives of SLE patients. In the present study, the authors purified these anti-Ids and treated two SLE patients with nephritis in parallel with conventional high-dose IVIG management with a commercial preparation (IVIG 6) in three controls for two months. Because pathogenic Ids of anti-DNA molecules, such as both 8.12 and F4 Ids, show a cationic mobility in isoelectric focusing, a commercial preparation of IVIG (11) was absorbed on a Sepharose column coupled with DC-305-39 myeloma protein, namely an 8.12+ and F4+ cationic IgG. Infusion of the eluate (EL-11) induced a prompt resolution of proteinuria levels and an evident decrease of serum levels of anti-DNA antibodies in both patients, whereas in the three controls, proteinuria and anti-DNA antibodies were scarcely reduced. In addition, plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha were also significantly influenced by both treatments. The mean values of both cytokines increased significantly after 1 h and then progressively declined over the next 48 h. It was of interest, however, that the increased TNF-alpha in the two EL-11-treated patients was significantly lower than in the three controls. The data suggest that reduction of active lupus nephritis by enriched specific anti-Id molecules is the result of two (or perhaps more) mechanisms: suppression of pathogenic idiotypes at the cellular level and improvement in the mesangium of the secretion of anti-inflammatory cytokines, such as IL-6, whose defective function is related to the autoimmune disorder.
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PMID:Intravenous immune globulin therapy of lupus nephritis: use of pathogenic anti-DNA-reactive IgG. 862 51

The murine MRL/lpr model of lupus nephritis is characterized by a systemic autoimmune syndrome closely resembling the human disease. The lpr mutation represents a defect in the expression of the apoptosis-signaling Fas antigen gene which causes accelerated autoimmune disease in MRL/ lpr mice and a milder, non-lethal autoimmune syndrome in C57BL6-lpr/lpr mice. The role of cytokines in autoimmune pathogenesis and its relationship with the lpr mutation remains poorly understood. In this study we utilized a RNase protection assay to quantitatively and simultaneously examine the expression of 10 different cytokine genes, namely IL-1 alpha, II-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, and TNF-beta in kidney, spleen, liver, and lymph nodes obtained from pre-diseased and diseased lupus-prone MRL/lpr, pre-diseased MRL/+2 and C57BL/6-lpr mice, as well as healthy non-autoimmune C57BL/6 and Balb/c mice. Diseased MRL/lpr mice demonstrated marked and predominant IL-1 beta gene upregulation in kidneys, liver, lymph nodes and spleen. Increased message for both TNF-alpha and IFN-gamma genes was also observed in lymph nodes, and less consistently, in the spleen, and kidneys derived from diseased MRL/lpr mice as compared to pre-diseased MRL/+2 or normal nonautoimmune control mice. Furthermore, a modest increase in the expression of both IL-1 beta and IFN-gamma message was observed in lymphoid organs of pre-diseased MRL/lpr and C57BL/6-lpr mice compared with MRL/+2 and C57BL/6 controls, respectively. Increased IL-1 beta gene expression was associated with the presence of the lpr mutation, was observed during the prediseased stage, and increased during active disease in both male and female mice. In summary, these results demonstrate that generalized up-regulation of IL-1 beta gene expression, in concert with a more limited up-regulation of both TNF-alpha and IFN-gamma expression, are prominent features of the autoimmune syndrome in the MRL/lpr model of SLE and may contribute to the disease-accelerating effect of the lpr mutation.
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PMID:Cytokine gene expression in the MRL/lpr model of lupus nephritis. 880 76

The purpose of this work was to the hypothesis that MHC encoded susceptibility factors for SLE lie in the TNF region. An association study was performed by analyzing 123 northern Italian SLE patients and 199 matched controls for three TNF markers: two polymorphisms in the TNFA promoter and the TNFa microsatellite. Haplotypic combinations of TNF markers were also compared in patients and controls. No significant association was observed considering either the whole SLE panel or SLE clinical and immunological subtypes. Three TNF-238/A homozygous patients were detected, while no homozygote was present in controls. The clinical and immunological phenotype of the three -238/A homozygotes suggests that the -238/AA genotype is a marker of a particular clinical subtype.
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PMID:Association between polymorphisms in the TNF region and systemic lupus erythematosus in the Italian population. 881 45

Celiac disease (CD) is an immune disease triggered by the cereal antigen gliadin, resulting in villous atrophy in the small intestine. Susceptibility to the development of CD is strongly influenced by genes in the major histocompatibility complex, in particular alleles of the DQ genes in the class II region. However recent evidence has suggested that the major histocompatibility complex (MHC) class III region may be linked to celiac disease independently of the class II region. Among the genes located in this area is TNF-alpha, which encodes the cytokine tumor necrosis factor-alpha which has a broad range of pro-inflammatory, immunomodulatory and catabolic activities. Therefore, aberrant expression of TNF-alpha could be important in the pathogenesis of MHC-associated immune disorders. A TNF-alpha variant with a polymorphism in its promoter region has been described and designated TNF2. TNF2 has been associated with a variety of MHC-linked diseases, including systemic lupus erythematosus, dermatitis herpetiformis and insulin-dependent diabetes mellitus (IDDM), as well as parasitic infections. TNF2 has previously been shown to be associated with the MHC haplotype HLA A1-B8-DR3-DQ2, which confers susceptibility to CD. We have analyzed the distribution of TNF2 alleles in a group of celiac patients (n = 52) compared to controls (n = 52) in an effort to evaluate its role, if any, in susceptibility to the condition. TNF2 has a frequency of 0.5000 (SE +/- 0.0490) in CD, compared to 0.1635 (+/- 0.0362) in a control sample (p < 10(-6)). Of 52 patients, 44 carried one or more TNF2 alleles. Analysis indicates that the distribution of TNF2 is best explained by assuming 100% allelic association between it and HLA-DQB1*0201 (frequency = 0.7791 +/- 0.0447). However, the number of TNF2 heterozygotes significantly exceeds expectations and measurements of linkage disequilibrium confirm that allelic associations spanning the DQ and TNF regions are strongly maintained in CD. Taken together, these results indicate that TNF2 may have a role in the pathogenesis of CD; however, since it is not an independent association, the possibility that TNF2 constitutes a passive component of the CD haplotype cannot be excluded.
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PMID:TNF2, a polymorphism of the tumour necrosis-alpha gene promoter, is a component of the celiac disease major histocompatibility complex haplotype. 881 55


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